Chloramphenicol pharmacokinetics in hospitalized patients. The apparent body clearance of chloramphenicol was investigated in 21 hospitalized adult patients on 27 occasions. Apparent body clearance was found to be significantly lower (1.99 +/- 1.49 ml/min per kg) in patients with total serum bilirubin concentrations of >1.5 mg/100 ml than in patients with serum bilirubin concentrations of </=1.5 mg/100 ml (3.57 +/- 1.72 ml/min per kg; P < 0.001). Serum protein binding of chloramphenicol was lower in cirrhotic patients (42.2 +/- 6.8% bound) than in normal adults (53.1 +/- 5.2% bound; P < 0.001). Low binding of chloramphenicol was also found in the serum of premature neonates (32.4 +/- 8.2% bound; P < 0.001). Reduced binding in neonates implies the need for a lower therapeutic range of total chloramphenicol concentration (3.5 to 13.9 mug/ml) compared with the usual adult range (5 to 20 mug/ml). Finally, three case reports are presented which demonstrate marked abnormalities and intrasubject variation in chloramphenicol clearance.


Relationship between serum and saliva chloramphenicol concentrations. The relationship between serum and saliva chloramphenicol (CAP) concentrations was evaluated in 27 paired specimens collected from 20 hospitalized patients during therapy with the drug. A significant (R = 0.80, P < 0.001) but variable relationship was found to exist. Serum protein binding of CAP was also evaluated (43.7 +/- 5.7% bound; N = 24). Differences in CAP binding did not apparently account for a significant portion of the variability in the observed saliva/serum CAP concentration ratios. The degree of variation observed indicated that saliva CAP concentrations could not be relied upon for the prediction of serum CAP concentrations.


Evaluation of human monocyte function in vitro. Mononuclear phagocytes play a role in immunologic phenomena as well as in defence reactions of the organism. It is therefore important that clinicians have possibilities of evaluating their functions. A combination of simple and reproducible methods was set up to make this evaluation possible. The tests described in this paper are performed using peripheral blood monocytes and include: (1) phagocytic capacity of Staphylococcus aureus and 51Cr-labelled sheep erythrocytes, (2) bactericidal capacity with S. aureus and (3) handling of 51Cr-labelled sheep erythrocytes after 18 h in culture. They explore both the afferent limb of the immune response and the capacity to remove and destroy foreign material. The results obtained from 45 normal subjects are reported.


Treatment of recurrent herpes simplex labialis with levamisole. Because deficient immune responses may play a contributory role in recurrent herpes simplex labialis, an immunomodulating agent, levamisole, has been advocated for therapy. Forty-two patients with a high frequency of recurrent herpes simplex labialis were followed for a mean of 7.8 months (range 4 to 12) and treated for 3 days at the onset of each episode of herpes with one of three different doses of levamisole or placebo in a randomized, double-blind study. Statistical analysis revealed that as the dosage increased, so did the frequency of recurrences (P = 0.007). Conversely, duration of the lesions and lesion pain decreased with increasing dosage (P = 0.05 and 0.03). These results indicate that levamisole is not an appropriate drug for the management of recurrent herpes simplex labialis. The paradoxical response to an immunomodulator (increased frequency, decreased severity) provides evidence that altered host responses may contribute to the pathogenesis of the disease.


Effect of cephalothin on measurement of creatinine concentration. Cephalothin, an antibiotic implicated as nephrotoxic, falsely elevates the creatinine concentration as determined by the Jaffé reaction in vitro. We studied this effect in vivo and demonstrated variable degrees of interference in determinations of plasma and urinary creatinine concentrations by two automated methods. Clinicians should be aware of this phenomenon in patients receiving cephalothin, both when monitoring renal function and when assessing patient reliability in the collection of timed urine specimens.


Pharmacokinetics of Bay k 4999, a new broad-spectrum penicillin. The pharmacokinetics of the broad-spectrum penicillin Bay k 4999 were studied in six healthy male volunteers. A 2-g dose was given by the intravenous route. The tissue penetration of the antibiotic was studied by both dermabrasion and blister techniques. A total of 26.4% of the drug was recovered in the urine in 24 h, 79% of this being excreted in the first 2 h. The elimination half-life in serum was 1.3 h. The dermabrasion levels of Bay k 4999 were generally similar to those in serum, but after 1 h the blister fluid levels of antibiotic were greater than those in serum. Different drug levels obtained by blister and dermabrasion techniques may be due to the different composition of the two fluids.


Pharmacokinetics and safety of cefamandole in newborn infants. Cefamandole, a new parenteral cephalosporin antibiotic, was administered to 23 newborn infants with pustular skin infection due to Staphylococcus aureus for an average duration of 7.5 days. All the patients improved clinically. Elevation of serum glutamic oxaloacetic transaminase and eosinophilia were observed in nine infants each transiently during treatment. There were no abnormalities of renal functions and Coombs' test results remained negative. The levels of cefamandole in serum after either intravenous or intramuscular administration were higher and the mean life was longer than those previously reported in older infants, children, and adults.


Phosphonopeptides as antibacterial agents: rationale, chemistry, and structure-activity relationships. Peptide mimetics with C-terminal residues simulating natural amino acids have been designed as inhibitors of bacterial cell wall biosynthesis. The phosphonopeptide series consisting of various l and d residues of natural amino acids combined with 1-aminoalkyl (and aryl-alkyl-) phosphonic acid residues had the most interesting antibacterial properties when the C-terminal residue was l-1-aminoethylphosphonic acid. The in vitro antibacterial activities of representative phosphonodi- to phosphonohexapeptides were investigated. The antibacterial action of the active compounds has been explained in terms of transport into the bacterial cell and intracellular release of the alanine mimetic, which interferes with the biosynthesis of the peptidoglycan of the bacterial cell wall.


Phosphonopeptides as antibacterial agents: mechanism of action of alaphosphin. The novel antibacterial peptide mimetic alaphosphin (l-alanyl-l-1-aminoethylphosphonic acid) selectively inhibited peptidoglycan biosynthesis in both gram-negative and gram-positive bacteria. It induced accumulation of uridine diphosphate-N-acetyl-muramyl-tripeptide in gram-positive organisms and significantly reduced the intracellular pool levels of d-alanine. Alaphosphin was actively transported into bacterial cells by stereospecific peptide permeases and was subsequently hydrolyzed by intracellular aminopeptidases to yield l-1-aminoethylphosphonic acid. This alanine mimetic rapidly accumulated inside susceptible cells to yield a concentration which was 100- to 1,000-fold in excess of that of the precursor peptide in the surrounding medium. In the case of susceptible gram-negative organisms, it was shown that 1-aminoethylphosphonic acid was incorporated into a metabolite which was tentatively identified as uridine diphosphate-N-acetylmuramyl-aminoethylphosphonate. The primary intracellular target site of 1-aminoethylphosphonic acid was alanine racemase (EC 5.1.1.1), which was reversibly and competitively inhibited in the gram-negative organisms Escherichia coli and Pseudomonas aeruginosa and irreversibly inhibited in a time-dependent manner in the gram-positive organisms Staphylococcus aureus and Streptococcus faecalis. A secondary target site could be uridine diphosphate-N-acetylmuramyl-l-alanine synthetase [EC 6.3.2.8(b)]. The mechanism of action of alaphosphin may be regarded as involving at least three stages: (i) active transport by peptide permeases; (ii) intracellular peptidase cleavage; and (iii) action of l-1-aminoethylphosphonate on alanine racemase.


Effect of fatty acyl group and sterol composition on sensitivity of lecithin liposomes to imidazole antimycotics. The specific affinity for membrane lipids and the membrane selectivity of three imidazole derivatives, clotrimazole, miconazole, and econazole, were studied using various types of liposomes with respect to the lecithin fatty acyl group composition and the liposome content and composition of sterol as membrane models. The sensitivity of liposomes to these drugs was primarily dependent upon the lecithin fatty acyl group composition. With sterol-free liposome systems, each imidazole induced maximum release of trapped glucose as a marker from the unsaturated dioleoyl lecithin liposomes, minimum release from the saturated dipalmitoyl lecithin liposomes, and intermediate release from egg lecithin liposomes. The sensitivity of the dipalmitoyl lecithin liposomes to any imidazole drug was not influenced by the incorporation of cholesterol or ergosterol. On the other hand, clotrimazole-induced permeability changes of liposomes prepared from unsaturated dioleoyl lecithin or egg lecithin were greatly enhanced by the incorporation of ergosterol, whereas they were suppressed by cholesterol incorporation. The sensitivity of liposomes prepared from these unsaturated lecithins to miconazole and econazole was also augmented by ergosterol incorporation, although it was scarcely altered by cholesterol incorporation. Negatively charged liposomes were more sensitive to the three imidazole drugs than positively charged liposomes.


Comparative penetration of various cephalosporins into inflammatory exudate. A rabbit sterile peritonitis model was used to determine the relative penetration of four cephalosporin antibiotics into exudate fluid. Male New Zealand white rabbits were given 120 ml of sterile saline intraperitoneally, and peritonitis developed over the following 8 h, with exudate fluid containing a mean of 17,188 granulocytes per mm(3) at 8 h. Each antibiotic was administered intramuscularly at a dose of 30 mg/kg 3 h after peritonitis was initiated, and serum and peritoneal concentrations were measured 0.5, 1, 2, and 4 h later. Cefamandole gave the highest mean peak serum level (26.8 mug/ml), and cephalothin, cephacetrile, and cephradine all gave peak serum levels between 13 and 15 mug/ml. When peak peritoneal exudate concentration was expressed as a percentage of peak serum concentration, cephradine developed 28.5% of the peak serum level, cephacetrile 27.7%, cephalothin 14.0%, and cefamandole 12.5%. These percentages of exudate penetration were inversely proportional to the degree of serum protein binding: cephradine 26.6%, cephacetrile 36.3%, cephalothin 50%, and cefamandole 88%.


Antifolate activity of isoaminopterin in HeLa cells. The antifolate activity and the transport characteristics of isoaminopterin (IA) in HeLa cells were studied and compared with those of methotrexate (MTX). Both IA and MTX inhibited the incorporation of [2-(14)C]deoxyuridine into HeLa cell DNA by 50% at a concentration of 0.09 muM by 8 h postaddition of the compounds. Unlike MTX, the inhibition of DNA synthesis by IA was time dependent and reached a maximum at 24 h. IA-induced inhibition was due to interference with folate metabolism, since it could be completely reversed with N(5)-formyl-tetrahydrofolate. Competitive transport experiments between IA and either radiolabeled MTX or radiolabeled folate showed that IA preferentially uses the reduced folate/MTX transport system. IA inhibited MTX uptake by 50% at a concentration of 6.8 muM but had a negligible effect on folate transport.


