The mast cell: III. Distribution and maturation in various organs of the young rat. The changing population-density of mast cells in various organs was plotted for rats aged 1/2 to 90 days and correlated with histochemical studies on the stage of maturation of cells. Mast cells are present at birth in liver and spleen and are particularly associated with foci of haemopoiesis. In bone marrow mast cells are absent at birth but become progressively more numerous with increasing age of the animal. The association of mast cells firstly with foci of extramedullary haemopoiesis and secondly with medullary foci coupled with their detection in peripheral blood strongly suggests that mastopoiesis may be analogous with granulopoiesis. In thymus mast cells are usually associated with interlobular connective tissue stroma, but in the parenchyma they are found toward the medullary side of the cortico-medullary junction. Such a distribution suggests the possible origin of mast cells from lymphocyte or thymocyte. In other tissues examined mast cells are frequently associated with connective tissue stroma and blood vessels.


Mucins and carcinoid tumours.

Mucins and carcinoid tumours. Mucin was demonstrated in 11 of 16 carcinoid tumours of usual histological appearances. The mucin was characterized histochemically and shown to be similar to that which is produced in the gastrointestinal as well as the respiratory tract. This relative ubiquity of mucin in carinoid tumours has not hitherto been appreciated and more obviously "mixed" tumours have been regarded as rareties. The importance of these findings with respect to the neural crest theory of origin of enterochromaffin cells is discussed.


Hepatitis B surface antigen and antibody status in biopsy proven chronic hepatitis in Singapore. During the period between January 1975 and August 1976, 203 liver biopsies were received at the Singapore General Hospital from patients with a variety of liver diseases. A histological diagnosis of chronic hepatitis was made in 29 patients: 13 cases of Chronic Aggressive Hepatitis (C.A.H.). 10 cases Chronic Persistent Hepatitis (C.P.H.) and 6 of Chronic Lobular Hepatitis (C.L.H.). C.P.H. and C.L.H. were found mainly in the third and fourth decades. C.A.H. was more common in the fifth to seventh decades and occurred principally in females. Hepatitis B antigenaemia was detected in 48.3% of these cases using the immunoelectroosmophoresis (EOP) technique and showed an even scatter in all histological sub-types. Using the reverse passive haemagglutination (rPHA) method for detection by HBs antigen and the radioelectrocomplexing (REC) method for anti-HBs, an immune sub-group (HBs Ag+/anti-HBs+) was identified in greater proportions in C.A.H. and C.P.H. compared to normal controls. This was interpreted to mean that these patients suffered from a primary immunodeficiency characterized by failure of production of high avidity anti-HBs with resulting failure to clear HBsAg leading to perpetuation of liver damage due to circulating immune complexes. It is also suggested that patients with C.P.H. belonging to this immune sub-group may progress to C.A.H. with its more ominous prognosis.


Arrest of alveolar multiplication in kyphoscoliosis. A detailed morphometric study of the lungs of an adult patient with severe kyphoscoliosis of childhood onset is reported. The number of alveoli was less than the normal adult range and corresponded to the predicted values for a 12-month-old infant. This may have been a result of both premature cessation of alveolar multiplication as well as alveolar atrophy. The alveolar size was larger than normal suggesting that after cessation of alveolar multiplication further lung growth occurred by an excessive increase in alveolar size.


Pulmonary lymphomatoid granulomatosis with immunodeficiency terminating as malignant lymphoma. Lymphomatoid granulomatosis was diagnosed in a 60-yr-old woman 2 yr after presentation with a multi-system disorder resembling sarcoidosis. Five months later autopsy revealed malignant lymphoma. Large aggregates of intracytoplasmic tubular structures resembling nucleocapsid material of the paramyxovirus group were found within cells of lymphoma deposits in the liver. Sequential immunological studies over more than 2 years demonstrated a relatively stable T-cell deficiency associated with variable B-cell dysfunction. The latter was characterized by the production of immunoglobulins of restricted electrophoretic mobility. Intermittent hypercalcaemia was associated with increases in serum IgG and appeared to be due to the presence of Ca-binding paraproteins. It is suggested that lymphomatoid granulomatosis may be a pre-malignant lymphoproliferation, with immune deficiency as a predisposing cause. The pattern of immunological abnormalities suggests that the lymphoma may have been due to B-cell malignant transformation.


Extrauterine mesodermal (müllerian) adenosarcoma. A case report. Extrauterine mesodermal (müllerian) adenosarcomas have only recently been described, and this is the first reported case from Australia. These tumours fall within the category of common epithelial tumours' in the World Health Organisation (W.H.O.) classification of ovarian tumours and comprise benign looking epithelial structures (glands, papillae) in association with sarcomatous stroma. They are thus distinct from malignant mesodermal mixed tumours in which both epithelial and stromal elements are cytologically malignant.


Effects of riboflavin on Gunn rats under phototherapy. Blue and white phototherapy was given to infant (and weanling) homozygous Gunn rats treated with different doses of riboflavin-5-phosphate (ribofl.5'p.) During the first hours after a flavin-injection, the effect of phototherapy with both types of fluorescent lamps was enhanced. With equal radiant power applied, the steepness of serum bilirubin decline depended on the ribofl.5'p. dose injected. After oral or cutaneous application, no similar effect occurred. After a single flavin dose, the serum bilirubin decline lasted for at least 3 hr. Nevertheless, in long-term studies with repeated injections (100 mg/kg every 48 hr), no protective effect beyond that of phototherapy alone could be ascertained on the Purkinje cells in the cerebella of the rats. In the skin of the animals, fluorescence was macroscopically noticeable after ribofl.5'p. injections. When an effective irradiance of about 3.0 mW/cm2 and a high flavin dose (100-200 mg/kg) was administered, histologic investigations of the skin in the abdominal and back region revealed a reversible inflammatory reaction with edema and morphologic changes in the epidermal cells that culminated 12-24 hr after the injection. After a further increase of the effective irradiance, tremendous vesicles on paws, ears, and tails were observed in most of the animals 24-72 hr after the flavin injections. The content of the blisters was primarily serous, later on, often hemorrhagic. Finally, necrosis developed. Acute toxicity of ribofl.5'p. differed markedly when the infant rats (homozygous jaundiced as well as heterozygous nonjaundiced) were kept in the dark or under intense blue phototherapy. Much higher doses were tolerated in the dark. Moreover, it could be demonstrated that ribofl.5'p. does not influence serum bilirubin of jaundiced Gunn rats kept in complete darkness. That suggests that the drug itself does not compete for albumin binding sites. But certain riboflavin ampules (Beflavin) contain stabilizers that considerably displace bilirubin from albumin bonds. Riboflavin disturbs direct photometric bilirubin measurements, but not the diazo reaction. When bilirubin is to be measured in sera containing riboflavin, lights must be extremely dim. Photodegradation in vitro is highly accelerated by the sensitizer.


Multiple deficiency of mucopolysaccharide sulfatases in mucosulfatidosis. Fibroblasts of four patients affected with mucosulfatidosis (multiple sulfatase deficiency, Austin variant of metachromatic leukodystrophy) were assayed for activities of the five sulfatases known to degrade mucopolysaccharides. These were iduronide 2-sulfate sulfatase, sulfamidase, N-acetyl-galactosamine 6-sulfate sulfatase, arylsulfatase B (N-acetylgalactosamine 4-sulfate sulfatase), and N-acetylglucosamine 6-sulfate sulfatase. The activities of these five sulfatases were severely depressed, thus confirming the known deficiency of arylsulfatase B and the absence of the Hunter and Sanfilippo III A corrective factors that have iduronide 2-sulfate sulfatase and sulfamidase activity, respectively. Together with earlier reports of the deficiencies of arylsulfatases A and C, cholesteryl sulfatase, and dehydroepiandrosterone sulfatae, mucosulfatidosis is now characterized by the deficiency of nine different sulfatases.


Determination of serum bilirubin by skin reflectance: effect of pigmentation. A noninvasive optical technique by which serum bilrubin can be estimated from skin spectral reflectance measurements has been further investigated. The original work on 30 healthy, full-term white infants and an independent study on 14 white and 30 black infants demonstrate that the method has potential not only for clinical use, but also for the study of the transport of bilrubin to, from and within the skin. The objectives of the present study are to evaluate the method on a larger sample population with special attention to natural skin pigmentation effects and the development of a physical model of the tissue to explain the relationship between serum bilrubin concentration and skin reflectance. Reflectance spectra (380-800 nm) and concurrent serum bilirubin measurements were taken on a sample population of 58 white and 45 full-term black infants (1-3 days of age). Multiple linear regression analysis, comprised of six wavelengths gave a correlation coefficient, r = 0.831 for the white infant group. For the black infant group, a five wavelength analysis provided r = 0.877 with the standard error of estimate being +/- 1.46 mg/100 ml for both groups. The model for establishing a physical basis for the relationship shows that a transformed, normalized Kubelka-Monk function xi (460, 510, 420) is linearly related to serum bilrubin concentration. This function is determined from the spectral reflectance values at three wavelengths, 420, 460, and 510 nm. The wavelength combination is such that effects due to hemoglobin and melanin pigments are minimized. Regression analysis showed that r = 0.778 and r = 0.865 for the white and black infant groups, respectively, with standard error of estimates being +/- 1.4 mg/100 ml for both groups. Routine determinations of total serum bilrubin by laboratory methods have standard errors of estimate ranging from +/- 1 to 1.5 mg/100 ml. Thus, the method herein described shows that the relationship between skin reflectance and serum bilrubin in full-term infants is close to the acceptable limits for clinical use. Furthermore, this work shows that skin pigmentation does not obscure this relationship.


Coagulation studies in extremely premature infants. Evidence of developmental evolution of coagulation can be seen when the studies of 10 thriving extremely premature (EPT) infants are compared to normal full-term (FT) infants. The prothrombin time, partial thromboplastin time, and thrombin time all became shorter with increasing gestational age. Fibrinogen levels and platelet counts appear to be comparable to term infant and adult levels. Fibrin degradation products (FDP) of 10 micrograms/ml or less were found in the thriving EPT infants. When compared to healthy full-term infants, there is a definite gestational dependency of anti-thrombin III levels. Factors II and VII appear to be related to intrauterine maturation after the age of viability (24 wk), but factor VII-X complex does not. The contact factors XI, XII, high molecular weight kininogen (Fitzgerald factor), and prekallikrein (Fletcher factor) are all markedly decreased in thriving EPT infants. The mean factor V level is lower than that found in FT infants. This study confirms a gestational age dependency of factor VIII activity. The ratio of factor VIII antigen to factor VIII clotting activity is increased (2.8 vs 1.01 in FT and adults). Thriving small for gestational age (SGA) infants had coagulation studies which were not statistically different from those of thriving EPT infants. The coagulation changes which occurred in severely ill EPT were mainly in the factors which decrease during intravascular coagulation (factors I, V, and VIII). The present study suggests that because of the high antigen to activity ratio seen in thriving EPT infants, a dysfunctional or fetal factor VIII may have been produced. However, the further elevation of this ratio in the severely ill EPT infants is in keeping with a pathologic proteolysis or increased endothelial release of factor VIII antigen.