Effectiveness of nafcillin, methicillin, and cephalothin in experimental Staphylococcus aureus endocarditis. Nafcillin, methicillin, and cephalothin (40 mg/kg every 6 h) were all effective in reducing the number of Staphylococcus aureus in vegetations in rabbits with endocarditis. Nafcillin and methicillin reduced the number of S. aureus at a significantly faster rate than did cephalothin. Nafcillin and methicillin also reduced titers of the S. aureus more rapidly than did cephalothin in vitro, both in broth and in rabbit serum.


Assay of flucytosine (5-fluorocytosine) in human plasma by high-pressure liquid chromatography. The use of the antifungal agent flucytosine has been associated with dose-related hepatotoxicity and bone marrow depression, and measurement of plasma concentrations is useful in determining dosage schedules. The present study describes a rapid, simple, and sensitive high-pressure liquid chromatographic analysis of plasma flucytosine which may be completed within 30 min of receipt of a plasma sample. Sample preparation is minimal and merely involves precipitation of plasma protein before injection onto a reverse-phase column. The method is accurate and reproducible and yields results comparable to or perhaps slightly superior to those obtained by conventional microbiological assay. The value of the procedure for routine use is enhanced by the freedom from interference by a large range of medications administered concurrently with flucytosine.


Biosynthesis of kitasamycin (leucomycin) by leucine analog-resistant mutants of Streptomyces kitasatoensis. The biosynthesis of kitasamycin in Streptomyces kitasatoensis B-896 was profoundly influenced by the addition of precursors to complex and defined media: l-valine and l-leucine directed biosynthesis towards the pairs A(4)/A(5) (R(2) = butyryl) and A(1)/A(3) (R(2) = isovaleryl), respectively, and total kitasamycin titers were doubled and quadrupled, respectively. S. kitasatoensis B-896 was very resistant (>20 mg/ml) to alpha-aminobutyric acid, an analog of l-valine, but very susceptible to l-leucine analogs 5', 5', 5'-trifluoroleucine and 4-azaleucine (5 to 10 mug/ml). The inhibition by 4-azaleucine could be reversed by l-leucine, but by none of the other amino acids of the pyruvate family or the amino acids of the aspartate pathway. 4-Azaleucine-resistant mutants were isolated which in the absence of any precursors overproduced l-leucine and a kitasamycin complex mainly consisting of the pair A(1)/A(3). These 4-azaleucine-resistant mutants are presumed to be regulatory mutants in which alpha-isopropylmalate synthase, the first enzyme of the l-leucine pathway, has become either derepressed or desensitized to leucine feedback inhibition. l-Leucine-regulatory mutants have economic value: in the absence of expensive precursors, they produce a kitasamycin complex in which the most potent pair A(1)/A(3) is dominant and the least active components are absent.


Ceftizoxime (FK 749), a new parenteral cephalosporin: in vitro and in vivo antibacterial activities. FK 749 is a new parenteral cephalosporin derivative which is more active against various gram-negative bacilli, including the opportunistic pathogens such as Enterobacter, Citrobacter species, and Serratia marcescens, than cephalosporins and cephamycins such as cefotiam, cefamandole, cefuroxime, cefotaxime, and cefmetazole. FK 749 was especially active against gram-negative organisms resistant to these related antibiotics. FK 749 was more potent in bactericidal activity than the other antibiotics, and the activity was clearly enhanced in the presence of 90% defibrinated rabbit blood. The therapeutic effect of subcutaneously injected FK 749 in mice infected with various gram-negative bacilli was far superior to that of cefotiam, cefamandole, cefuroxime, and cefmetazole and was almost the same as that of cefmetazole in mice infected with Staphylococcus aureus and that of ticarcillin in mice infected with Pseudomonas aeruginosa. FK 749 has, in general, nearly the same in vitro and in vivo antibacterial activities as cefotaxime. The former had more potent bactericidal activity in the presence of the blood than the latter and showed more excellent therapeutic effect than cefotaxime against infections caused by large inoculum sizes.


Inactivation of cephalosporins by Bacteroides. We investigated the relationship between beta-lactamases of Bacteroides fragilis organisms and their resistance to cephalosporins. Timed killing curves were used to study the in vitro activity of three cephalosporins, cephalothin, cefazolin, and cefamandole, and a semisynthetic cephamycin, cefoxitin. Measurements of residual antibiotic concentrations in culture supernatants were made, and they were compared with the beta-lactamase activity of the microorganism. A cephalosporin-susceptible strain was rapidly killed by cephalothin, cefazolin, cefamandole, and cefoxitin. Four cephalosporin-resistant strains were not killed by cephalothin, cefazolin, or cefamandole but were killed by cefoxitin. An inoculum effect was noted with cefazolin and not with cefoxitin. The resistant strains of Bacteroides inactivated the three cephalosporins, but there was no inactivation of cefoxitin. A constitutive beta-lactamase was detected in all the isolates of the B. fragilis group that were resistant to the cephalosporins. There was no distinction of the species based on isoelectric focusing of the enzyme. These data suggest that inactivation by beta-lactamase may be the mechanism for resistance of B. fragilis to the cephalosporins and would explain the enhanced in vitro activity of cefoxitin.


Amantadine aerosol in humans.

Amantadine aerosol in humans. Seven well volunteers and three patients with a naturally occurring influenza A/USSR/77 (H1N1)-like infection were given amantadine by small-particle aerosol with a Collison generator modified for this purpose. Inhalation periods for the volunteers were increased on consecutive weekends from 15 min to 1 h, 4 h, 9 h, and 2 consecutive days of 6 h each. The particle size was 1.2-micrometer mass median diameter, and the concentration of inhaled aerosol ranged from 47 to 75 microgram/liter. Estimates of retained doses in 9 h were 74 to 149 mg. About two-thirds of the dose was recovered in the urine. Pulmonary function studies did not vary significantly from base-line values and were within a normal range for five of seven volunteers. Two volunteers with a moderate reduction in mid-maximal flow before exposure had a total of three episodes of coughing and wheezing associated with moderate reductions in mid-maximal flow values. These episodes cleared spontaneously or improved promptly after isoproterenol therapy. The patients with influenza tolerated the treatment well and recovered promptly.


Rapid assay for determination of trimethoprim and sulfamethoxazole levels in serum by spectrofluorometry. A rapid spectrofluorometric method for determining the levels of both trimethoprim and sulfamethoxazole from the same specimen of serum is described. The method involves stepwise extraction of the specimen first with chloroform at an alkaline pH (pH 9.0) for trimethoprim followed by n-butyl chloride at an acidic pH (pH 2.0) for sulfamethoxazole. To quantitate trimethoprim, the chloroform layer was subjected to fluorometry by exciting the specimen at 295 nm and measuring the relative intensity at 330 nm. To determine sulfamethoxazole levels, the n-butyl chloride layer was subjected to fluorometry by exciting the specimen at 285 nm and measuring the relative intensity at 330 nm. Relative intensities were linear (r greater than 0.99) over the concentration ranges of 0.5 to 40 microgram/ml for trimethoprim and 1 to 400 microgram/ml for sulfamethoxazole. Values obtained by this spectrofluorometric procedure were in excellent agreement with those obtained by a conventional fluorometric assay for trimethoprim and a colorimetric assay for sulfamethoxazole. Elevated levels of endogenous metabolic products and numerous other drugs, including a number of antimicrobial agents, did not interfere with the method. Although salicylates interfere with the determination of sulfamethoxazole, an appropriate correction can be made. This method can also be used to determine the drug levels in cerebrospinal fluid.


Pharmacokinetics of cefamandole and ampicillin in experimental meningitis. The penetration of cefamandole and ampicillin into the cerebrospinal fluid of rabbits with and without pneumococcal meningitis was evaluated. In normal animals, a mean maximum concentration of 0.22 +/- 0.13 microgram of cefamandole per ml was measured in the spinal fluid after a dose of 150 mg/kg given intramuscularly; with 25 and 50 mg/kg doses, no antibiotic was detected in the cerebrospinal fluid. With ampicillin, in intramuscular doses of 200 and 300 mg/kg, the mean maximum concentrations encountered in the cerebrospinal fluid were 1.59 +/- 0.4 and 1.47 +/- 0.44 microgram/ml, respectively. Penetration of cefamandole, and to a lesser extent ampicillin, was increased after 24 h of experimental meningitis. With cefamandole, the concentration of drug in the cerebrospinal fluid exceeded the usual inhibitory concentration for Haemophilus influenzae only with the 150 mg/kg dose. After 48 h of meningitis, there was a trend toward higher levels of antibiotic in the cerebrospinal fluid, but the difference between animals infected 24 versus 48 h was not statistically significant. In animals with meningitis, serum concentrations after 150 mg of cefamandole per kg and both ampicillin doses studied were 32 to 38% lower than the serum levels achieved in normal rabbits after identical doses of antibiotic.


Biosynthetic pathway leading to gentamicin C2b. Incubation of Micromonospora purpurea SC 1210 (NRRL 5467) with L-[methyl-14C]methionine yielded [methyl-14C]gentamicin A and methyl-14C-labeled antibiotic JI-20A in a molar radioactivity ratio of 9:2. We did not isolate methyl-14C-labeled gentamicin X2, which was expected as an intermediate based on the biosynthetic pathways proposed by others. Addition of methyl-14C-labeled antibiotic JI-20A to M. purpurea SC 1124 (NRRL 8102) yielded [methyl-14C]-gentamicin C1a and [methyl-14C]gentamicin C2b in variable molar radioactivity ratios. These data do not support the biosynthetic pathway leading to gentamicin C2b proposed by Testa and Tilley.


Pharmacokinetics of cefotaxime.

Pharmacokinetics of cefotaxime. The pharmacokinetics of cefotaxime after intramuscular injection and intravenous infusion were determined. The mean peak serum level after the 500-mg intramuscular dose was 11.7 micrograms/ml, and it was 20.5 micrograms/ml after a 1,000-mg dose. The serum half-life was 1.2 and 1.3 h, respectively for the two doses. The apparent fractional volumes of distribution of 32 and 37 liters were not significantly different for the two doses, and the fractional serum clearance was approximately 315 ml/min per 1.73 m2 for both doses. The mean peak serum level after 1,000 mg administered by intravenous infusion over 30 min was 41.1 micrograms/ml. The half-life was 1.13 h, apparent volume of distribution was 33 liters, serum clearance 341 ml/min per 1.73 m2, and renal clearance was 130 ml/min per 1.73 m2. The pharmacology of cefotaxime is similar to the pharmacology of other cephalosporin antibiotics, but the low inhibitory levels which it has against gram-positive and gram-negative bacteria suggest that lower dosage regimens should be possible.