Platelet dysfunction in homozygous beta-thalassemia. This report details the results of studies performed in nine patients with homozygous beta-thalassemia evaluating platelet function and prostaglandin formation. Platelet malonyldialdehyde (MDA) formation in the presence of N-ethyl maleimide (NEM 1 mM) or thrombin (0.5 u/ml) was used as an indicator of platelet prostaglandin synthesis. The data on the nine patients revealed two distinct subgroups of patients. Six of nine thalassemics, demonstrated platelet abnormalities. Their mean bleeding time was 7.5 +/- 2.5 min (1 SD), significantly prolonged (P less than 0.005) when compared to a value of 3.5 +/- 1.0 min in normal controls. MDA formation in the presence of NEM was significantly decreased (P less than 0.005) to 2.41 +/- 0.49 (1 SD) when compared to a control value of 3.24 +/- 0.33 nmoles MDA/10(9) platelets. Similarly, the mean value for thrombin induced MDA was 0.98 +/- 0.18 nmoles which was decreased (P less than 0.02) when compared to a value of 1.26 +/- 0.2 in the controls. Platelet aggregations with adenosine diphosphate (ADP), epinephrine, and collagen were abnormal in all six patients. However, when platelets from these patients were mixed with platelets from donors who had ingested aspirin 2-8 hr before donation mutual correction and secondary irreversible aggregation of the mixture resulted. No mutual correction was observed when the thalassemic platelets were preincubated with aspirin in vitro before mixing with platelets from donors who had recently ingested aspirin. Although the total amount of platelet malonyldialdehyde formed by the thalassemic platelets in response to NEM and thrombin was decreased when compared to normal controls, this reduction was not the cause of the platelet aggregation abnormalities. This appears to be so because the amount of MDA, and, thus, prostaglandin endoperoxides synthesized by these platelets in response to external stimuli was sufficient to cause irreversible aggregation of platelets from donors who had recently ingested aspirin, and were, therefore, unable to synthesize their own endogenous platelet endoperoxides. In the remaining three patients, bleeding times, platelet aggregation, and MDA formation was normal. No correlation was observed between the platelet abnormalities noted and the magnitude of iron overload, presence of fibrin degradation products, liver function abnormalities, or the use of iron chelators in the individual patient. Family studies were normal. Although the platelet dysfunction does not appear to be of major significance in the usual patient with thalassemia major under normal circumstances, antiplatelet aggregating agents should be used with caution. Aspirin inhibits platelet endoperoxide and prostaglandin formation and this effect may potentiate the platelet dysfunction present in some patients with thalassemia major.


Elevated cystine levels in cultured skin fibroblasts from patients with I-cell disease. Cultured skin fibroblasts from patients with I-cell disease (mucolipidosis II) exhibit multiple deficiency of acid hydrolase activities associated with a defect in the mechanism of packaging of these enzymes into lysosomes. The authors have examined such cells to ascertain whether the impairment of lysosomal function is of so broad a nature as to result in the storage of the amino acid cystine in a manner similar to that seen in cells derived from patients with cystinosis, an unrelated lysosomal storage disease of unknown etiology. Of 10 I-cell lines examined by automated amino acid analysis, seven were found to possess abnormally high levels of total free cyst(e)ine (i.e., greater than 1 nmole 1/2 Cys/mg protein). The mean half-cystine content of those I-cell lines subjected to multiple analysis ranged from 3-10 nmole/mg protein. levels which are comparable to those seen in homozygous cystinotic cells. The cystine content of several of these lines appeared to increase with subculture. Cultured fibroblasts from two patients with the biochemically similar, but clinically less severe, mucolipidosis III (pseudo-Hurler polydystrophy) exhibited normal to marginally elevated levels of cystine, whereas cells from individuals with three different mucopolysaccharide storage disorders contained normal levels of the amino acid. It was concluded that cystine, and not cysteine, was the predominant form of this amino acid in these cells, because previous reaction of I-cell extracts with N-ethylmaleimide did not alter the observed cystine levels. The further identification of excess cystine in these cells was corroborated by analytical results obtained with a highly specific cystine-binding protein method as well as by high-voltage electrophoresis of extracts from cells pulsed with 35S-cystine. Comparative analysis of intracellular amino acids in normal and I-cell fibroblasts indicated that the elevation of csystine seen in the latter was unique to this amino acid and did not reflect a generalized increase in the total free amino acid content of these mutant cells.


Utilization of purines by an HPRT variant in an intelligent, nonmutilative patient with features of the Lesch-Nyhan syndrome. The patient, H.Chr.B., was among the first reported with hyperuricemia and central nervous system symptoms. He has been found to have a variant of hypoxanthine guanine phosphoribosyl transferase (HPRT; E.C.2.4.2.8) distinct from the enzyme present in patients with the Lesch-Nyhan syndrome. The patient had chroeoathetosis, spasticity, dysarthric speech, and hyperuricemia. However, his intelligence was normal and he had no evidence of self-mutilation. There was no activity of HPRT in the lysates of erythrocytes and cultured fibroblasts when analyzed in the usual manner. Using a newly developed method for the study of purine metabolism in intact cultured cells, this patient was found to metabolize some 9% of 8-14C-hypoxanthine, and 90% of the isotope utilized was converted to adenine and guanine nucleotides. In contrast, cells from patients with the Lesch-Nyhan syndrome were virtually completely unable to convert hypoxanthine to nucleotides. The patient's fibroblasts were even more efficient in the metabolism of 8-14C-guanine, which was utilized to the extent of 27%, over 80% of which was converted to guanine and adenine nucleotides. The growth of the cultured fibroblasts of this patient was intermediate in media containing hypoxanthine aminopterin thymidine (HAT), whereas the growth of Lesch-Nyhan cells was inhibited and normal cells grew normally. Similarly in 8-azaguanine, 6-thioguanine, and 8-azahypoxanthine, the growth of the patient's cells was intermediate between normal and Lesch-Nyhan cells. These observations provide further evidence for genetic heterogeneity among patients with disorders in purine metabolism involving the HPRT gene. They document that this famous patient did not have the Lesch-Nyhan syndrome.


Cystic fibrosis serum effect on the short circuit current of rat jejunum. Sera from 100 subjects were tested for the presence of the cystic fibrosis (CF) "factor" utilizing the short circuit current rat jejunum bioassay. Comparing the mean percent decrease in short circuit current, the presumed normal group differs from the homozygous CF group at P = 0.001 and from the heterozygous group at P = 0.05. The two CF genotypes are statistically different at P = 0.004. There is, however, a large overlap among the three groups, which limits the assay's utility as a guide for factor purification as well as clinical use.


Response of the fetal and newborn lamb to glucose and tolbutamide infusions. Tolbutamide infused into the chronically catheterized sheep fetus produced significant secretion of insulin. An optimal dose range of 100-200 mg/kg estimated fetal weight was demonstrated. Paired tolbutamide and glucose infusions using a square wave technique demonstrated that although early phase insulin secretion is dimished in the fetus, this is not due to an absolute deficiency of stored insulin. Tolbutamide produced peak insulin concentrations of 51.6 +/- 9.0 muu/ml by 20 min postinfusion in the fetus. When similar tolbutamide infusions were performed in neonatal lambs, qualitatively similar insulin response curves were demonstrated although peak insulin levels were much greater (260 +/- 70 muu/ml at 20 min). A fall in plasma glucose was demonstrated in both fetal and neonatal lambs (to 75 and 39% of control values, respectively) by 60 min after tolbutamide infusion. In the fetus, this fall was not associated with changes in maternal glucose concentration.


A short communication. Congenital renal alkalosis. Patients with idiopathic hypokalemic metabolic alkalosis and hyperrenienmia have been lumped under the heading of Bartter's syndrome. However, the clinical picture is not totally uniform. Recently, Gullner et al. described a familial disorder with hypokalemic metabolic alkalosis, hyperreninemia, and aldosteronism, but without juxtaglomerular hyperplasia. They suggested that this family had a condition other than Bartter's syndrome. The present report details the followup from infancy to adulthood of a patient with hypokalemic metabolic alkalosis, salt wasting, and hyperreninemia, but with normal aldosterone level and without juxtaglomerular hyperplasia. The authors suggest that this new condition be termed renal alkalosis. The studies suggest that the distal tubular reabsorptive capacity was defective in this patient.


Total surface bearing self suspending above-knee sockets. A new type of above-knee socket has been designed to provide total surface support and to dispense with ischial bearing as the primary weight bearing area. The socket is based upon the hypothesis that if the soft tissues of an above-knee stump are adequately supported in a suitably shaped container they will behave under load as an elastic solid with low stiffness. A method has been devised for taking the cast for the new type socket using an elastic sleeve as a "compliant socket". The grip of the elastic sleeve and the use of traction weights deform the stump tissues to the required shape while the cast is setting. The results of laboratory measurements of the transinterface pressures in these sockets under axial loading conditions have correlated well with the figures forecast by calculation. The new socket is now available to patients at a number of Centres in England.


Colic in the horse. A clinical and clinical chemical study of 42 cases. 42 horses were examined. The physical signs with relation to circulatory insufficiency and the abdominal disease were registered following a two-phased examination procedure. Great prognostic value was found in the degree of circulatory insufficiency judged by pulse rate and character, filling of the jugular vein, skin temperature, colour of mucous membranes, capillary refill time, sweating, depression, skin turgor and degree of enophthalmus. In making a causal diagnosis the abdomen was examined for shape, tenderness, peristaltic sounds, gastric dilation by siphoning, abnormal rectal findings and macroscopic changes in peritoneal fluid. Greatest diagnostic difficulties were encountered in cases of intestinal atonia, acute enteritis and torsion of the colon. In selected (severe) cases laboratory tests were obtained. Blood samples were examined for packed cell volume, hemoglobin, red and white blood cell counts, differential white blood cell count, blood gases and acid-base status, lactate, serum total protein and albumin, plasma sodium, potassium, chloride, calcium, magnesium, inorganic phosphorus, glucose, creatinine, BUN, total bilirubin, ASAT, CK, BASP and GGT. Peritoneal fluid was examined for red blood and white cell counts, total protein, specific gravity, pH and lactate, and enzymes as in  blood. Laboratory results generally confirmed the clinical signs of shock, and packed cell volume and blood lactate were regarded to be of greatest prognostic interest. Although the performed laboratory information, macroscopic evaluation was thought to reveal sufficient information in most cases. It was concluded that supervening shock is of decisive importance in severe forms of colic, and that a careful and repeated evaluation of the circulatory insufficiency often provides one with a tentative prognosis although the final diagnosis is not obtained. In spite of therapy fatal outcome was found in all seriously shocked horses.