Clinical evaluation of mezlocillin.

Clinical evaluation of mezlocillin. The safety and efficacy of intravenous mezlocillin were determined in 25 patients with aerobic, anaerobic, and mixed infections. Included were pleuropulmonary, urinary tract, skin, and soft-tissue infections, osteomyelitis, and abdominal and breast abscess. Nineteen patients (76%) were cured without recurrence as determined by clinical and bacteriological parameters. In three, the infection recurred (12%); two patients failed (8%), and in one, it was indeterminate (4%). No serious adverse effects were noted except for severe thrombophlebitis in three (12%) patients. Our preliminary data suggest that mezlocillin is a safe (except for thrombophlebitis) and effective antibiotic in the treatment of aerobic anaerobic, and mixed infections.


Disk diffusion testing of susceptibility of Mycobacterium fortuitum and Mycobacterium chelonei to antibacterial agents. Although recent studies have suggested that some antibacterial agents have good activity against the rapidly growing mycobacteria Mycobacterium fortuitum and Mycobacterium chelonei, an easily applicable method for susceptibility testing of clinical isolates is not yet available. We evaluated a disk diffusion method with Mueller-Hinton agar and 48-h readings with 59 strains of M. fortuitum and 11 strains of M. chelonei and compared the results to agar dilution susceptibilities for nine antimicrobial agents. All isolates were susceptible to 16 micrograms of amikacin or kanamycin per ml with minimum zone diameters of 14 and 18 mm, respectively. Amikacin inhibited 100% of isolates of M. fortuitum at 2 micrograms/ml, whereas 10 of 11 (91%) of M. chelonei strains had minimum inhibitory concentrations of 4.0 micrograms/ml or greater. Doxycycline and minocycline had almost identical activities, inhibiting 44% of strains at 4.0 micrograms/ml, and both allowed easy differentiation between susceptible and resistant strains by disk diffusion. Although most isolates of M. chelonei grew better on 7H10 agar, this media gave two- to eight-fold higher minimum inhibitory concentrations than were obtained with Mueller-Hinton agar. Disk diffusion susceptibility testing appears to be a simple and reliable means of predicting susceptibility results for M. fortuitum and most isolates of M. chelonei by the agar dilution method.


Clinical pharmacokinetics and safety of high doses of ceforanide (BL-S786R) and cefazolin. The pharmacokinetics and safety of ceforanide and cefazolin were compared in normal subjects after 30-min intravenous infusions of 2-, 3-, and 4-g single doses and 4-g twice-daily doses for 10 days. No significant differences were observed in plasma-renal pharmacokinetic parameters between single and multiple doses of ceforanide. Half-life (t((1/2)), 2.8 h), plasma clearance (Cl(p), 48 ml/min per 1.73 m(2)), and renal clearance (Cl(0-12h) (r), 47 ml/min per 1.73 m(2); tubular secretion, 44%, and glomerular filtration, 56%) did not change with increased dose or on multiple dosing. No significant change was observed in t((1/2)) (1.9 h), area under the plasma concentration-time curve, Cl(r) (60 ml/min per 1.73 m(2); tubular secretion, 80%, and glomerular filtration, 20%), or Cl(p) (75 ml/min per 1.73 m(2)) for 4-g single doses compared with twice-daily administration of cefazolin. A small increase in cefazolin clearance was observed when plasma concentrations were greater than 100 mug/ml, when the single dose was increased from 2 to 4 g; this was a result of the decrease in percentage of plasma protein binding and increased renal clearance due to increased glomerular filtration. The increase in renal clearance resulted in a lack of linear proportionality of the plasma area under the curve with dose over a range of 2 to 4 for both cephalosporins, although this effect was much less marked with ceforanide. Both compounds were well tolerated both locally and systemically. There was no evidence of any change in renal function based on clearances of drug, p-aminohippuric acid, or creatinine, and other standard clinical parameters.


Evaluation of the Bactec serum gentamicin assay. A radiometric assay for gentamicin was compared with an established radioimmunoassay protocol. The coefficients of variation for within-run, day-to-day, and overall runs were consistently higher for the radiometric method as compared with the radioimmunoassay. The coefficient of correlation for 84 patient sera tested by the two methods for gentamicin levels was 0.82. Though less precise, the radiometric method was felt to be an acceptable means of determining gentamicin levels in laboratories where the radioimmunoassay is unavailable.


Induction and prevention of experimental arteriovenous fistula infections. Arteriovenous fistulae (AVF) between the femoral vessels were prepared in 20 rabbits to determine if local endovascular infections could be induced and if antibiotic prophylaxis could prevent infection. Twenty-four hours after bacterial challenge with 10(6) Staphylococcus aureus all 20 AVF were culture positive, whereas 19 of the 20 contralateral, unoperated femoral vessels were sterile. Two rabbits with AVF, followed for 30 days after receiving staphylocci, had intermittently positive blood cultures and had positive cultures of the AVF and heart valves at autopsy. Two groups of ten rabbits with AVF received either prophylactic oxacillin or vancomycin 0.5 h before bacterial challenge. Only 2 of 10 animals receiving oxacillin and 1 of 10 receiving vancomycin had positive AVF cultures at 24 h, a significant reduction in the incidence of endovascular infection compared with that in controls (P less than 0.001 by Fisher's exact test). This model, which reliably results in infection, can be used to study the pathophysiology, prevention, and treatment of AVF infections.


LY127935, a new beta-lactam antibiotic, versus Proteus, Klebsiella, Serratia, and Pseudomonas. One hundred eight clinical isolates of Proteus, Klebsiella, Serratia, and Pseudomonas spp. were tested in vitro against LY127935, cefamandole, cefoxitin, ticarcillin, carbenicillin, gentamicin, tobramycin, and amikacin by broth microdilution. The activities of LY127935 were greater than or equal to those of the other antimicrobial agents against Proteus vulgaris, Klebsiella pneumoniae, and Serratia marcescens. Inhibitions were greatest, however, for ticarcillin and carbenicillin versus Proteus morganii and gentamicin versus Pseudomonas aeruginosa.


Amantadine aerosols in normal volunteers: pharmacology and safety testing. The acceptability and pharmacology of intermittent aerosol administration of amantadine was assessed in healthy volunteers. Amantadine solutions of 2.5, 1.5, or 1.0 g/100 ml were used for 12 30-min, twice-daily aerosol treatments in 15 subjects. Overall, the aerosol treatments were well tolerated. During and up to 1 h after aerosol exposures, nasal irritation, rhinorrhea, dysgeusia, or a combination of symptoms was experienced by some of the subjects receiving either of the two higher amantadine concentrations. Aerosol treatments were associated with small but statistically significant decreases in maximal expiratory flow rates. One hour after aerosol treatments with the 1.0-g/100 ml solution, amantadine levels in nasal wash samples (mean, 30.3 micrograms/ml; range, 1.7 to 108 micrograms/ml) greatly exceeded blood and nasal wash levels reported after oral administration. Amantadine can be administered safely by small-particle aerosol to humans in doses that could be expected to exert an antiviral effect in influenza A virus infections.


Mezlocillin pharmacokinetics in patients with normal and impaired renal functions. The pharmacokinetics of intravenous bolus doses of 1.0 g of mezlocillin were studied in 13 persons with normal and reduced renal functions. In renal failure a moderate increase was observed for the terminal serum half-life(t1/2 beta). This changed from a mean of 1.1 h at a glomerular filtration rate of 100 ml/min to 1.6 h at 10 ml/min. The difference was not statistically significant. The excretion of unchanged drug in urine during 24 h was reduced from a mean of 59.4% (range, 52 to 77) in subjects with glomerular filtration rate above 50 ml/min to 10% (range, 7.9 to 12.1) in two patients with glomerular filtration rate of 10 to 20 ml/min. The volume of distribution during the beta-phase, Vd,b, was 14% of the body weight. Much of the antibiotic was metabolized, and this proportion increased upon reduction in renal function.


Variability in the susceptibility pattern of Bacteroides fragilis in four Detroit area hospitals. Recent clinical isolates of Bacteroides fragilis selected at random from four Detroit area hospitals were collected over a 3-month period, and the minimum inhibitory concentrations were determined within several days. The levels of antimicrobial agents used in this survey breached the concentration attainable in the patient's serum. The antimicrobial susceptibility patterns of these isolates to five antimicrobial agents suggest that there is a 20% variation in the resistance to clindamycin and also up to 20% variation among the other four antibiotics in the four area hospitals. The changing susceptibility pattern of B. fragilis to antibiotic resistance suggests that minimum inhibitory concentrations should be determined for all isolates from serious clinical infections.


Susceptibility of Naegleria fowleri to delta 9-tetrahydrocannabinol. Growth of the pathogenic amoeboflagellate Naegleria fowleri is inhibited by delta 9-tetrahydrocannabinol (delta 9-THC). delta 9-THC is amoebostatic at 5 to 50 micrograms/ml. delta 9-THC prevents enflagellation and encystment, but does not impair amoeboid movement. Calf serum at 10 and 20% (vol/vol) reduces the antiamoeba activity of delta 9-THC. Only 1-methoxy delta 8-tetrahydrocannabinol, of 17 cannabinoids tested, failed to inhibit growth of N. fowleri. Antinaeglerial activity was not markedly altered by opening the pyran ring, by converting the cyclohexyl ring to an aromatic ring, or by reversing the hydroxyl and pentyl groups on the benzene ring. delta 9-THC prevented the cytopathic effect of N. fowleri on African green monkey (Vero) cells and human epithelioma (HEp-2) cells in culture. delta 9-THC afforded modest protection to mice infected with N. fowleri.


Relative potencies of different anti-herpes agents in the topical treatment of cutaneous herpes simplex virus infection of athymic nude mice. Thirteen established anti-herpes compounds have been directly compared in a single assay system for their effects on the development of herpetic skin lesions, and mortality associated therewith, in athymic nude (nu/nu) mice inoculated intracutaneously with herpes simplex virus type 1 (KOS). When applied topically (at 1% in a water-soluble ointment), phosphonoacetic acid, E-5-(2-bromovinyl)-2'-deoxyuridine, acycloguanosine, and trisodium phosphonoformate emerged as the most active agents.


Hydrolysis of cefamandole nafate in dialysis patients. The hydrolysis of cefamandole nafate was examined in vivo in five dialysis patients and five subjects with normal renal function. The plasma half-life of cefamandole was prolonged in the patients with renal failure compared with normal subjects (18.3 +/- 4.5 [standard deviation] versus 10.35 +/- 1.4 min, P less than 0.01). The pharmacokinetics of cefamandole nafate best fit two-compartment, open-model kinetics. We conclude that patients with severe renal failure are capable of hydrolyzing cefamandole nafate to cefamandole and formate at a rate sufficiently rapid so as not to allow an accumulation of cefamandole nafate. The difference in half-life may be related to urinary excretion of cefamandole nafate in normal individuals.