Haemophilus parahaemolyticus serotypes. Serological response. Serotypes 1,2,4 and 5 of Haemophilus parahaemolyticus were inoculated into, respectively, 4,4,2 and 5 pigs. Serum samples were tested for circulating antibodies by the modified complement fixation test (CF test). When individual serotypes were used as antigen, titers were found only to the serotype which had been used for inoculation. Using antigen in which the serotypes were pooled, antibodies were demonstrated in sera from all the pigs. The CF titers obtained with the pooled antigen were equivalent to those found with each serotype separately. When the CF test was used for serological examination of field sera there was full agreement between the results obtained with the pooled antigen and those obtained with serotype 2 antigen alone. No cross reactions were found with the pooled antigen in herds that were sero-positive to Haemophilus parasuis, strain 4800. The experiment has shown that there is no serological cross reaction between serotypes 1, 2, 4 and 5 when they are used as antigen in the CF test. Also, the results imply that with a pool of the different serotypes of Haemophilus paralyticus as antigen similar results may be obtained as with the single serotype 2 antigen.


Serum protein changes in chickens with experimental Marek's disease. Serum protein alterations in chickens contact-exposed to Marek's Disease Virus (MDV) were studied by crossed immunoelectrophoresis. Total protein values of infected chickens were initially, i.e. in the 4th week, low and later not significantly changed from those of the controls. In all infected chickens a significant increase was seen in the IgG components. Three of 6 infected chickens showing a prolonged period of clinical illness presented the most pronounced changes in other serum proteins, moderate or drastic decrease of albumin and alpha-1 lipoproptein and marked increase of arc 24 glycoprotein. Ceruloplasmin and C3 complement beta-1-C and beta-1-A were also increased in infected chickens. No such changes were seen in sera from control chickens. The significance of these changes with reference to previous work and induced pathology is discussed.


Spontaneous fracture of the navicular bone in the horse. After a short review of previous literature about fractures of the navicular bone in horses, the symptoms and the pathological-anatomical changes of the condition are described. The most important clinical symptom is acute severe lameness without significant swellings, but with pronounced pain reaction to rotation of the coffin joint. After rest the lameness is reduced considerably, but without treatment it can persist for several years. Adherences between the deep flexor tendon and the site of the fracture and eventual damage to the coffin joint are considered to be the cause of the persisting lameness. Three case reports are given where the horses were shoed with full bar shoes with clips and high calks, and were given two months rest in a box. After that the rehabilitation was started with increasing load on the leg in question in spite of some initial lameness. The three horses all regained their full working capacity after ca. 6 months' treatment. There is no formation of callus at the site of the fracture, but only a firm formation of fibrous tissue which does not bother the horse unless the fragments are too much dislocated giving rise to a greater destruction of the coffin joint. Radiographically the fracture line persists for the rest of the horse's life.


Simulated small intestinal volvulus in the anesthetized horse. Experimental closed loop small intestinal volvulus was studied in the anesthetized horse. Volvulus was simulated by ligation of the mesenterial veins to a segment of small intestine. Physical signs and hemodynamic, hematologic, clinical chemical, bacteriologic and peritoneal fluid values were examined. Compared to conscious horses anesthesia highly delayed and modified the clinical signs of shock (changes in mucosal colour, dehydration, decreased skin temperature, elevated pulse rate, low blood pressures) and of small intestinal volvulus (altered peristalsis, gastric dilation). Plasma glucose response to shock was also modified by unconsciousness. However, a dose response relationship was indicated between the extent of small intestinal damage and clinical symptoms. The same was applicable to changes in blood pressures, blood acid-base balance, lactate, potassium, chloride, glucose, inorganic phosphorus, creatinine, creatine kinase, red blood cell and total white blood cell counts and serum total protein. The relationship was also indicated in the following peritoneal fluid values: volume, lactate, pH, total white cell counts, alkaline phosphatase and bacteriology. Changes related to shock (insufficient tissue perfusion) were low blood pressures and metabolic acidosis due to anaerobic glycolysis with accumulation of lactic acid. Also low plasma glucose and elevated plasma potassium, creatinine, inorganic phosphorus and creatine kinase were regarded as consequences of shock.


DNA methylation: organ specific variations in the methylation pattern within and around ovalbumin and other chicken genes. The restriction enzymes HhaI and HpaII, whose activity is inhibited by cytosine methylation within their recognition sites, have been utilised as probes to study methylation in the vicinity of the ovalbumin gene in DNA from various chicken tissues. This was complemented by a preliminary study of methylation in the regions of chicken ovotransferrin (conalbumin), ovomucoid and beta-globin genes. From our data we conclude that HaI or HpaII sites can be divided in 3 classes according to their pattern of methylation in different tissues. In the first class of sites (mV class) the extent of methylation varies in different tissues. The patterns obtained show that methylation at the sites located within and around the 3 genes which code for egg white proteins is in general lowest in oviduct of laying hen, where these genes are expressed. However some sites are not methylated (m- class) and others are 95 to 100% resistant (m+ class) to digestion by HhaI or HpaII in the DNAs of all the tissues which were tested. Our study has also revealed a remarkable number of allelic variants for the presence of HhaI or HpaII sites in the region of the ovalbumin gene.


DNA methylation: correlation with DNase I sensitivity of chicken ovalbumin and conalbumin chromatin. To analyse the relationship between DNA undermethylation at some sites in the ovalbumin and conalbumin gene regions (1) and the expression of these genes in chick oviduct, digestions with HhaI, which differentiates between methylated and unmethylated HhaI restriction sites, was performed on DNA isolated from chicken erythrocyte or oviduct chromatin treated with DNase I which degrades preferentially "active" chromatin. This was followed by analysis with ovalbumin- and conalbumin-specific hybridization probes. We conclude that the residual DNA methylation found at some sites of the ovalbumin and conalbumin gene regions is derived from the fraction of cells in which the chromatin of these genes is not in an "active" form. On the other hand, the ovalbumin and conalbumin sites which are partially unmethylated in erythrocyte DNA correspond to chromatin regions which are not DNase I-senitive. We have also detected a site about 1 kb downstream from the 3' end of the conalbumin gene that is hypersensitive to DNase I in all tissues tested.


Southern bean mosaic viral RNA has a 5'-linked protein but lacks 3' terminal poly(A). Nuclease digestion of SBMV RNA releases a protein of molecular weight approximately 12,000 in addition to the four mononucleotides. The lack of reactivity of SBMV RNA to polynucleotide kinase and the absence of a capping group suggest that the protein is covalently attached to the 5' end of the RNA. RNA sequencing shows that the 3' terminus of SBMV RNA is not polyadenylated.


Isolation of messenger RNA coding for the "fast" protein of embryonic chick feathers. The messenger RNA coding for the "Fast" protein of embryonic chick feathers has been purified from the overwhelming relative amounts of keratin mRNA which are present in the developing feathers. The "Fast" protein mRNA represents about 4-8% of the total mRNA population of the feather. Despite differences between the size of the "Fast" proteins and the keratins the two mRNA species are very similar in molecular weight as judged by electrophoresis under denaturing conditions. However, by electrophoresis in 8 M urea gels at 55 degrees C, the "Fast" protein mRNA could be separated from keratin mRNA, presumably reflecting differences in messenger RNA secondary structure.


Effects of nuclear disruption on the macromolecular composition of nucleosome subfractions. The macromolecular composition of nucleosomal subfractions obtained by limited action of micrococcal nuclease upon trout testis chromatin has been analyzed with the purpose of comparison with the properties of transcriptionally active nucleosomal fractions derived by similar treatment of intact nuclei. The results indicate that when the native chromatin structure of intact nuclei is disrupted prior to the nuclease action, the nucleosomal subfractions that are subsequently generated have an altered composition.


Methylation of somatic vs germ cell DNAs analyzed by restriction endonuclease digestions. Bacterial restriction endonucleases containing the dinucleotide CpG in their cleavage sequences were used to compare the methylation patterns of primarily repeated DNA sequences in (1) bovine somatic cell native DNAs vs bovine sperm cell native DNA and (2) native vs renatured bovine liver and sperm cell DNAs. The restriction patterns of sperm native DNA differ markedly from those of somatic cell native DNAs when using Hpa II, Hha I, and Ava I but not when using the enzymes Eco RI and Msp I. Digestion patterns of germ cell renatured DNA differed significantly from those of germ cell native DNA when using Hpa II but not when using Msp I or Eco RI. The results may not be due to artifacts of renaturation of the DNAs. The results are consistent with the concept that germ cell DNA may be strand asymmetrically hemimethylated. The data also suggest that methylation of the 5'-cytosine in the sequence CCGG renders this site insensitive to cleavage by Msp I.


Methylation of DNA in mouse early embryos, teratocarcinoma cells and adult tissues of mouse and rabbit. The distribution and amount of 5-methylcytosine (5-MeCyt) in DNA was measured for early embryos of mouse strain CF1 (2 to 4 cell stage to blastocyst) and mouse teratocarcinoma cells. In each case, the pattern of methylation was examined by use of the restriction enzymes Hha I and HPA II HPA II, which cut DNA at the sites 5'GCGC and 5'CCGG respectively, when the cytosines at these sites are not methylated. Mouse embryo DNA was found to have the same level of methylation as adult mouse tissues, and no changes in methylation were seen during differentiation of the teratocarcinoma cells. The ratio of 5-MeCyt/Cyt in DNA was measured by high performance liquid chromatography for the differentiating teratocarcinoma cells and for several adult mouse and rabbit tissues. The variation between tissues or between teratocarcinoma cells at different stages of differentiation was less than 10 percent. These results are discussed in view of proposals that 5-MeCyt plays a role in differentiation.


The preferential codon usages in variable and constant regions of immunoglobulin genes are quite distinct from each other. The pattern of codon utilization in the variable and constant regions of immunoglobulin genes are compared. It is shown that, in these regions, codon utilizations are quite distinct from one another: For most degenerate codons, there is a selective bias that prefers C and/or G ending codons to U and/or A ending codons in the constant region compared with the bias in the variable region. This would strongly suggest that, in immunoglobulin genes, the bias in code word usage is determined by other factors than those concerning with the translational mechanism such as tRNA availability and codon-anticodon interaction. A possibility is also suggested that this differance of code word usage between them is due to the existence of secondary structure in the constant region but not in the variable region.


S1 nuclease definition of highly repeated DNA sequences in the Guinea pig, Cavia porcellus. Native DNA of the Guinea pig, Cavia porcellus, purified from liver or tissue culture cells, was heat denatured and reassociated to a Cot value of 0.01 (equivalent Cot value of 7.2 x 10(-2)). The reassociated DNA was isolated by digestion with the single-strand DNA specific enzyme S1 nuclease. Spectrophotometric and radioactivity assays demonstrated that 24% of the total DNA was resistant to S1 nuclease treatment. Zero-time reassociation indicated that approximately 3% of the DNA was inverted repeat sequences. Thus, highly repeated sequences comprised 21% of the total genome. CsCl buoyant density ultracentrifugation indicated that this fraction was composed of both main band and satellite sequences. Although actinomycin D - CsCl density gradients failed to give significant separation of the repetitive sequences, distamycin A - CsCl gradients were able to fractionate the DNA into several overlapping bands. The heterogeneity of the repetitive DNA was further demonstrated by the first derivative plots calculated from their thermal denaturation profiles. This analysis revealed six major thermalytes which indicate that there may be at least six discrete components in the repetitive DNA.


Nucleosome dissociation and transfer in concentrated salt solutions. We have examined the dissociation of nucleosomes into histones and free, 4.5S DNA over a range of sodium chloride concentrations between 0.25 and 1 M. We have also studied this dissociation as a function of nucleosome concentration at two salt concentrations, 0.8 M and 0.9 M. In addition, we have measured the kinetics of transfer of histone cores from nucleosomes onto recipient bacteriophage T7 DNA in 0.6, 0.7 and 0.8 M NaCl solutions. Although the mechanism of nucleosome transfer is unknown the data presented here are consistent with either a reversible dissociation of the nucleosome or DNA strand displacement by another DNA.


Effects of selective monoamine oxidase (MAO) inhibitors on conditioned avoidance responses (CAR) of rats. Dopamine (DA) insufficiency in the ipsilateral corpus striatum produced by unilateral electrolytic lesion of the substantia nigra (SN) resulted in an impairment in rats' behavior as tested by one-way and two-way avoidance techniques. Selective MAO-A inhibitor, clorgyline (1 mg/kg sc daily for 7 days), improved the reduced learning capacity of SN lesioned animals, restored the decreased DA content in the corpus striatum, and caused significant hyperactivity as tested in the open field. At the same time the selective MAO-B inhibitor (-)deprenyl (injected the same way) proved to be ineffective. J-508, a selective MAO-B inhibitor, used in a non-selective dose (1 mg/kg), acted like clorgyline. The results support the hypothesis that in the rat nigrostriated system (but not in human beings) DA is preferentially deaminated by the A form of MAO.


An evidence for the central serotoninergic activity of viloxazine. The effects of viloxazine on the flexor reflex of the hind limb of the spinal rat and the blood pressure in the pithed rat were studied. Viloxazine (1--16 mg/kg) stimulated the hind limb flexor reflex in the dose-dependent manner. This effect of viloxazine was inhibited by serotonin receptor blockers, cyproheptadine, danitracen and metergoline, and by serotonin uptake blocking agents imipramine and clomipramine. H22/54, an inhibitor of serotonin synthesis, was much less active in this respect. Desipramine, a noradrenaline uptake inhibitor, had no effect on the stimulatory action of viloxazine. Viloxazine (similarly as serotonin) elevated blood pressure in the pithed rat. This action of viloxazine was abolished by cyproheptadine but potentiated by pargyline, an inhibitor of MAO. It is suggested that viloxazine may facilitate the serotonergic transmission in the central nervous system.


Naloxone-induced facilitation of conditioned avoidance behavior in rats. Conditioned two-way avoidance behavior was studied in male Wistar rats. Experimental group received naloxone (2 mg/kg sc) 5--7 min before training session, control group received appropriate volume of saline. It was observed that naloxone significantly enhanced acquisition of avoidance response during 3--9 days of training.


The relationship between catecholamine levels in the hypothalamus and amygdala under influence of glucose overloading in hungry and sated rats. The effect of intragastric glucose infusion (1.5 g per rat) to sated rats on the catecholamine content in the medial basal and lateral hypothalamic regions and in the nuclei of the amygdaloid body was investigated. The effect of glucose overloading on the noradrenaline (NA) and dopamine (DA) content in the ventromedial (VMH) and arcuate hypothalamic nuclei was also studied in rats deprived of food for 48 hr. Glucose administration to rats fed ad lib. resulted in an increase in NA in the VMH and a decrease in DA in the central nucleus of the amygdaloid body. In fasted animals glucose overloading partially reversed the changes of NA concentration in the arcuate nucleus produced by starvation, whereas in the VMH glucose was not effective in producing any changes of catecholamine content. Possible interrelations between the amygdala and hypothalamus in respect to the role of catecholamines in the regulation of food intake are discussed.


Inhibition by deprenyl of dopamine uptake in rat striatum: a possible correlation between dopamine uptake and acetylcholine release inhibition. Optical isomers of deprenyl inhibit the resting and ouabain induced release of acetylcholine (ACh) in isolated striatal slices of the rat and this effect correlates with the capability of deprenyl to inhibit the uptake of 3H-dopamine in striatal homogenate in a concentration of 10(-4)--10(-4) M. The release of ACh is significantly increased in striatal slices taken from rats pretreated with a single dose of 250 micrograms of 6-hydroxydopamine. 5 mg/kg of deprenyl given 30 min prior to 6-hydroxydopamine treatment prevented completely the chemical destruction of the dopaminergic neurons. In contrast to deprenyl, clorgyline potentiated the effect of 6-hydroxydopamine.


Thromboxane B2 release and 3H-noradrenaline accumulation by a synaptosomal fraction of rat brain. Release of thromboxane B2 (TXB2) and accumulation of 3H-noradrenaline (3H-NA) by a synaptosomal fraction of rat brain were investigated. TXB2 release was temperature-dependent and was inhibited by three different TX-synthetase inhibitors: imidazole, 9,11-azoprosta-5,13-dieonic acid (AZO) and 11,9-epoxyiminoprosta-5,13-dionic acid (EPI). While high concentrations of imidazole decreased the 3H-NA accumulation in the synaptosomes significantly, AZO and EPI were ineffective. The results show that TX synthesis is not essential for 3H-NA uptake and the effect of imidazole in 3H-NA accumulation is unrelated to its inhibitory effect on the enzyme TX-synthetase.


Haloperidol-induced changes in the regional cerebral pharmacokinetics of apomorphine. Haloperidol did not change significantly the rate of penetration of apomorphine to three investigated structures of the rat brain: striatum, limbic forebrain and cerebellum. It depressed, however, significantly the accumulation of apomorphine in the striatum and limbic forebrain; in the cerebellum, in which the accumulation of apomorphine was very low, haloperidol did not change it. In haloperidol-pretreated rats the pattern of elimination of apomorphine from the striatum changed, revealing the presence of two compartments; this was not observed in the limbic forebrain, from which the elimination was linear, both in the presence and absence of haloperidol.


Systemic opportunistic fungal infections. The clinical manifestations of "opportunistic" fungal infections in compromised hosts, asthenomycoses, differ from those caused by the same fungus in otherwise normal people. Examples are given on the field of dermatophytoses, aspergillosis, candidiasis and cryptococcosis.


Alteration of brain noradrenaline, dopamine and 5-hydroxytryptamine levels during vanadium poisoning. Effects of subacute and chronic intoxication with vanadium on the levels of noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-HT) were examined. It was shown that subacute as well as chronic intoxication caused changes in levels of biogenic amines in the rat brain. NA concentration decreased whereas DA and 5-HT levels significantly increased. Vanadium in concentrations of 10(-3) and 10(-4) M inhibited the uptake of 3H-NA by cerebral cortex slices in vitro.


Imported fungal infections.

Imported fungal infections. Data on mycoses known to be imported into the United Kingdom are sparse. Estimates on the prevalence of fungal infections have to be based on indirect and incomplete figures, obtained from isolation figures and reports of individual cases to co-ordinating centres such as the Mycological Reference Laboratory and the Communicable Disease Surveillance Centre of the Public Health Laboratory Service. Imported species of dermatophytes account for less than 1% of the total number of isolations made annually at mycological laboratories throughout the U.K. A suggested prevalence of dermatophytosis in this country is c. 250 000 cases per annum. Trichophyton rubrum may now be the most common species of dermatophyte. Other estimates of the frequencies with which infections are recorded each year include mycetoma (7-10), histoplasmosis (2-5), aspergilloma (50-80), invasive aspergillosis (10-30), Candida vaginitis (greater than or equal to 1 000 000), invasive candidiasis (10-80), Candida endocarditis (1-2) and cryptococcosis (6-10).


Imported mycoses: some diagnostic problems. Infections by actinomycetes or by true fungi may cause diagnostic difficulties in countries where they are not familiar. Illustrative cases from a series of 353 instances are given together with rare indigenous examples of the same infections. Early, accurate diagnosis is essential for rational and effective treatment.


Mycoses imported from the West Indies. A report of three cases. There have been isolated case reports of deep fungal infections from the Caribbean area but little is known about the distribution of mycoses there. Three cases, one of mycetoma, one of chromomycosis, one of histoplasmosis, are described. Their management and the advantages and disadvantages of treatment outside the area of origin are discussed.


Some histochemical and electrophysiological effects of isatin. Qualitative and semiquantitative histochemical investigations of acetylcholinesterase after a single or repeated administration of isatin, 160 mg/kg ip once or daily for 8 consecutive days have revealed a significant decrease of the histochemical reaction for acetylcholinesterase in chronically treated rats. The cholinergic effect of isatin was tested in the electrophysiological experiment after a single dose of 160 mg/kg isatin and was partially antagonized by atropine.