In vitro activity of three tetracycline antibiotics against Acinetobacter calcoaceticus subsp. anitratus. The in vitro activity of three tetracycline antibiotics against 127 strains of Acinetobacter calcoaceticus (Herella vaginicola) were compared. Almost all strains were susceptible to minocycline and doxycycline, whereas most strains were resistant to tetracycline.


Cyclopiazonic acid production by Penicillium camemberti Thom and natural occurrence of this mycotoxin in cheese. Every Penicillium camemberti strain freshly isolated from 20 commercial cheese brands produced cyclopiazonic acid in two culture media at 25, 13, and 4 degrees C; the toxin yield was greatly dependent on the strain and environmental parameters (medium, temperature, and incubation time). The toxigenic ability appeared as a log-normal distribution. This mycotoxin was found in the crust (0.05 to 0.1 microgram/g in three samples, 0.1 to 0.2 microgram/g in five samples, and 0.4, 1, and 1.5 microgram/g in three other samples) but not in the inner part. When its acute toxicity is considered, doses eventually ingested by consumers are very low (lower than 4 microgram). Means for prevention are discussed. A highly toxigenic strength and rate appear to be necessary features leading to natural contamination in cheeses. The distribution of toxigenic ability makes possible without delay a choice of weakly toxic strains.


Blue light inhibits mycotoxin production and increases total lipids and pigmentation in Alternaria alternata. Light inhibits production of the mycotoxins alternariol and alternariol monomethyl ether, both polyketids produced by Alternaria alternata. This effect seems to be general because seven isolates of A. alternata with different alternariol- and alternariol monomethyl ether-producing abilities all respond to continuous light with reduced levels of alternariol and alternariol monomethyl ether when the mycotoxins were calculated on a microgram-per-milligram (dry weight) basis. Blue light inhibited alternariol and alternariol monomethyl ether production 69 and 77%, respectively. Red light gave no reduction of toxin levels. Total lipids were increased 25% when mycelium was grown in blue light as compared with red light or darkness. In white or blue light, but not in red light or darkness, a red-brown pigment accumulated by the mycelium.


Determination of endotoxins in sugar with the Limulus test. The Limulus amebocyte lysate test has been used for determination of pyrogens in sugar of different qualities. All the samples of domestic white sugar and beet raw sugar produced in Sweden during 1976 had a very low content of endotoxins, less than 10 ng/g of sugar. Imported cane raw sugar was, however, highly contaminated. The highest value obtained corresponds to about 100 mg of Escherichia coli endotoxin per g of raw sugar. Such crude sugar cannot, even after refining, be used for medical purposes. Instead, Swedish beet sugar is used as the raw material for production of invert sugar solutions for parenteral administration. The amount of endotoxin in this sugar is less than 1 ng/g.


Influence of pork consumption on human infection with Mycobacterium avian-intracellulare. The hypothesis that eating pork from animals infected with organisms of the Mycobacterium avium-intracellular complex is a significant cause of human mycobacteriosis was examined by skin testing students with purified protein derivative from M. intracellulare to determine their sensitivity to M. avium-intracellulare. No significant differences in sensitivity could be demonstrated between those individuals who had never eaten pork and those who ate pork routinely. It was concluded that sensitivity to purified protein derivative from M. intracellulare in this population did not involve eating pork.


[Development of cutaneous innervation in the chick: ultrastructural and quantitative analysis (author's transl)]. In the chick, at the thoracic level, the dorsal branches of spinal nerves form at 4 days of incubation (stage 25) and reach the skin between 5 1/2 and 6 days (stages 28-29). At 6 days, the growing nervous peripheral processes ("axons") form large bundles (200-1,000 fibers). At 10 days, young Schwann cells divide the bundles into groups of axons. The perineurium and endoneurium differentiate between 10 and 14 days (but epineurium is formed after hatching). At 14 days of incubation, the adult pattern of cutaneous innervation is established. At this same stage, myelogenesis begins but develops mainly after hatching : 1% of the axons is myelinated at 16 days of incubation, 4% at hatching, 40% in 6-week old chickens and 60% in adults. Thus, less than 10% of myelinated axons of the adult are already myelinated at hatching. Two modes of myelogenesis were observed: 1) early myelination, starting in the embryo around axons measuring about 1 micrometer in diameter: 2) delayed myelination, occurring in the older chickens after an increase in axon diameter. These observations suggest that there is, in the development of chick skin innervation, a critical stage (14-15 days of incubation) apparently corresponding to the stabilization of cutaneous nerve supply.


The nucleus of the basal optic root in the pigeon: an electron microscope study. The ultrastructure of the nucleus of the basal optic root in an avian species (Columba livia) was investigated. The ectomamillary nucleus (EMN) in which terminates the basal optic tract reveals three types of neurons: 1) small round neurons bearing a scanty cytoplasm in organelles, 2) medium-sized neurons, spindle-shaped with a dense population of organelles and 3) large multipolar neurons with well developed perikaryal elements. Some of these neurons have their inner plasma-membrane which fuse to make junctional zones alternating between attachment plates and gap junctions. The analysis of the neuropil displays four types of vesicle-containing profiles (VCP), Type I VCP, identified as optic terminals, are numerous (49%), contain round vesicles (500-550 A) and establish Gray type I contacts principally with dendrites. They also participate in serial and triadic arrangements. Type II VCP have lighter hyaloplasm and are less numerous (6,7%). Rounded vesicles (450-500 A) with a clear content synapse also with Gray type I active zones on dendrites. Some of these profiles have the peculiarity of both a chemical and electrical transmission known as mixed synapses. Type III VCP are larger and contain a mixed population of rounded and flattened vesicles which synapse according to Gray type II. Type IV VCP are characterized by a light hyaloplasm where the microtubules are a predominant organelle. Their active zones are also of Gray type II.


[Testosterone and dihydrotestosterone radioimmunoassays in Müllerian ducts of control and testosterone propionate injected quail embryos (author's transl)]. Testosterone (T) and dihydrotestosterone (DHT) have been quantitated by means of radioimmunoassay in Müllerian ducts (CM) from control quail embryos (6 to 8-day male and 6 to 15-day female) and from female embryos injected with 50 nanograms of testosterone propionate (PT) on the 8th day. These hormones are demonstrable in undifferentiated CM from 6-day control embryos. In control males although a highly significant decrease of the CM weight occurs during the CM involution, the detected amounts of androgens remain at a constant level. In control females, the right CM shows a slight increase of the androgen content during the rudimentation, i.e. from day 8 on; in the left CM: the highest steroid levels are found on the 6th day; while the CM differentiate, concentrations decrease and become similar to those found in neutral tissues. Given testosterone propionate on day 8 female embryos: right CM: both testosterone and DHT levels highly increase until day 14; the CM of treated embryos contain 8 times as much steroid as control; left CM: testosterone and DHT increase after injection until day 9,5; they slightly decrease between days 9,5 and 12, and then remain constant on day 14. Differences in concentrations are highly significant between CM of control and of PT - injected embryos. It seems that the binding sites of these androgens are more numerous during the involution and that bound testosterone or DHT could take a part in CM regression in male embryos and right CM rudimentation in female embryos.


[Ultrastructural morphogenesis and functional differentiation of the dogfish thyroid follicle (author's transl)]. From the 20 mm stage, in the cells of the dogfish embryo thyroid, some Golgi vesicles get the ability to trap iodine. At subsequent stages, electrondense intracytoplasmic cavities with microvilli are observed in the Golgi field; their membranes also trap iodine. These cavities increase in volume, draw toward the cellular periphery and export their contents in an intercellular space previously limited by tight junctions. The same events occur in several adjacent cells, which constitute the first follicular lumen. The last stage of follicular individualization is basement membrane formation. Arguments are given which support the hypothesis of the Golgi origin of intracytoplasmic cavities with microvilli. Iodine organification just as thyroid hormones synthesis and secretion occur at 25 mm stage, when cells are not grouped in follicle. It is concluded that cells containing intracytoplasmic cavities with microvilli are fully functional units.


Rectal administration of diazepam in solution in the acute treatment of convulsions in infants and children. In a prospective study 44 children, aged 6 months to 5 years, admitted to hospital with febrile convulsions or epilepsy, were treated with diazepam in solution administered rectally during 59 generalised attacks. Rectal administration of diazepam was effective in the acute treatment of convulsions in 80% of cases. In 10% the treatment failed, whereas diazepam administered intravenously had prompt effect; another 10% of the convulsions wer resistant to diazepam, irrespective of the route of administration. The therapeutic effect was significantly correlated with the duration of convulsions before treatment started. Early treatment (convulsions less than or equal to 15 minutes) had effect in 96%, and late treatment (convulsions greater than 15 minutes) in 57% of cases. A total of 317 children admitted with febrile convulsions were treated prophylactically with diazepam administered rectally whenever the temperature was greater than or equal to 38.5 degrees C. No case of significant respiratory depression or other serious side effects was observed. The rapid and reliable anticonvulsant effect of diazepam given rectally and the very few side effects makes this treatment a valuable alternative to IV administration in childhood.


Water loss from the skin of term and preterm babies. Water loss from the skin of term and preterm babies, nursed naked in incubators under neutral thermal conditions, was measured by a method based on estimating the water vapour pressure gradient close to the skin surface. 199 sets of measurements were made on 78 babies whose gestational ages ranged from 26 to 41 weeks, during the first 4 weeks of life. Babies of 34 to 41 weeks' gestation had high water losses in the first 4 hours after birth, which then fell to low levels averaging 6 g/m2 per hour. Babies of 30 to 33 weeks' gestation had high water losses in the first week which then fell to levels similar to those of mature babies. Babies less than 30 weeks' gestation had strikingly high losses, averaging 32 g/m2 per hour in the first 4 days of life. At 2 weeks, levels were still higher than those of mature babies. Light-for-dates babies had skin water losses appropriate for their gestations. The high water losses in extremely preterm babies are probably transepidermal and the result of a thin, poorly keratinised stratum corneum. Water loss from the palms and soles was high in term babies and although low in preterm babies it rose steadily in the first 4 weeks of life. This is thought to represent the onset of emotional sweating. In terms of actual heat and water lost, skin water loss is relatively unimportant in term babies nursed naked under neutral thermal conditions. However, in babies less than 30 weeks' gestation, weighing less than 1 kg, skin water loss makes a major contribution to overall water balance. Furthermore, evaporative heat loss from the skin may exceed resting heat production. It is suggested that reduction of skin water loss in these babies may increase their chances of survival and their rates of growth.