Failure of treatment in chronic dermatophyte infections. A proportion of dermatophyte infections fail to respond to normally adequate courses of griseofulvin and topical antifungal therapy. The organism Trichophyton rubrum was isolated from 96% of 50 patients studied, but no instances of in vitro resistance were seen. Of these patients, 57% had an underlying condition, commonly hay fever/asthma, atopic eczema, collagen disease or ichthyosis. Defective delayed type hypersensitivity responses and leucocyte migration inhibition to the specific antigen, trichophytin, were demonstrated. Immediate type hypersensitivity was seen in 58% and this was partially suppressible with chlorpheniramine and cimetidine. The relationship between these abnormalities and failure of treatment is discussed.


Therapy of fungal infections of the central nervous system. Fungal infections of the central nervous system present a considerable challenge to available chemotherapy and other forms of treatment. The particular difficulties are discussed here, after an account of the fungi involved and their sensitivity to antifungal agents. Cryptococcal, coccidioidal and candidal infections are considered in more detail.


Aspergillus sinusitis.

Aspergillus sinusitis. Since 1969, 79 cases of fungal maxillary sinusitis have been diagnosed. Forty-nine were due to Aspergillus fumigatus. There were no underlying diseases which depressed cellular immunity and no patient was receiving immunosuppressive drugs or corticosteroids. Most patients had received antibacterial therapy before the appearance of FMS. Treatment was by surgery, nystatin and econazole.


Rhinocerebral mucormycoses with emphasis on clinical diagnosis, altered host defensive mechanisms and management. Two cases of malignant form of mucormycosis are presented. In spite of extensive treatment with surgery and antifungal drugs, both cases were fatal. Diminished cellular immunity was demonstrated and considered an important factor in the poor outcome.


The role of chemotherapy in the management of fungal endocaridits following homograft valve replacement. Initial intensive combined chemotherapy, with late re-operation when indicated, appears to give better results than immediate excision of the infected valve. The combination chemotherapy used in this series was amphotericin B (up to 100 mg/patient/day) and flucytosine (up to 12 g/patient/day). Serious side effects attributed to this chemotherapy were extremely rare. Candida infections were the most common and the Aspergillus infections were uniformly fatal. Embolectomies and excisions of large mycotic aneurysms were generally successful. Re-operation for late valve malfunction was common and yielded satisfactory results.


Ketoconazole, an oral antifungal: laboratory and clinical assessment of imidazole drugs. Miconazole, a parenterally administered imidazole antifungal agent has been shown to produce responses in systemic fungal infections in man. Ketoconazole, an analogue, can be given by mouth. It is inhibitory in vitro at low concentrations to most fungi. Blood levels after oral administration to animals and man greatly exceed these inhibitory concentrations for several hours. The efficacy of this drug has been demonstrated in animal models. Initial clinical evaluation has produced responses to therapy with 200-400 mg/day in 13 of 16 evaluable patients with systemic and superficial fungal infections, involving 10 fungal pathogens. No toxicity has been noted to date in these human studies. Ketoconazole is a promising agent needing further extensive evaluation.


Pharmacokinetics of imidazole antimycotics. According to data on the imidazole antimycotics at present on the market, none of these products satisfactorily fills the gaps which exist in the treatment for mycoses of internal organs, although they have brought considerable progress in the topical treatment of mycoses. On the basis of their very broad spectrum and high intensity of activity under suitable test conditions, and the comparatively tolerable amount of side effects in man, the present imidazole antimycotics are considered to be an encouraging start for future development of derivatives which will lead to products with considerably better pharmacokinetic, and therefore better therapeutic, properties.


Pharmacokinetics of amphotericin B and flucytosine. The absorption of flucytosine from the digestive tract is very good but minimal with amphotericin B. For this reason, amphotericin B has to be injected intravenously. Fungistatic levels are achieved rapidly with flucytosine and slowly with amphotericin B, since the dose has to be increased slowly. Distribution of flucytosine in other body fluids is high, whereas with amphotericin B it is poor. Flucytosine is excreted mainly via the kidney without metabolism, whereas amphotericin B is eliminated mainly by metabolism. Therefore, amphotericin B dosage does not have to be adapted to kidney function, which is the case for flucytosine. The half-life of flucytosine is short (hours), that of amphotericin B is long (days); flucytosine is haemodialysable, whereas amphotericin B, probably owing to the high protein binding, is not.


The influence of carbohydrases on the growth of fungal pathogens in vitro and in vivo. Mixtures of mycolytic enzymes from various sources release protoplasts from living fungal tissue under suitable conditions. Such enzyme mixtures obtained from Coprinus comatus (mycolase I), Physarum polycephalum (mycolase II) and Lycoperdon pyriforme (mycolase III) are of low toxicity in mammals when given parenterally and are able to cure experimental systemic fungal infections in mice when administered alone or in conjunction with normally ineffective levels of conventional antimycotic drugs such as amphotericin B. The effect is believed to be due to enzymic degradation of the fungal cell wall either killing the fungus directly or enhancing activity of existing antifungal agents by increasing access to the cell interior.


In vitro synergy and antagonism of antifungal agents against yeast-like fungi. Some antifungal agents have been tested qualitatively in various associations against species of Candida, Cryptococcus and Torulopsis. The method used was the channel test and the results are confirmed by comparison with the serial dilution test in agar. The antagonism in vitro with the combination of amphotericin B imidazole suggests that caution must be exercised before prescribing the antifungal drugs in combination for man. The frequent synergy of flucytosine with econazole is, however, encouraging because of the low toxicity of the 2 drugs. Under the limited conditions described, the combination of flucytosine and amphotericin B was not found synergistic but additive on the strains of C. albicans used in this study. This combination was found synergistic for a strain of C. parapsilosis and is useful for avoiding resistance to flucytosine.


The host and the parasite.

The host and the parasite. The role of the host in the management of patients with mycotic infection is considered. In vivo studies with ketoconazole indicate the importance of the host and the possibility of stimulating host immune mechanisms by an immune modulator.


Lasalocid in prevention of turkey coccidiosis. Lasalocid was tested at graded feed concentrations in controlled battery experiments against single and mixed Eimeria species infections in 2-week-old turykey poults. Eimeria meleagrimitis, E. gallopavonis, E. adenoeides, and E. dispersa infected poults medicated with lasalocid at concentrations of 0.15, .0125, .01, .0075, and .005% were heavier, converted feed more efficiently, showed lower lesion scores (ADI), shed fewer oocysts, and showed reduced or no mortality as compared to the infected, unmedicated controls. Lasalocid activity was similar against the few field isolates tested. Lasalocid responses were dose related, the higher the concentration, the greater the effect. The optimum dose level in these battery studies was approximately .0125%. Lasalocid fed at two times the optimum dose level to poults for a four week period did not have any adverse effect on growth or feed conversion performance.


Efficacy of salinomycin and stenorol against various species of Eimeria and effect on chick performance. Three experiments were designed to test the efficacy of salinomycin and stenorol against infection by various Eimeria species on cage reared broiler type chicks. Efficacy was based on a coccidial index. Sixty parts per million salinomycin alone or in combination with 50 ppm 3 nitro significantly improved the index over basal treatments or when 3 nitro was used alone. The differences in index values recorded for coban and salinomycin were not significant. Stenorol significantly improved the index and appeared to be a most effective anticoccidial product. Broiler chickens reared in floor pens to 8 weeks showed a significant reduction in weight gain when the diet contained salinomycin +3 nitro or coban. Stenorol at 3, 6, or 9 ppm reduced body weight, with linear regression for this effect being highly significant (P less than .01). No coccidiosis was observed.


Therapeutical trials with antimicrobial agents and cultured cecal microflora in Salmonella infantis infections in chickens. The efficacy of short antimicrobial therapy was examined in chicks infected with S. infantis on the day of hatching. An attempt was made to prevent the reappearance of salmonellae by treating the chicks with a culture of cecal microflora to re-establish the normal intestinal flora. The following drugs were used: neomycin/polymyxin, oxytetracyline/neomycin, dihydrostreptomycin, furazolidone, and trimethoprim/sulphadiazine. The oxytetracycline/neomycin therapy was most effective, but reappearance of the infection was not avoided. Combined therapy with other antimicrobials and the culture reduced the number of infected chicks compared with the respective control groups. A slight reduction was also found when the culture was used alone without any preceding antimicrobial treatment.


Distribution and depletion of radioactivity in hens treated dermally with 14C-labeled permethrin. The 25/75 cis-trans mixture of permethrin (BW21Z), one of the new broad-spectrum pyrethroid insecticides, was labeled with 14C in the alcohol methylene carbon moiety and mist sprayed at two rates (3.77 or 11.94 mg/hen) on 28 hens. Peak permethrin equivalents in both treatment groups were found in the skins, .414 and l.69 ppm, respectively. Total permethrin equivalents peaked 3 days after treatment, but permethrin equivalents in eggs peaked 5 days after treatment.


The effect of exercise on the toxicity of aflatoxin B1 in chickens. Three trials were conducted to study the effects of exercise on aflatoxicosis in young broiler and layer chicks. Aflatoxin B1 was fed at levels of 0 or 5 ppm in a corn-based diet. Exercise was conducted on a motorized treadmill. In one trial, the growth rate of aflatoxin-fed birds was found to be increased significantly (P less than .05) by exercise, but it was not equal to that of the control birds. In other trials, growth rates were increased by exercise in birds receiving aflatoxin, but not significantly. Feed consumption measurements indicated that the decreased growth rates in the aflatoxin-fed birds were due to decreased feed consumption. Glucose-6-phosphate dehydrogenase levels were decreased significantly in the unexercised broiler chicks fed aflatoxin (P less than .025). In one trial, liver weights of broiler chicks were increased significantly by aflatoxin (P less than .005). In the birds fed aflatoxin and exercised, liver weights also were increased but to a lesser degree (P less than .01).


Studies on duck nutrition. III. Arginine and lysine requirements of mule ducklings. Growth assays were conducted to determine the dietary arginine and lysine requirements of mule ducklings. The metabolizable energy content of the basal diets used for the arginine and lysine requirement studies was 2810 and 2828 kcal/kg, respectively. Two-day-old ducklings of mixed sexes were fed on a starter diet for one week, fasted for 8 to 12 hr and then were fed on experimental diets for 12 or 14 days. Weight gain and feed consumption were recorded at the end of each experiment. The minimum requirements for arginine and lysine were obtained by regression analysis of weight gain or feed efficiency against arginine or lysine content in the diet. The minimum arginine requirements for maximum growth and efficiency of feed utilization were 1.08% of the diet or 6.0% of the dietary crude protein. The minimum requirements of the total lysine and available lysine were 1.06% and .97%, respectively, of the diet or 5.9% and 5.4%, respectively, of the dietary crude protein for both maximum growth and feed efficiency.