Role of viruses in febrile convulsions.

Role of viruses in febrile convulsions. A disseminated viral illness was demonstrated by isolating a virus from the CSF, blood or urine in 27% of 73 children who were admitted to hospital after a first febrile convulsion. However, a viral aetiology could be implicated for 86% of the children after combining results of tissue culture, electron microscopy, mouse inoculation, complement fixation tests, and interferon assay. Parallel bacterial cultures showed a possible pathogen in 29% of children, but in only 4% was the pathogen isolated from the CSF, blood, or urine. No correlation was found between the nature of the pathogen (or evidence of its dissemination) and the severity of the convulsion, degree of fever, CSF protein, CSF white cells, or the WBC. The results suggest that a febrile convulsion could be a response to invasion of the blood stream or central nervous system by a micro-organism which is usually a virus. Invasion may be of such brief duration that successful isolation of the virus from the blood, CSF, or urine in not more commonly achieved.


Family resemblances of height, weight, and body fatness. In a study of 256 families, among whom were twins, midparent-adult son correlations for height, weight, and combined skinfold measurements were 0.67, 0.47, and 0.23 respectively. The corresponding midparent-adult daughter correlations were 0.63, 0.42, and 0.24. Midparent-growing offspring correlations were highest for height, less for weight, and insignificant for combined skinfold measurements. These data and the resemblances found between twins and siblings led us to conclude that there is a significant genetic contribution to the variation of height and weight, but that body fatness appears largely to be determined by environmental factors.


Vomiting after pyloromyotomy for infantile hypertrophic pyloric stenosis. An analysis of the factors which may predispose towards postoperative vomiting after pyloromyotomy for hypertrophic pyloric stenosis was carried out in 72 infants at this hospital. 26 (36%) infants experienced moderate to severe postoperative vomiting of sufficient intensity to cause the postoperative feeding regimen to be modified or interrupted. Only two parameters were found to be of statistical significance. These were the state of the oesophageal mucous membrane on endoscopical examination and the presence of haematemesis in the preoperative period. No evidence for a gastric mucosal lesion could be found. An advanced oesophageal mucosal lesion was found in 30% of patients, and this was the source of the haemorrhage in all 11 in whom haematemesis was noted postoperatively. The stay in hospital was prolonged (8 days) in those infants with troublesome vomiting postoperatively compared with those with lesser problems (3 days).


Chronic pericardial constriction with effusion in childhood. Five cases of children with nontuberculosis pericardial constriction with effusion are reported. The disease is not as rare as has been thought, and the aetiology in these cases was probably a previous virus infection. A previous diagnosis of hepatitis, nephrotic syndrome, or protein-losing enteropathy had been made and the correct diagnosis was delayed for months or even years. Pericardiectomy produced immediate relief from symptoms in 2 patients but in 2 others there was evidence of poor myocardial function postoperatively.


Accuracy of pre- and postnatal assessment of gestational age. The gestational age at delivery in a group of 20 neonates was estimated prenatally from measurements of the biparietal diameter made by ultrasound during pregnancy, and postnatally from the newborn infant's neurological and external physical criteria or maturity using the method of Dubowitz et al. (1970). These two assessments were compared with the gestational age at delivery calculated from the date of the last menstrual period (LMP) in mothers certain of their dates. Gestational age derived from the ultrasound data correlated well with that derived from the mother's LMP, and much better than did gestational age derived from the postnatal scoring system.


Breast milk and breast feeding in very low birthweight infants. The feeding of 17 babies weighing less than 1500 g was examined retrospectively. 12 babies started breast feeding at a mean weight of 1324 g and 10 of them were fully breast fed by a mean weight of 1600 g. Their weight gains were comparable with bottle-fed babies receiving expressed breast milk. Practical aspects of breast feeding were considered to be: a knowledgeable maternal and nursing attitude, close mother and baby contact, early expression of breast milk, and early suckling. The increased incidence of breast feeding by mothers of both low birthweight and term babies ensures regular supplies of fresh breast milk. Therefore, sterilisation or storage of breast milk there is unnecessary.


Should we follow up children with Henoch-Schönlein syndrome? We reviewed 31 children who had had Henoch-Schönlein syndrome without nephritis at least 5 years before. None was found to have progressive renal disease and these patients do not require the same long-term follow-up as those with clinical renal involvement.


The effect of antifungal agents on pancreatic and gastric secretion in rats. This study was designed to investigate the effects of griseofulvin, 5-fluorocytosine (5-FC), and amphotericin B on pancreatic and gastric secretion after the administration of a single large dose, or repeated small doses for 3 weeks, in male albino rats. The exocrine functions of the main digestive glands were only slightly affected by griseofulvin and were not affected by 5-FC. In contrast, a single large dose of amphotericin B caused a marked inhibition of exocrine functions of the main digestive glands. The rats treated with 5-FC lost body weight markedly during 2 weeks of administration.


Study of erythrocyte delta-aminolevulinic acid dehydratase activity in porphyria cutanea tarda. The erythrocyte delta-aminolevulinic acid dehydratase activity was studied in porphyria cutanea tarda patients, compared to healthy controls, in an attempt to resolve the contradictions in the relevant literature data. In an in vitro experimental system, a study was also made of how the erythrocyte delta-aminolevulinic acid dehydratase activity varies on the action of the activators -SH and Zn2+. It was found that, compared to the healthy controls, the erythrocyte delta-aminolevulinic acid dehydratase activity of porphyria cutanea tarda patients is significantly decreased, but it is restored to the original activity level on the addition of -SH and Zn2+. Since there is a general -SH requirement of delta-aminolevulinic acid dehydratase, the most obvious explanation for the decrease of the activity in the case of the patients is the shift of the natural redox systems of the erythrocytes, and the decrease of the reduced glutathione/oxidized glutathione ratio.


Is the excretion of sebum regulated?

Is the excretion of sebum regulated? The kinetics of sebum excretion on the forehead of volunteers were measured over a period of at least 7 h. The transmission data obtained by the ground glass method were transformed into weight (sebum/cm2). The excretion time function can be described by the equation: w = A . (1 - B . e -C.t). This nonlinear function is typical for modes of excretion in the biological field. Regulation of sebum excretion is probable. Objections against such regulation by feedback were discussed.


Soluble and insoluble collagen and elastin in the rat hair cycle. Soluble and insoluble collagen and elastin were chemically evaluated in the dorsal skin of rats during the third hair cycle. Both fractions of collagen remain unchanged during anagen, while they increase considerably in the first days of telogen to drop afterwards. Elastin content gradually increases throughout anagen and falls in telogen. The authors suggest that the increasing amounts of collagen in the first part of telogen may be responsbile for the progressive block in the downwards movements of previously growing follicles into the dermis. Elastin data could be the result of a mechanical readjustment of skin to the expansion provoked by growing follicles.


The phospholipid pattern in the involved and the uninvolved psoriatic epidermis. The phospholipid pattern of the involved and the uninvolved epidermis from 48 psoriatic patients and of the normal epidermis from 23 healthy controls was determined by thin-layer chromatography. A higher amount of total phospholipids was found only in the involved psoriatic epidermis, whereas significant alterations in the phospholipid pattern were observed in the psoriatic lesion and in the lesion-free epidermis. Namely, the decrease of phosphatidylserine and the increase of phosphatidylinositol were identically present in both the involved and the uninvolved psoriatic epidermis. It seems likely that these alterations in the phospholipid pattern in psoriasis may be related to subclinical alterations of the epidermis in this disease.


Comparative histological studies of regional lymph nodes of 201 melanoma patients. (Microscopic features in relation to individual age, site, and metastatic spread). Since May 1968 a total of 2.108 regional lymph nodes (l.n.) dissected from 201 melanoma patients (86 axillary, 107 groin, and 8 neck) have become available for study. The purpose was to detect histological differences between the l.n. of 134 patients lacking and those of 67 patients exhibiting l.n. metastases, histologically verified in 104 of 706 nodes. The main finding is a more than six-fold increase in number and an eleven-fold increase in total area (evaluated by a microscope micrometer) of germinal centers in the lymph follicles of patients with, as compared to those without, l.n. metastases (P less than or equal to 0.05). Paracortical areas were found to be diminished in 56.7% of cases with metastatic spread. Accumulations of plasma cells were mainly seen in the nodes of elderly patients (48.4%) and of those exhibiting regional metastases (47.8%). The observation of numerous and dilated blood vessels in the interfollicular regions noticeably corresponded to the occurrence of lymphatic metastases (P less than or equal to 0.01), suggesting a "tumor angiogenic factor". A negative correlation with metastatic involvement was found as to histiocytosis of marginal sinuses and with respect to the observed fibrinoid hyalinosis of pulp vessels (P less than or equal to 0.01). The marked hyperplasia of lymph node B-lymphocyte regions as opposed to diminished T-lymphocyte areas prevailing in cases with metastatic melanoma is in accord with findings of humoral immunologic blocking activity and impaired T-cell response in advanced malignant melanoma.


Animal experiments investigations on the action of topical corticoids on the normal guinea pig skin. By means of the test procedure described, the action of topical corticosteroids on the untreated skin of guinea pigs may be exactly assessed and quantified. Of significance is the statistically verifiable observation that the steroid-induced epidermal hypoplasia is completely reversible after the withdrawal of the corticosteroid preparation. Moreover, the onset of a reactive epidermal spreading occurs, which exceeds the initial value to a small extent.


LDH isozymes in epidermis and skin carcinoma in hamsters. Lactate dehydrogeanse (LDH) isozymes in the epidermis and in transplantable epidermal carcinoma from Syrian hamsters were studied by polyacrilamide electrophoresis. A 5-band pattern with occasional loss of 1--2 anode fractions in certain tumor samples is typical. In the epidermis of 14 to 15-day-old foetuses, in the regenerating epidermis, and in tumor cells cathode of M subunits predominate, in particular the fifth fraction in the last two cases. In the epidermis from new born, 25-day-old (growing stage of the hairs) and 60 to 80-day-old (resting stage of the hairs) animals a relative increase of the H subunits is striking. These results reveal a foetal-like pattern of LDH isozymes in regenerating and tumorous epidermis, as has been observed in other isozymes and in other tissues.


Kaposi's sarcoma: venous capillary haemangioblastoma. A histochemical and ultrastructural study. Histochemical and ultrastructural studies in two patients with Kaposi's sarcoma revealed that spindle cells have the pattern of venous capillary endothelium.