Incidence of degenerative myopathy among turkeys fed corn or wheat based rations. Turkeys were fed either corn based or wheat based rations and necropsied between 28 and 118 weeks of age. Practically all birds affected with degenerative myopathy were detected among those killed between 77 and 85 weeks of age. The incidence of the disease was 0% among 125 males and 7.9% among 139 females. No significant difference in incidence was observed between birds fed corn based and birds fed wheat based rations.


Physiological changes in caged layers during a forced molt. 3. Plasma thyroxine, plasma triiodothyronine, adrenal cholesterol, and total adrenal steroids. The effects of forced molting on plasma levels of thyroxine (T4), triiodothyronine (T3), and adrenal cholesterol and total adrenal steroid content were studied. Commercially available strains of Single Comb White Leghorn (SCWL) hens, reared and maintained under commercial conditions, were used in the three trials. The hens were moved to environmentally modified facilities prior to the forced molt which was accomplished by reducing daylength and by withdrawing feed and water. Egg production ceased within one week of initiation of this procedure. The hens were sampled either daily or an alternate days for up to 22 days beginning at the time of feed removal. Plasma T4 initially decreased upon removal of feed, but increased above control levels by the sixth day of feed withdrawal. Plasma T3 levels remained relatively constant throughout the feed withdrawal period. Resumption of feeding with a fortified ground corn ration resulted in a decrease in T4 and concomitant increase in T3. Changes in adrenal cholesterol and total adrenal steroids were not consistent. However, there was a trend toward increased total adrenal steroids during feed withdrawal, and an increase in adrenal cholesterol upon the resumption of feeding.


Hatchability of bobwhite quail eggs incubated in various temperature combinations. Five experiments were conducted to compare the effects of various incubation temperature combinations on the hatchability of Bobwhite quail eggs. A starting incubation temperature of 40.6 C resulted in numerically lower hatchability. Incubation at 37.5 C resulted in a greater number of pipped, unhatched eggs, and a later, less uniform hatch. Temperatures during the hatching period (22 to 25 days of incubation) of 36.9 C and 38.1 C resulted in lower hatchability than the hatching temperature of 37.5 C.


Serum luteinizing hormone, progesterone, and estradiol levels in relation to broodiness in the turkey (Meleagris gallapavo). Changes in nesting frequency, serum LH, progesterone, and estradiol were measured in relation to the onset of broodiness in turkeys. In each of two experiments the frequency of nest visits increased about four-fold in the 5 to 7 day interval before oviposition of the last egg associated with the onset of broodiness. In the 9 day period prior to oviposition of this egg LH levels declined from about 12 ng/ml to 6 to 7 ng/ml (Experiment 1) and from about 9 ng/ml to less than 5 ng/ml (Experiment 2). Progesterone levels declined during this same period going from about 2 to 2.5 ng/ml down to less than .5 ng/ml. In the 5 day period following the nadir in serum LH, which occurred on or a day or two after the last egg, levels of this hormone again rose substantially. Estradiol levels, assayed in Experiment 2, were generally low with many samples below detectability (less than 3 pg/ml). There were no consistent changes in serum estradiol until the day before oviposition of the last egg. On this day, and on the subsequent four days, mean estradiol levels were at a nadir (6 to 9 pg/ml) and rose to levels averaging over 11 pg/ml in the following five day period.


Infertility in the turkey. I. Effects of anti-sperm immune globulins on fertilizing ability of turkey spermatozoa. Two experiments were conducted to study the effects of globulins, isolated from sera of turkey hens immunized against semen, on the fertilizing ability of spermatozoa and the hatchability of eggs. Sperm were incubated in sera from hens immunized against semen and in sera from non-immunized hens as well as in globulin solutions isolated from these various sera. In neither experiment did sera from control hens or gamma globulins isolated from their sera affect the fertilizing ability of sperm. In contrast, all sera from immunized hens drastically reduced the fertilizing ability of sperm. In Experiment 1, .75% gamma globulin solutions from two hens did not depress fertility but a 1.5% solution from one of the immunized hens significantly (P less than .05) reduced it. In this experiment none of the treatments had a significant effect on hatchability. Antisemen globulin solutions of 2.25 and 4.50% from 12 hens significantly reduced the fertilizing ability of sperm in dose related fashion. The higher of the two levels suppressed it to the level of whole sera. Hatchability of fertile eggs was significantly reduced by the anti-semen sera and globulins isolated from it in the second experiment.


Infertility in the turkey. III. Effects of sera from sterile and fertile females on the fertilizing ability of spermatozoa. In an attempt to understand the cause for spontaneous infertility in female turkeys, sera were obtained from a flock suffering this condition. These sera, from hens of known fertility, were tested for anti-fertility actions by incubating semen in them. After incubation, semen was inseminated into unrelated recipient hens. In the first of two experiments, semen incubated in sera from high fertility hens (average 89%) produced a fertility level of 72.7% over an 8 week period while semen incubated in sera from sterile hens significantly reduced fertility to 52.3%. In a second experiment sera from sterile donors again caused a significant reduction in the fertilizing ability of sperm (56.3% for sera from sterile hens vs. 73.5% for sera from high fertility hens). These results indicate the presence of a factor(s) in the sera of sterile hens which may be causally related to their infertility.


Effects of hypothalamic deafferentation on light-stimulated ovarian function in turkeys. Previous studies in the turkey have shown that lesions placed in the preoptic brain (POR) block ovulation, while lesions placed in the tuberal hypothalamus (TH) induce regression of rapidly growing ovarian follicles. In the present experiments, the nature of the neural pathways to and between these regions is explored by the method of neural transection performed with a small, stereotaxically positioned knife. Superior deafferentation of the POR allowed light-stimulated rapid growth of ovarian follicles but appeared to block or suppress ovulation. Complete deafferentation of the TH prevented development of the ovary as indicated by the failure of ovarian follicles to enter the phase of rapid growth. Partial cuts that severed anterior inputs to the TH blocked follicular growth, whereas cuts that severed lateral and posterodorsal connections or posterior connections to this region had no effect on development of a functional ovary. Deafferentation of the posterior two-thirds of the TH, which created an island including the posterodorsal region of the infundibular nuclear complex, did not block ovulation.


[Plasma amino acids and nitrogen balance during the postoperative period in metabolically healthy patients. 2nd communication (author's transl)]. Under parenteral and following oral nutrition in ten metabolically healthy patients the plasma amino acids were determined before and after vaginal hysterectomy. Starting from normal preoperative values there is a fall in the plasma concentration of most amino acids. The branched-chain amino acids decreased significantly, but under oral feeding they rose above the initial values. With increased plasma phenylalanine and methionine levels the concentration of cystine and tyrosine remained nearly unchanged. Glycine showed no increased levels while serine concentration was decreased even under substitution.


[Interaction between intensive care patients; a comparison of different intensive care units (author's transl)]. A study was made of the extent and type of contact which patients of an intensive care unit established with each other. The information was obtained by interviewing 92 patients in 4 different types of intensive care units. In evaluating and interpreting the results special attention was paid to the possible influence of 10 patient-specific and disease-specific parameters. 81 per cent of the interviewed persons had established contact, mostly of a verbal nature, with their fellow patients. The majority appreciated the companionship and attached a positive value to the contacts made: communication with the other patients relieved the mental stress arising from their condition and detracted from their anxiety and tendency to brooding; on the other hand, they were also, to some extent, worried that too much excitement might adversely affect their condition. Encouraging talks by the medical team greatly helped towards reducing stress. Even severely ill persons who could no longer actively communicate felt happier in a multi-bed ward: they felt less isolated and more involved and therefore, psychically supported. The fact that the great majority of patients preferred multi-bed units to single rooms suggests that the former have a stabilizing effect, both physically and psychically - an aspect of intensive care that has so far been ignored.


[Hydrothorax as a complication due to left internal jugular vein catheterisation (author's transl)]. We present a case of hydrothorax, which occured in a young man following unrecognized vein perforation by a left internal jugular vein catheter two days after cannulation. The mechanism of this complication and methods for its prevention are discussed.


[Severe complications after caval vein catheterization (author's transl)]. In 13 autopsy cases after catheterization of the superior caval vein a surprisingly high rate of incorrect positions of the catheter tip within the right atrium was seen. This had resulted in wide spreaded lesions of the endocardium and in voluminous thrombosis around the catheter tip. In one case a pericardial serous effusion with letal cardiac tamponade was found because of such malpositioning of a caval catheter. The mechanical stress to the endothelium by the catheter tip is held responsible for the intima lesions in the right atrium. The need for X-ray-control of the catheter position and its fixation at the site of entry through the skin is stressed.


[An unusual complication of subclavian vein catheterisation (author's transl)]. A complete knot of a central venous catheter is a rare complication of subclavian vein catheterization. The knot was pulled tight and minimised, because it was impossible to untie the catheter by the "guidewire-technique" (9). After that, the catheter was removed without damage to the venous wall.


[Obstructive diseases of the respiratory tract caused by industrial allergens (author's transl)]. Obstructive diseases of the respiratory tract caused by allergising substances at the place of work, must be classified and compensated as occupational diseases - provided certain conditions are fulfilled - according to item No. 4301 of the currently valid Industrial Health Insurance legislation. The article discusses the aetiopathogenesis as well as the special features of clinic and diagnosis of occupationally conditioned allergic obstruction of the respiratory tract, previously known as asthma bronchiale. In contrast to "spontaneous" allergy, the occupational cause of the disease is due to the often massive exposition to allergens at the place of work, as well as the frequently aggressive potency of several industrial allergens, these being considered as the actual "shaping" factors. The article stresses the need for early diagnosis, as far as possible already in the is allergic conjunctivitis and rhinitis. Treatment directed at removing the causes includes, fundamentally, prophylaxis against exposure (considering the time during which the allergens remain dormant without triggering an allergy); obviously, this involves change of occupation or place of work, whereas specific treatment aimed at producing hyposensibilisation must remain an exception. The article concludes with a description of the possibilities of prevention mainly from the medical point of view.


[Clinical characteristics of patients with pollen allergy (author's transl)]. 134 patients with pollen allergy were studied in a medical practice. The frequency of hay fever was 56%, hay fever with cough 9% and pollen asthma 35%. The following differences were stated: 53.2% of the asthmatics but only 9.3% of patients with hay fever had a history of nonallergic bronchial irritation in the case of acute bronchitis, exercise or irritant gases. Asthmatics showed significantly more frequently positive skin reactions additionally to pollen. The distribution of age of onset of hay fever was similar in both groups. The prevalence of both diseases was the same up to the age of 20 years, after which it remained constant up to 29 for asthmatics and declined in hay fever. In patients with asthma and hay fever the two diseases began within the same year in 48,9%, asthma followed hay fever in 26,7% within 4, in 15,6% within 5--9 and in 8,6% within ten years or later after the begin of hay fever. It could be shown, that the frequency and the distribution of some characteristics of patients with pollen allergy of a medical practice are comparable to epidemiological findings and may be used for long time studies with the purpose to watch the transition of pollinosis to pollen asthma.


[Primary resistance to isoniazid (author's transl)]. Primary resistance to isoniazid is to be expected in 3.4 per cent of all tuberculous persons in the German Federal Republic including Berlin (West). An increased incidence in primary isoniazid resistance was observed during 1974--1977 in two neighbouring districts. Potential causes and the clinical consequences of the increased resistance are discussed.


[A pilot and a controlled study of the influence of ethambutol on serum urate concentration and uric acid clearance (author's transl)]. Ethambutol is said to be capable of elevating serum urate concentration. This statement was reconsidered in three investigations using strictly supervised administration of ethambutol in a single daily dose of 25 mg. per kg. of body weight: (1) In short term administration 10 healthy subjects received ethambutol for eight days. (2) In a pilot study 13 patients suffering from pulmonary tuberculosis were treated with a triple combination including thambutol for six months. (3) In a controlled trial 23 patients were randomly allocated to one of the following regiments: In the first group patients received ethambutol plus isoniazid plus rifampicin for six months. In the second group patients received streptomycin plus isoniazid plus PAS for three months and thereafter streptomycin plus isoniazid plus ethambutol for another three months. Serum urate concentrations and clearances of uric acid and of creatinine were determined periodically in all subjects. A slight increase in serum urate concentration occurring in long term therapy showed no relation to ethambutol administration, but was obviously dependant on parameters related to the course of the disease in form of increase in body weight and physical activity, or related to the well known syntropy of chronic alcoholism and tuberculosis.


[Evaluation of lung function tests by means of a programmed minicomputer (author's transl)]. A computer programme for a small programmable electronic calculator is introduced which considerably facilitates the offline evaluation of tests of the ventilatory lung function and mechanics of breathing, including the establishment of individuel ideal values. This favourably priced computer reduces the time required for calculation by about one-third compared with the conventional method. The process of assessment is rendered strikingly simple and hence safer by this highly versatile computer.


[Smoking and lung cancer in women (author's transl)]. 60 per cent (108) of 180 women with lung cancer were cigarette smokers as compared with only 21 per cent (75) smokers in a control group of 360 female patients. The former group had been smoking for an average of 40 years, with a preference for high-tar cigarettes in 78 per cent of the cases. The women in the control group had started smoking about 33 years ago and 57 per cent preferred low tar cigarettes. The differences were significant. The exposure pattern of male and female lung cancer patients was markedly the same.


[Comparative examination of theophylline-serum-concentrations and bronchospasmolytic effect of cholintheophyllinate (euspirax) and theophyllin-aethylendiamine (euphyllin retard) in patients with obstructive airway diseases (author's transl)]. 12 patients with obstructive airway diseases were given a single oral dose of 400 mg resp. 600 mg Cholintheophyllinate (Euspirax) and 350 mg Theophyllin-Aethylendiamine (Euphyllin retard). In an intra-individual comparative study the theophylline-serum-concentrations and the bronchospasmolytic effects of both drugs have been checked over a period of 12 hours. A very good resorption and the highest mean blood levels of 9,13 +/- 2,88 mg/1 resp. 12,11 +/- 2,55 mg/1 resulted from Cholintheophyllinate 2 hours after application. The effect on the lung function parameters was most expressed 2 to 4 hours after application of this drug and correlated well with the theophylline-blood-levels. The higher dose of Euspirax was followed more frequently by side effects. 2, 4 and 12 hours after application of Euphyllin retard the serum-concentrations were strikingly low. The mean values were 2,04 +/- 1,22 mg/l, 3,00 +/- 2,18 mg/l resp. 3,38 +/- 2,01 mg/l. In spite of the low blood levels a significant improvement of the lung function parameters could be noticed after 4 to 6 hours. The qualities of both drugs as to their bioavailability and effect on airway obstruction shall be examined by means of another comparative study.


[Sonographic differentiation of pulmonary opacities (author's transl)]. Sonography offers a supplementary diagnostic method in cases where X-ray examination has established the presence of opacities in the lungs. Simple criteria generally allow differentiation between solid and liquid structures and thus to distinguish between effusions, haematoma, empyema and adhesions and tumors. - Sonographically directed needle biopsies following the sonographic localization of encysted effusions or a tumor ensure the correct site of puncture and provide the means to establish the diagnosis histologically, cytologically and bacteriologically.


[Haemangioma capillare of the pleura with ipsilateral haemopneumothorax (author's transl)]. 1. The article introduces a patient with left-side haemangioma capillare of the pleura parietalis with haemopneumothorax and ipsilateral cystic changes of the left upper lobe of the l,ng. 2. The aetiopathogenesis of the disease is discussed as an abortive type of Rendu-Osler-Weber disease (hereditary haemorrhagic telangiectasia), the diagnosis being based exclusively on histological findings as the only possibility of diagnosis. 3. The therapeutic approach is discussed.


[Various characteristics of energy metabolism in diabetes mellitus]. In the blood of patients (104) with diabetes mellitus of various severity some energy metabolic indices (lactate, pyruvate, nonesterified fatty acids, and in some patients also glycogen and glycogenolytic activity of the blood), tissue oxygen tension and immunoreactive insulin were studied simultaneously. The glycogen content, a and b phosphorylase activity were determined in the liver and the skeletal muscles, and lactate, glycogen, and pyruvate in the blood of animals with experimentally induced diabetes mellitus (alloxan and immune diabetes). Changes in the energy metabolism were revealed in all forms of diabetes mellitus: in hyperinsulinism accompanying early forms of diabetes mellitus there was activation of anaerobic processes and tissue hyperoxygenation, and at the late stages of the disease a tendency to tissue hypoxia. Experimental diabetes was accompanied by glycogen reduction in the skeletal muscles together with the growth of b phosphorylase activity. This could be due to the reduction of glucose-6-phosphate in the muscles and to a disturbed activity of the other systems regulating glycogen metabolism.


[Dynamics of erythrocyte hexokinase activity during glucose tolerance test in children with hereditary diabetes mellitus]. In determining the changes in hexokinase activity in erythrocytes during the glucose tolerance test in children with heredity aggravated by diabetes mellitus in comparison with such in apparently healthy children it was shown that in latent diabets the enzyme activity failed to alter during the whold period of study (on fasting stomach, 30, 60 and 180 minutes after glucose load), and increased 60 minutes after glucose load in potential diabetes, but to a lesser extent than in the control group. Changes of erythrocyte hexokinase response to glucose administration could serve as an auxiliary criterion for determination of the degree of risk in children with threatening diabetes.


[Oral administration of insulin with synthetic polymers]. A saccharolytic action of insulin given orally with various synthetic polymers to rabbits was studied. Blood sugar level gave the greatest fall when insulin mixtures with strong electrolytes were used. In this case when the weight proportion of insulin-polymers was 1 : 5 insulin action was prolonged to 5 hours, addition of surfactants permitted to get an analogous saccharolytic effect with reduction of the insulin dose by half (50 AU per animal).


[Relationship between the results of glucose tolerance test and plasma content of immunoreactive insulin in the relatives of patients with juvenile form of diabetes mellitus]. Relatives (67) of patients with a juvenile form of diabetes mellitus and in 17 persons of control group were investigated. Hyperinsulinemia was revealed in close relatives and in persons with adiposity. The highest insulin response to glucose load was in persons with "doubtful" glucose tolerance test results. Insulinemic curve was flattened in the group of persons with latent and particularly with manifest diabetes. On the basis of the results obtained and the literature data a conclusion was drawn that hyperinsulinemia was one of the significant indices of disturbances in the regulation of insulin secretion in persons with hereditary aggravation by diabetes mellitus and could serve as a diagnostic index of the early stages of this disease.


[Bile acids in the bile in diabetes mellitus]. Hepatic and gall bladder bile of healthy persons (8) and of patients with severe form of diabetes mellitus (17) was studied. Paer chromatography was applied for determination of cholic, chenodeoxycholic, deoxycholic bile acids and their conjugates with glycin and taurine. An absolute content and percentage of glycodeoxycholic and glycochenodeoxycholic bile acids were increased, and glycochenodeoxycholic acid content and taurates proportion were decreased in the gall bladder and hepatic bile of diabetic patients. The data obtained pointed to disturbed hepatic function in severe diabetes mellitus; it was expressed in suppression of bile acids synthesis and conjugation, and also in depression of transformation of deoxycholic into cholic acid.


[Histopathological changes in the kidneys of the progeny of rats with aloxan diabetes]. A histological study (hematoxylin-eosin staining, and PAS-reaction) of the kidneys was carried out in 5 pubertal rats with diabetic test for glucose tolerance from the progeny of a female with alloxan diabetes and intact male. Changes of the type of diabetic intracapillary glomerulosclerosis were revealed. There were no changes in the kidneys of pubertal rats from the progeny of intact female and male, and an intact female and a male rat with alloxan diabetes.


[Effect of various 1,3,5(10)-estratrien derivatives on the estrogen receptor transport into the nucleus in the guinea pig uterus]. The capacity of five derivates of 1, 3, 5 (10)-estratrien to be transported together with estradiol receptor from the cytoplasm into the nucleus in the uterus of sexually immature guinea pig was investigated. The extent of this transport was assessed by the amount of estrogen receptor in the nucleus following incubation of the uterine slices in the presence of the compound tested (2.5.10(-7) M). The content of estrogen receptor in the nucleus of the intact guinea pig uterus served as control. Incubation of the uterine slices with compounds containing 17 beta-hydroxyl group (2-brom-1, 3, 5 (10)-estratriendiol-3, 17 beta, 4-brom-1,3,5 (10)-estratriendiol, 3, 17 beta, 1, 3, 5 (10)-estratrienol-17 beta), led to a 1.9--4.2-fold increase in the content of nuclear estrogen receptor, this pointing to the transport of the estrogen receptor complex with these compounds into the nucleus. Two compounds (1, 3, 5 (10) estratrienol-3 beta and 3-methoxy-1, 3, 5 (10)-estratrien) contained no 17 beta-hydroxyl group and failed to increase the contents of the estrogen receptor in the nucleus in comparison with control. 17 beta-hydroxyl group is apparently necessary for the formation of conformative changes in the receptor molecule transforming the steroid-receptor complex into the active one, capable of transporting into the nucleus.