The quantitative distribution of percutaneously applied caffeine in the human skin. The distribution coefficient of caffeine (water/n-Octanol) and the estimation of caffeine in urine after local application indicate to a high permeation rate of caffeine through the skin. This could be confirmed by using different vehicles in vivo and in vitro. 14C labeled caffeine penetrates rapidly the epidermis and corium. The maximum of absorption is reached at 100 min after local application in vivo. In vitro by absence of the transport possibilities of blood and lymph vessels, the concentration at 1,000 min after local application is 450 X higher than in vivo. Therefore, after 1,000 min in vivo the concentration of caffeine in the different skin layers is very low.


[Seminal vesicular cysts associated with renal agenesis, ipsilateral ureter and hemitrigone. Report of a case]. A case is presented of seminal vesicular cyst associated with kidney agenesia, ipsilateral ureter and hemitrigon; this is the 17th case presented in the world literature reviewed. A study is made of all the cases published and the authors recommend deferento-vesiculography as the best means of diagnosis and total excision of the cyst as the most effective treatment.


[Monotopic coralliform calculus and simultaneous contralateral lithiasis]. A study is made of 15 patients with monotopic coralliform stones, suffering from simultaneous, contralateral, renoureteral lithiasis. There are certain special features in these patients which we consider to be sufficient to distinguish them as a separate group amond cases of lithiasis in general and coralliform stones in particular. The high percentage of septic complications observed in these patients demand special treatment within the field of urinary lithiasis.


[Ultrastructural study of the basal cells of the prostatic gland]. The ultrastructure of basal cell in canine and bovine prostate is studied. In the canine prostate only one type of basal cell could be specified, however in the bovine prostate type I and type II basal cells could be described. Canine basal cell and bovine type I have similar characteristic and never reach the alveolar lumen whereas bovine type II basal cell is columnar in shape, has numberous mitochondria in the apical pole and ocassionally reaches the alveolar lumen. Type II is a clearly defined intermediate cell between type I and secretory elements. All types of basal cells in both species have ultrastructural features which correspond to those of undifferentiated stem cells.


[Parathyroid adenoma and renal lithiasis. Report of a case]. A case is presented of nephrolithiasis in a patient with no other symptoms than the urological ones and in which considerable hypercalcemia led to a study being carried out on his phospho-calcium metabolism and the diagnosis reached was primary hyperparathyroidism caused by a parathyroid adenoma. Surgical treatment was performed on the lithiasis and the adenoma as a result of which the symptoms completely disappeared and the biochemical readings returned to normal.


[Removal of calculi located in the navicular cavity by means of a Zeiss loop]. The authors present a case of a patient with recurring stones suffering from disectasia of the vesical neck. Two of the stones situated in the navicular cavity were easily removed by means of Zeiss' loop without any complications and therefore the authors think that this simple method may be used when attempts to remove the stone by means of forceps or other techniques have failed and before proceeding to an external meatotomy which in always more traumatic and this system may even be applied as the initial and best method in these patients. After having made a review of the bibliography at their disposal, the authors have found no descriptions of any case in which this method was used, as in the cases of ureteral lithiasis.


The renin-angiotensin system and the antihypertensive effect of atenolol in man. The effects on arterial pressure of saralasin and short-term (seven days) administration of the cardioselective beta-blocker atenolol were compared in 21 patients with various forms of hypertension. During saralasin administration mean arterial pressure (MAP) decreased by 8.8 +/- 2.1 per cent. Atenolol administration was associated with a MAP fall of 23.6 +/- 2.9 per cent. The change in MAP induced by atenolol was higher than that produced by saralasin (P less than 0.001) and no significant correlation (r = 0.40, P greater than 0.05) between their respective effects was found. These results suggest that the antihypertensive action of atenolol is not related to pre-treatment activity of the renin-angiotensin system as estimated by the hypotensive effect of saralasin. Other mechanisms should be sought in order to explain the effectiveness of this betablocker in hypertensive patients.


Effect of intracerebroventricular administration of dopamine on urinary function in goats. Dopamine (DA) and several blocking substances were administered into the 3rd ventricle of conscious goats to study the effects on water and electrolyte excretion. Intracerebroventricular infusion of DA in hydrated goats induced a significant dose-dependent inhibition of both the urine flow rate and the renal free water clearance. A biphasic response pattern of urinary electrolyte excretion, consisting of an initial fall, followed by an increase in the excretion rate was observed. The antidiuretic effects induced by DA could be prevented by prior administration of haloperidol, pimozide or phentolamine into the 3rd ventricle. Atropine, hexamethonium or propranolol were ineffective. It seems that excitatory responses of periventricular neurons resulting in vasopressin release in the goat may be mediated by both alpha-adrenoceptors and excitatory DA receptors. Furthermore, single injection of haloperidol or pimozide into the 3rd ventricle of goats with a normal water balance induced both a significant diuretic response and an increase in renal free water clearance. The data suggest that endogenous DA in the hypothalamus could be responsible for vasopressin release.


Negative dromotropic effect of diazepam on the AV node of dog heart in situ. Effect of diazepam on the AV nodal conductivity was studied using a direct perfusion technique of the canine AV node artery in situ. As compared to acetylcholine which induced a rapid onset of third degree AV block with prompt recovery, diazepam injected into the AV node artery in doses from 300 micrograms to 3 mg elicited first to third degree AV blocks of longer duration following gradual prolongation of PR interval. The response was not affected by bilateral vagotomy and sympathectomy. Pretreatment of the AV node with hexamethonium or atropine also failed to modify the diazepam-induced AV blocks. Thus, diazepam seemed to suppress conductivity of the AV node by a direct action. The AV nodal tachycardia induced by infusion of norepinephrine was readily antagonized by a single injection of diazepam, but norepinephrine failed to reverse the AV block induced by diazepam infusion.


DBM mice as a pharmacological model of maturity onset diabetes. Studies with metformin. Hyperglycemic obese and hyperinsulinemic mice of DBM strain develop a diabetic syndrome which can be compared to human maturity onset diabetes. In this study 6 to 49 weeks old female mice were used. Hyperglycemia and concomitant obesity were observed at 9 weeks. Plasma immunoreactive insulin (IRI) was maximum at 15--20 weeks, then decreased progressively with broad individual variations. Metformin, administered at 200 mg/kg per os, ineffective dosage in normal mice, showed a strong hypoglycemic effect in younger mice (11--18 weeks) with a plasma IRI decrease and no blood lactate and liver glycogen alteration. Plasma metformin concentration curve showed an exponential elimination fitted to a one compartment model with a plasma half-life of 2.7 hours. Metformin-induced hypoglycemia was lower in older mice (23--29 weeks) and corroborated their lower initial plasma IRI. All these results are in accordance with those reported in man and show that DBM mice provide a suitable model for a better understanding of antidiabetic drugs effects.


Variation of postjunctional natures along the length of the rat vas deferens as a cause of regional difference in the sensitivity to norepinephrine. Sensitivity to norepinephrine (expressed as pD2) was different between the prostatic and the epididymal half of the rat vas deferens. The epididymal half was more sensitive than the prostatic half; difference in pD2 was 0.826 +/- 0.095 (mean +/- S.E., 13 experiments). Between the two halves, nearly the same difference in pD2, 0.745 +/- 0.125 (6 experiments), was observed in the responses to methoxamine, which is not incorporated into the adrenergic nerve terminals. In the two halves, 3 x 10(-6) M phentolamine produced a smiliar decrease in pD2 of norepinephrine: 1.485 +/- 0.056 and 1.282 +/- 0.080 in the prostatic and epididymal half, respectively (6 experiments). Only in the prostatic half, 10(-5) M propranolol produced a slight increase in pD2 of norepinephrine, 0.344 +/- 0.133 (6 experiments). Sensitivity to K+ was also different between the two halves. These results suggest that the difference in the sensitivity to norepinephrine between the prostatic and the epididymal half is due to postjunctional natures varying along the length of the rat vas deferens.


An alteration in sensitivity to cholinergic agents on guinea-pig ilea and atria after repeated administration of an organophosphate and an antagonism by a carbamate. The effect of 4-methylthiophenyl dipropylphosphate (propaphos, organophosphorus insecticide) and 2-sec-butylphenyl-N-methylcarbamate (BPMC, carbamate insecticide) on the sensitivity to the effects of acetylcholine (ACh), carbachol (CCH) and nicotine was investigated on guinea-pig isolated ilea and atria. The response of these tissues to ACh was significantly enhanced in the presence of propaphos (3.3 x 10(-7) M) or BPMC (4.5 x 10(-6) M), while that to CCH was unaffected. The repeated administration of propaphos (5 mg/kg/day, p.o.) for 7 days had no effect on the contractile responses of guinea-pig ilea to potassium chloride. The responses of ilea and atria to ACh and nicotine were markedly increased by the administration of propaphos, and the values of ED50 and ED80 for their responses were significantly decreased. On the other hand, the response to CCH was decreased as was demonstrated by a significant increase in these values. Pretreatment with BPMC (25 mg/kg/day p.o., 7 days) significantly reduced the alteration in the responsiveness of the tissues to ACh, CCH and nicotine produced by the propaphos administration. The activity of cholinesterase (ChE) declined by 50--70% in blood and tissues from propaphos-treated animals, and its inhibition was significnatly reduced by the pretreatment with PBMC to 30--40%. These results indicate that changes in synaptic ChE activity, as reflected by the changes in ChE activity of blood and tissues, may be responsible for the alteration in sensitivity of ilea and atria to cholinergic agents produced by the repeated administration of propaphos and for the antagonism by BPMC.


The effect of atropine on acetylcholine-induced depressor responses in adult domestic fowl. In pentobarbital-anaesthetized, spontaneously breathing adult chickens, intravenous administration of acetylcholine, histamine and 5-HT produced a dose-related fall in carotid arterial pressure, rise in central venous pressure and highly variable effects on heart rate. Atropine at low doses (0.1 to 0.2 mg/kg) selectively antagnoized depressor-responses to acetylchline. The blockade persisted for 20 to 30 min. At medium doses (0.5 to 2 mg/kg) atropine strongly antagonized acetylcholine for 50 to 110 min, and also partially antagonized responses to 5-HT and histamine. At higher doses (6 mg/kg), atropine-induced cholinergic blockade persisted for 280 min. It also nonselectively and significantly blocked responses to histamine and 5-HT. Therefore, it is concluded that the effectiveness and persistence of cholinergic blockade in chickens depends upon the dose of atropine used. It seems to rule out the opinion that high doses of atropine are required for cholinergic blockade in chickens.


Excitatory effects of ergot alkaloids and their derivatives on the excitability of an identifiable giant neuron of the African giant snail (Achatina fulica Férussac). The effects of various ergot alkalids and related substances on the neuronal excitability were examined using a spontaneously firing neuron (PON, periodically oscillating neuron) identified in the suboesophageal ganglia of the African giant snail (Achatina fulica Férussac). Of the substances examined, ergometrine and methylergometrine had a marked excitatory effect on the neuron (their critical concentration by bath application: 5 x 10(-6) kg/l). D-lysergic acid (the critical concentration: 3 x 10(-5) kg/l), D-lysergic acid amide (3 x 10(-5), D-lysergic acid 3-hydroxypiperidinamide (3 x 10(-5) and D-lysergic acid 4-hydroxypiperidinamide (10(-4) had also an excitatory effect which was weaker than that of the two alkaloids mentioned above. Agroclavine and elymoclavine had a very slight excitatory effect in some cases. The other substances examined, for example, lysergine, 9, 10-dihydro-D-lysergic acid, 9, 10-dihydro-D-lysergic acid amide, nicergoline, metergoline, methysergide, ergotamine, bromocriptine, lergotrile etc., had no effect on the neuron at a high concentration (10(-4) kg/l). When local (microdrop) application of ergometrine and methylergometrine in the physiological state was performed, the depolarizing shift of the PON membrane and exaggeration of the membrane potential oscillations were observed. In the Na+-free (replaced with Li+) state, local application of the two effective alkaloids produced a marked frequency increase of tonic spike discharges with depolarization of the neuronal membrane.


Central hypotensive action of alpha-methyldopa: an iontophoretic study in the cat. The central site and mechanism of alpha-methyldopa-induced hypotension were examined with the microiontophoretic technique which permits the topical application of drugs to single neurons of the bulbar vasomotor center in decerebrate cats. Cardiovascular neurons were identified by their response to an increase in arterial blood pressure following a small intravenous pressor dose of norepinephrine. Microiontophoretic application of alpha-methyldopa was found to have an inhibitory effect on the spontaneous firing rate of cardiovascular neurons. Furthermore, alpha-methyldopa was found to completely block the excitatory response of cardiovascular neurons to iontophoretically applied norepinephrine. Non-cardiovascular neurons, recorded from the same brain area, were unaffected by iontophoretic application of alpha-methyldopa at the same or greater doses that produced responses in cardiovascular neurons. While peripheral factors cannot be entirely ruled out, the present findings are contrary to the postulate that alpha-methyldopa lowers arterial blood pressure by stimulating central alpha-adrenoceptors, causing a reduction of sympathetic outflow to the periphery. Rather, the data indicate that alpha-methyldopa or its metabolites act directly on central alpha-adrenoceptors in a manner which results in reduced activity.


Effect of crowding on amphetamine-induced disaggregation of brain polyribosomes. DL-amphetamine's actions on brain polyribosomes were studied in crowded and uncrowded mice. The administration of 20 mg/kg DL-amphetamine induced disaggregation of brain polyribosomes in both crowded and uncrowded mice 30 min post drug administration. However, the magnitude of polysome dissociation was observed to be greater in crowded animals than in uncrowded ones. In studying the dose-response relationship there appears to be a relationship between drug dose and polysome disaggregation in both groups of animals, although the effects were always greater in crowded mice. The magnitude of polysome dissociation appears to parallel both in the intensity of central nervous system stimulation, and degree of crowding. Haloperidol was able to block the increased locomotor activity due to drug dose and crowding at 1 mg/kg, and significatnly suppress disaggregation of brain polysomes in crowded animals. A possible role of the effects of crowding on the central nervous system in the presence of amphetamine as it relates to polysome dissociation has been presented.


Potentiation of dopamine-induced contractions of the rat vas deferens by low concentrations of its antagonists. Pimozide (5--10 ng/ml), haloperidol (0.5--5 ng/ml) and yohimbine (2--5 ng/ml) selectively potentiated dopamine-induced and methoxamine-induced contractions of the rat vas deferens. The concentration-response curves were significantly shifted to the left and the maximal responses were significantly increased. Responses of the vas deferens to noradrenaline were not so influenced. Concentrations of the antagonists in excess of 50 ng/ml produced concentrations-related parallel shifts of dopamine concentration-response curve to the right. These antagonists behaved in a similar manner towards methoxamine, a directly acting sympathomimetic amine which has a low affinity for neuronal uptake, suggesting that the mechanism of this potentiation may be independent of neuronal uptake inhibition.


Effect of vasopressin on vascular smooth muscle from cold- and warm-acclimated rabbits. Contractile properties of helical auricular arterial strips from warm- and cold-acclimated (WA and CA) rabbits were studied to determine whether vascular smooth muscle shows a cold-induced alteration in response to vasopressen (Vp), similar to the effect seen with catecholamines. The CA response was decreased at all Vp concentrations tested and the decreases were significant at doses between 0.4--100.0 mUnits Vp/ml. Results are discussed in relation to the altered renal tubular response to Vp which has previously been reported to occur in cold-acclimated animals.


Comparison of the in vitro effects of prazosin, nifedipine, and dihydralazine in isolated human mesenteric and crural vessels. The inhibitory and relaxing effects of prazosin, nifedipine, and dihydralazine on contractions induced by noradrenaline (NA), or potassium (K+), were investigated in isolated human crural and mesenteric arteries and veins. Vascular ring preparations were suspended in organ baths and isometric tension was recorded. Prazosin was the most potent of the drugs in counteracting NA-induced contractions in all types of vessels except crural veins, in which the effect of nifedipine was the more pronounced. On K+-induced contractions prazosin was completely devoid of relaxing or inhibitory effects, whereas nifedipine was by far the most effective of the investigated drugs. Nifedipine had a more marked effect in venous than in arterial preparations from the peripheral circulation, but no such difference was seen in mesenteric vessels. Dihydralazine was found to have a very low potency in all types of vessels, and no difference between the effects on arterial and venous preparations was found. The results suggest that the in vitro effects of prazosin, nifedpine, and dihydralazine are different from those observed in vivo. Thus, the balance between the effects on arteries and veins in vitro was quite different from those reported in clinical studies on the three vasodilatators. The results give no support to the hypothesis of an unspecific vasodilatating effect of prazosin. The clinical usefulness of dihydralazine cannot be explained from the poor in vitro effects of the unmetabolized drug.


The relative contribution of pre- and neonatal ethanol administration to changes in mice behavior. Parent C57BL/10Bg and DBA/1Bg inbred mice were fed 10% ethanol in their drinking solution during mating and pregnancy and/or early post parturition period. The susceptibility to audiogenic seizures and the open field behavior of their offspring were tested at age 29--33 days. Our previous experiments have indicated that continuous exposure to ethanol during pre- and neonatal periods enhanced the susceptibility to audiogenic seizures in both strains and decreased open field activity only in the strain C57. The present study, while confirming previous findings, assessed the relative contribution of the prenatal and the neonatal administration of ethanol to the behavioral changes. Among C57 mice, the neonatal period was most important for the induction of changes in seizures, but prenatal exposure which alone had no effect, enhanced the outcome of neonatal administration. Among DBA mice either period induced seizures, but the contribution of the neonatal period was the most significant. Early ethanol administration affected open field behavior only in C57 mice. There was an additive interaction between the two periods (latency), no effect by any period alone but together they produced a full effect (ambulation), or that either period alone was sufficent to produce a full effect (defecation).


Attenuation of ethanol intake by 5-hydroxytryptamine uptake blockade in laboratory rats. I. Involvement of brain 5-hydroxytryptamine in the mediation of the positive reinforcing properties of ethanol. The role of 5-hydroxytryptamine (5-HT) uptake blockade in the mediation of the positive reinforcing peroperties of ethanol in male wistar rats was investigated. It was demonstrated that treatment with zimelidine (H102/09) a 5-HT uptake inhibitor, specifically attenuated ethanol consumption. In an attempt to extinguish the ethanol drinking response, ethanol preferring animals in a second experiment, were provided with ethanol as the only source of fluid in combination with zimelidine treatment. Animals treated in such a manner subsequently reduced their ethanol consumption when presented with a free-choice between ethanol and water. These results were attributed to an increased availability of central 5-HT, suggesting that central 5-HT mechanisms may in some way be involved in the mediation of the positive reinforcing properties of ethanol.


Attenuation of ethanol intake by 5-hydroxytryptamine uptake blockade in laboratory rats: II. Possible interaction with brain norepinephrine. This experiment was undertaken to examine whether the attenuation of ethanol consumption following treatment with zimelidine (H102/09) could be due to an invasion of surplus serotonin into norepinephrine neurons. In an attempt to prevent this proposed invasion by serotonin, ethanol preferring animals were pre-treated with desmethylimipramine (DMI), a norepinephrine reuptake inhibitor, prior to treatment with zimelidine. The results demonstrated that those animals treated in such a manner consumed significantly more ethanol than those animals treated with zimelidine alone. Based on these results it is suggested that the observed attenuation of ethanol consumption following zimelidine treatment, could be partially due to a serotonin-induced functional depletion of norepinephrine.


Role of dopaminergic and GABA-ergic interactions in seizure susceptibility. The seizure susceptibility to electroshock in mice is decreased by apomorphine and piribedil; the effect of the two dopaminergic agonists is reduced by haloperidol. The seizure susceptibility is not influenced, increased or reduced by the different doses of haloperidol. The seizure threshold is elevated by amino-oxyacetic acid; its effect is reduced by picrotoxin, haloperidol and reserpine, and not influenced by apomorphine. The interaction between dopaminergic and GABA-ergic systems has been established; however, its characteristics are different from the well known interaction in the nigrostriatal region.


Effect of anticonvulsants on experimental cortical epilepsy induced by tungstic acid gel in rats. Effects of anticonvulsants were electroencephalographically (EEG) and behaviorally examined on experimental epilepsy induced by cortical application of tungstic acid gel in rats. The animals showed spike, spike and wave complex, and secondary generalized seizure (SGS) with high frequency components on EEG within 1 hr after the gel application. Such SGS often recurred with a constant interictal period over 2--3 hr. Behaviorally, head twitching, forelimb clonus, and violent convulsion with kangaroo posture occurred. Diphenylhydantoin Na (10--40 mg/kg, i.v.), phenobarbital Na (20, 40 mg/kg), and diazepam (0.5--2.0 mg/kg) shortened the duration of SGS and prolonged the interictal period. Trimethadione and dipropylacetate Na (160 mg/kg) shortened the duration but did not change the interictal period. In addition, diazepam, dipropylacetate, and taurine suppressed the interictal spikes. These drugs, except taurine, depressed kangaroo posture and changed it to weaker convulsive behavior. It is suggested that this epileptic model is suitable for predicting the effectiveness of a potential anticonvulsant in the epilepsies associated with the cortex and for elucidating its mode of action.