[Electrolyte metabolism in thyrotoxicosis with energy-dynamic cardiac insufficiency]. In 70 patients with thyrotoxicosis and in 24--with ischemic heart disease with energy-dynamic cardiac insufficiency a study was made of electrolyte metabolism in the blood plasma, erythrocytes and 24-hour urine. The sodium and potassium content in erythrocytes rose, and sodium gradient diminished in the patients examined, this being related to the development of energy-dynamic cardiac insufficiency.


[Platelet serotonin absorption in Turner's syndrome]. Functional activity of platelets was studied in 20 patients with Shereshevsky-Turner's syndrome. There was revealed a significant rise of platelet serotonin (5-hydroxytryptamine) content and also a reduction of exogenous serotonin absorption by platelets. The noted disturbances pointed to dysfunction of these cells, this serving as an auxiliary factor pointing out that the ageing process involved the blood elements. Reduction of platelet functional activity in patients with monosomia X was apparently due to chromosomic unbalance and with the associated hormonal control disturbances.


Sampling schemes and ascertainment.

Sampling schemes and ascertainment. Previous approaches to the ascertainment problem have been in terms of a registry-type situation in which the sampled structure is a random variable. However, with the exception of Bailey (1951), previous authors have conditioned on this structure. In extending the theory to pedigrees, a registry situation may also be considered, providing neither the structure nor any part of it (e.g., ages of individuals) are conditioned upon, but it may often be neither practicable nor relevant to do so. In many studies the sampling scheme may fix the number of pedigrees, analyzed, and classical "ascertainment probabilities" are no longer applicable. In an infinite population, in which the ascertainment of and phenotypic observations on, affect neither the distribution of other ascertainments or phenotypic distributions on other pedigrees and chance multiple ascertainments cannot occur, ascertainment corrections are relatively straightforward. However, effective population sizes with regard to particular rare traits may often be small, and the problem of ascertainment corrections in this case has not been fully analyzed, although some preliminary results are presented.


Inheritance of susceptibility to juvenile onset diabetes. Regardless of the well-documented population associations between juvenile-onset diabetes (JOD) and certain HLA types, whatever haplotypes are segregating in JOD families may be followed to provide information on mode of inheritance of the disorder. It is essential to group together for analysis families with the same number of affected sibs. We assume a single locus determining susceptibility, closely linked to the HLA region, and ignore recombination, expected to be rare. Our first approach also assumes that the frequency of the susceptible genotype is so small that affected individuals may be considered to arise from only one mating type; the particular mating type depends on the mode of inheritance of susceptibility. Our sample is the result of pooling our own data with published studies of HLA haplotype segregation in families with two or more JOD offspring. Given the assumptions, we find that the data are more plausibly explained by a one-dose than by a two-dose or "recessive" hypothesis. We then develop the analysis further by adding a crude but explicit estimate of the frequency of the susceptible genotype, based on disease prevalence and penetrance of the genotype. The one-dose hypothesis is strongly supported by this analysis as well. We also consider some problems of ascertainment arising from heterogeneity of the disorder and selection against diabetics. Studies involving unaffected relatives of diabetics are suggested which might test further the conclusions drawn here.


Changes induced by hashish constituents on human erythrocyte phospholipids. The possible effect of delta 9-THC on human erythrocyte phospholipids of chronic hashish users was studied. Changes in individual phospholipids concentrations were observed in heavy hashish users after smoking the drug. Results are discussed in relation to the possible alterations of enzymatic mechanisms which require the presence of essential for their activation phospholipids.


Suppressant effects of naltrexone on water intake in rats. Parenteral administration of naltrexone to water-deprived female rats suppressed water intake when injected 4, but not 12 hours prior to the drinking session. Intraperitoneal injection 5 mg/kg naltrexone twice daily or oral self-administration of naltrexone in doses sufficient to block morphine-induced analgesia failed to reduce water intake or to alter body weight in non-deprived animals. These findings suggest that the suppressant effects of naltrexone on appetitive behavior are mediated by a different population of opiate receptors than those mediating morphine-induced analgesia.


Non-specific enhancement of ethanol-induced taste aversion by naloxone. The conditioned taste aversion paradigm (CTA) was used to examine the effects of naloxone on ethanol-induced aversion towards a saccharine solution (3 conditioning and 11 extinction trials). Six groups of rats received conditioning trials consisting of two IP injections after saccharine presentation of different combinations of either ethanol (E: 1.75 g/kg), LiCl (L: 12 mEq/kg, 0.1 M), naloxone (N: 10 mg/kg) or saline (S); S-S, S-N, E-S, E-N, L-S and L-N. Naloxone by itself produced no aversion to the saccharin flavor. Based on the onset and extinction of aversion, naloxone significantly enhanced ethanol but also LiCl-induced CTA. The comparative data argues in favor of different mechanisms of action (1) between the aversive central effects of ethanol and morphine and (2) between ethanol's acute behavioral effects and negatively reinforcing properties. Enhancement of ethanol and LiCl-induced CTA by naloxone is compatible with hypernociceptive action of the opiate-antagonist and with the pain-modulating role of opiates in the CNS.


Effects of acetone and toluene vapors on multiple schedule performance of rats. Six rats were trained to press a lever for a liquid food reward on a multiple fixed ratio--fixed interval (FR--FI) schedule of reinforcement. When lever-pressing rates became relatively stable, the animals were exposed to 150 ppm of either acetone or toluene for duration times of 1/2, 1, 2 and 4 hr. Exposures were conducted at least three weeks apart. Acetone produced minimal changes on the FR--FI responding during the 1/2 hr exposure. During the 1 hr exposure period, both FR and FI rates increased while during the 2 hr exposure, both FR and FI responses decreased below control levels. During the 4 hr exposure FI responses approximated control levels for 2 rats and were above the control level for the third animal while FR rates were below controls for 2 of the 3 subjects. Rate changes under toluene were generally qualitatively similar to those produced by acetone. An initial enhancement of FR and FI rates occurred during the shorter exposure periods followed by a decrease in rates during the longer exposure periods.


Systemic administration of Met-enkephalin, (D-Ala2)-Met-enkephalin, beta-endorphin, and (D-Ala2)-beta-endorphin: effects on eating, drinking and activity measures in rats. Rats were given four daily, interperitoneal injections (80 micrograms/kg) of Met-enkephalin, (D-Ala2)-Met-enkephalin-NH2, beta-endorphin, (D-Ala2)-beta-endorphin or the diluent (0.9% NaCl acidified to, 0.01 M with acetic acid). Animals were subsequently tested for food and water inake and activity. Met-enkephalin injections did not affect any of the measures but its (D-Ala2) analog reduced food intake and some of the activity measures in a complicated way. beta-Endorphin injections did not affect food or water intake; in familiar situations these animals were less active while novel situations seemed to potentiate activity. The (D-Ala2) analog reduced wheel running over 24 hours.


Free-choice ethanol intake and ethanol metabolism in the hamster and rat. Hamsters, as previously reported, demonstrated greater ethanol intake and preference than rats. However, as ethanol was gradually added to a sweet solution, hamster ethanol intakes did not consistently exceed ethanol metabolic capacity for prolonged periods. In ethanol-naive hamsters and rats, alcohol dehydrogenase activities and ethanol metabolic rates of isolated hepatocytes in vitro and blood ethanol elimination rates in vivo show consistent large interspecific differences corresponding to the species' differences in ethanol intake and preference. The data suggest a limiting role of ethanol metabolism in the regulation of maximized free-selection ethanol intake by rodents, and provide an explanation for the absence of continuously elevated blood ethanol levels and alcohol withdrawal syndrome in hamsters during periods of comparatively high daily ethanol intake.


Resolution of two biochemically and pharmacologically distinct benzodiazepine receptors. Brain-specific binding sites have been isolated on synaptosomal membrane fragments which recognize pharmacologically active benzodiazepines (BDZ's) and triazolopyridazines (TPZ's). While early evidence indicated the existence of a single homogeneous class of BDZ binding sites, more recent biological and pharmacological studies support the notion of BDZ receptor multiplicity. We now propose that two biochemically distinct BDZ receptors exist in brain which are responsible for the mediation of different pharmacological activities. Type I BDZ receptors display a high affinity for both BDZ's and TPZ's, are not coupled to GABA receptors or to chloride ionophores, and are the sites which mediate anxiolytic actions. Type II BDZ receptors display a high affinity for BDZ's, display a low affinity for TPZ's, are coupled to GABA receptors and/or chloride ionophores, and are the sites which mediate pharmacological effects other than anxiolytic activity.


Pharmacokinetics of furosemide in patients with congestive heart failure. Since patients vary in their response to furosemide, a pharmacokinetic study of this drug was undertaken in 7 patients with severe congestive heart failure. The extent of oral availability, determined by the ratio of areas under the oral to intravenous plasma concentration-time curve, averaged 61%, but varied widely from patient to patient, from 34 to 80%. Absorption of the drug was often delayed, with a lag time before appearance in the plasma averaging 28 +/- (SD) 15 min. The volume of distribution of furosemide (averaging 114 ml/kg) was not diminished in the presence of congestive failure; likewise, drug clearance and elimination half-lives are similar to values reported in normal subjects. Urinary flow rates 1--2 h following dosing were significantly less after oral than intravenous dosing, but flow rates over 4, 8 or 24 h after dosing were similar for both routes of administration.


Monoamine oxidase inhibition by substituted benzylideneamino guanidines and their CNS activities. The present study reports the synthesis and characterization of eight new substituted benzylideneamino guanidines. All compounds inhibited the monoamine oxidase (MAO) activity of rat brain mitochondria in vitro. The I50 values were determined and were found to be in the range of 10(-4) to 10(-5) mol/l. Preincubation, dialysis and kinetic studies carried out with isolated brain mitochondria by conventional Dixon plot revealed reversible and noncompetitive type of MAO inhibition. These compounds were also screened for anticonvulsant and antidepressant activities. In the present series of compounds only one compound -- 1-amino-3-(4-chloromethylbenzylidene-amino)guanidine hydroiodide -- was found to afford 20% protection against pentetrazol-induced seizures in mice. 1-Amino-3-(3,4-dichlorobenzylideneamino)guanidine hydroiodide which produced maximum inhibition of MAO activity, also produced reversal of reserpine-induced sedation and miosis into excitation and mydriasis in mice.