Analgesic action of cyclazocine: blocking nociceptive responses induced by intra-arterial bradykinin-injection and tooth pulp stimulation. Cyclazocine, a benzomorphan derivative, suppressed the flexor reflex of the hind-limb of intact rats induced by intra-arterial injection of bradykinin, a potent pain-producing substance, in a dose-dependent manner, without remarkable influence on motor performance. This suppressive effect was antagonized by naloxone, a specific opiate antagonist. The ED50 values for cyclazocine were 0.054 mg/kg s.c., 5.6 mg/kg p.o., and 1/27, 1/11 of those for pentazocine by the respective routes of administration. In spinal rats, however, the inhibitory effect of cyclazocine and pentazocine on the bradykinin-induced flexor reflex was markedly reduced. Furthermore, cyclazocine as well as pentazocine selectively inhibited the EEG arousal response induced by electrical stimulation of the tooth pulp, which elicits the single sensation of pain. These results indicate that cyclazocine in doses used had a specific analgesic action, and that the main site of action probably is in the supra-spinal structures, such as seen in the case of pentazocine.


Negative and positive chronotropic effects of procaine on the canine SA node in situ. Effect of procaine on the SA node of the dog heart was studied in situ using a selective perfusion technique of the SA node artery. Procaine in doses from 100 mug to 1 mg produced a sinus depression followed by a prolonged phase of the increased heart rate. The depression became more prominent with increasing the dose. The threshold dose for inducing the tachycardiac response was lower, but the sinus acceleration was not proportional to the dose. The initial depression was not affected by atropine, whereas the occurrence of the stimulatory phase was inhibited by prior administration of propranolol or tetrodotoxin into the SA node artery or in the reserpine-treated dogs. The results indicate that the biphasic response is induced by a direct negative chronotropic action of procaine on the SA node and by an indirect effect mediated by an interaction with the postganglionic adrenergic nerves.


Involvement of the cholinergic system in the precocious puberty caused by estradiol in immature female rats. Subcutaneous administration of 0.05 mug estradiol benzoate to sexually immature female rats caused precocious ovulation and a decreased acetylcholine content in the hypothalamus and the amygdala. A higher dose of estradiol benzoate, 2 mug/rat, did not stimulate ovulation but did cause a further decrease in the acetylcholine content in the hypothalamus and the amygdala. The steady state levels of acetylcholine in the hippocampus and the striatum were unchanged with either dose of estradiol. These observations suggest a relationship between the occurrence of ovulation and the decrease in the steady state level of acetylcholine in the hypothalamus and amygdala in sexually immature rats after estradiol treatment.


Biosynthesis of aryl carotenoids: inhibitor studies of chlorobactene biosynthesis in Chlorobium limicola f. thiosulfatophilum. The biosynthesis of the aryl carotenoid, chlorobactene, was examined in the green sulfur bacterium, Chlorobium limicola f. thiosulfatophilum. Nicotine, which was used to inhibit carotenoid cyclization, caused the accumulation of the acyclic carotenoid, lycopene. Cells reincubated in fresh medium, after removal of nicotine, synthesized chlorobactene more readily from newly synthesized lycopene rather than from the pool of lycopene accumulated during nicotine inhibition. When the cells were reincubated in the presence of diphenylamine, which inhibited de novo carotenogenesis, a portion of the lycopene which had accumulated during nicotine inhibition was converted into chlorobactene. There was no evidence that neurosporene, rather than lycopene, was the precyclization intermediate. The involvement of gamma-carotene as the cyclic precursor of chlorobactene also was shown. The pathway for chlorobactene biosynthesis is discussed in terms of a possible arrangement of the enzymes involved in carotenoid biosynthesis.


[Supraventricular tachycardia in newborn infants and infants]. Four types of supraventricular tachycardia were identified in a retrospective study of 71 babies who presented under the age of 3 months. The arrhythmia originated in the atrium in the first two types (25% of cases, atrial tachycardia 10 cases, chaotic atrial tachycardia 7 cases). In the other types the arrhythmia originated at the atrioventricular node. Reciprocal rhythms were most common (62%) and those starting in the bundle of His the least common (5%). It is relatively easy to distinguish the different types which are important because treatment may vary. Overall 75% recover completely, 11% have sporadic recurrences and 10% have a chronic arrhythmia. The junctional varieties have the worst prognosis.


[Maturation of nerve conduction velocity from birth to 5 years of age]. The Hoffmann monosynaptic reflex was recorded in the soleus muscle in 105 healthy children aged between 2 days and 5 years. From this the nerve conduction velocity in the proximal segment of the sciatic nerve was calculated. The tibial nerve conduction velocity (motor) was also measured in 59 of these children. The conduction velocity in the proximal and distal parts of the nerve develop in parallel and in an exponential manner but the conduction velocity in the reflex arc (afferent and efferent) is always faster than the motor conduction. Conduction time slightly but significantly decreases during the first year despite the increase in length of the nerve. Thereafter the conduction time slowly increases and by 5 years the values are similar to those in the neonatal period.


[Peripheral retinal lesions in the premature infant]. The periphery of the retina was examined with the use of contact lenses at the age of 5 years in children who were born prematurely and weighed less than 1,500 g at birth. In this retrospective series 65% of the children were found to have lesions similar to the classical findings in retrolental fibroplasia although only to a minor degree. Low oxygen levels with a short duration of the exposure cannot completely prevent these sequalae. This retinopathy which is limited to the periphery, may account for the frequency and severity of myopia in children who were premature. Later in childhood and more rarely retinal detachment or tears may occur which cause severe visual impairment.


[Acute leukemia in 3 children with chronic juvenile arthritis treated with chlorambucil]. Three children out of a total of 40 who had been treated with chlorambucil for juvenile rheumatoid arthritis developed acute leukaemia. No malignancy was detected in 160 patients in those treated with steroids and/or other anti-inflammatory drugs. Chlorambucil may have induced the malignancies and its use should be avoided in rheumatoid arthritis.


["Pedunculated tumor" of the right ventricle in an infant]. A infant is reported who had pulmonary valve stenosis with a pedunculated throbus in the right ventricle. On angiocardiography this appeared as a tumour. The origin of the thrombus and the diagnostic problems interpreting the angiocardiographic appearances are discussed.


[Value of the intravenous route for the use of phenobarbital in asphyxiated full term newborn infants]. Phenobarbital (20 mg/kg) was given intravenously to asphyxiated full term neonates who were less than 48 hours old. Further doses were given for 4 days (5 mgs/kg/d). Plasma levels were within the therapeutic range from 5 to 36 hours after the first injection but the maintenance dose always resulted in overdose by 5th day. The exact maintenance dose needs to be determined.


[The pediatrician and school difficulties]. Difficulties at school are amongst the most frequent encountered in paediatric practice but paediatricians are infrequently consulted by those who are responsible for the children from day to day. As a result decisions are often contrary to the elementary principles of physiology. Unfortunately the chronological age is still the important criteria for determining school progress. Thus the age for learning to read is fixed arbitrarily at 6 years. Small children have specific difficulties even though they are normal intellectually. Overall the rhythm of life of the child is not considered by the exacting scholastic requirements. Finally the school forgets the need of the sick child too easily and demands a major effort of adaptation without making any allowances itself.


[The inborn cervical block vertebra. Part I: morphology and localisation (author's transl)]. Reviewing the X-rays of 72 patients with 77 congenital block vertebrae of the spine a morphological classification of this deformity of the spine is given as well as a description of radiological signs. Four different basic types are found according to the degree of deformity. Definition and pathogenesis of the congenital block vertebra of the cervical spine are separated from acquired synostoses of vertebrae. The frequency of anatomical localisations is described as well as differences due to sex.


Damage analysis of the Harrington rod fracture after scoliosis operation. Fracture of the distraction rod is one of the complications following operative treatment of scoliosis by the device of Harrington. It is reported to occur in about 7% of cases. We found this complication twice in our own number of 41 patients during a follow up period of 1 to 4 years. The rods had broken 18 and 23 months after operation, but we never saw a breakage in the 1st postoperative year during the time of cast fixation. The fracture surfaces of each rod were examined under the scanning electron microscope. In one case a fatigue fracture with two beginnings at the opposite sides of the rod was found in combination with a forced fracture in the middle. The number of alterations of load from the beginning of the fracture to the complete breakage was about 10,000. The X-ray showed a loss of correction in the curve of 20 degrees with a pseudoarthrosis visible in the fusion. In the other case a typical pure fatigue fracture was seen 23 months after the operation with 18,000 alterations of load. The X-ray showed only a slight loss of correction of less than 5 degrees and no pseudoarthrosis was visable, neither in the X-ray nor in the operative exploration of the fusion. The breakage of the distraction rod results not only from a pseudoarthrosis but also from other explained facts of the procedure. Further treatment depends on a proven pseudoarthrosis.


Antibiotic irrigation-perfusion treatment for chronic osteomyelitis. This paper reports 125 antibiotic irrigation-perfusion treatments of chronic osteomyelitic patients. The localisation of the osteomyelitic process, the duration of the disease, the duration of the treatment, the age distributions of the patients, and the results of the treatment are noted. The study revealed that only one third of the patients healed after the irrigation-perfusion treatment. This rate falls short of the results reported in the literature. The possible causes are discussed and emphasis is given to the technical problems. On the basis of this survey the author is of the opinion that this method is to be employed only in exceptional cases of bone infections. The indication and contraindications are precisely defined.


[The supracondylar fracture of the humerus in children (author's transl)]. To find out the cause of posttraumatic varus and valgus deformity of the elbow a long-term follow-up examination of 183 dislocated and 20 undislocated supracondylar extension-fractures of the humerus was done. There were different methods of treatment: In most of the cases closed reduction was performed and fixation in acute angle-plaster or by percutaneous radial or radial and ulnar wires. 75% showed radiologically and 55% clinically an alteration of the carrying angle. The clear reason for this deformity was a rotation displacement, which leads in oblique fractures directly, in transverse fractures--caused by an instability--indirectly seldom to a valgus, in most of the cases to a varus deformity of the elbow. A special quotient to judge the rotation displacement is presented: the rotation failure quotient (rfq). There is no influence of lateral compression to the carrying angle. Lateral tilting is in any case a result of rotation displacement. Growth disturbance after supracondylar fractures is possible without lesion of the epiphysial plate: but as growth disturbances are seldom and their extent small, they are of no significant clinical importance. Extension displacement of the distal fragment will be spontaneously corrected in ca. 80% of all cases during the further growth. The clinical importance of posttraumatic deformities and the primary management to avoid them is discussed. The crossed percutaneous rotation-stable wire osteosynthesis is recommended as the best way of treatment. For all kinds of treatment the challenge is asked to avoid the ventral spur as a sign of rotation till consolidation of the fracture. By correct reposition in all other planes complicated measurements and reflections, as for instance the alpha-angle by Baumann, oblique or transverse fracture, pro- or supination of the forearm during fixation a.o. are unnecessary.