text:
BioMed Research International
Volume 2015, Article ID 462387, 11 pages
Chronic Ingestion of High Dosed Phikud Navakot Extraction Induces Mesangiolysis in Rats with Alteration of AQP1 and Hsp60 Expressions
1Academic Services Office, National Laboratory Animal Center, Mahidol University, 999 Salaya, Puttamonthon, Nakorn Pathom, Bangkok 73170, Thailand
2Department of Tropical Pathology, Faculty of Tropical Medicine, Mahidol University, 420/6 Ratchawithi Road, Ratchathewi, Bangkok 10400, Thailand
Received 13 December 2014; Accepted 10 February 2015
Academic Editor: Brad Upham
Copyright © 2015 Kanchana Kengkoom and Sumate Ampawong. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Phikud Navakot (PN) is commonly used in Thai traditional medicine for alleviation of cardiovascular and cerebrovascular symptoms; however little is known about the chronic toxicity effects of the extracts from the herbs in PN. Repeated extraction doses of 10, 100, and 1,000 mg/kg/day were randomly administered to both male and female Sprague Dawley rats for 12 months. Histopathological study revealed that mesangiolysis was predominately found at the highest dose. Aquaporin 1 (AQP1) expression in the mesangiolytic glomeruli was significantly lower than in the intact glomeruli. This may be relevant to an imbalance of vascular function manifested by AQP1 alteration. In the mesangiolytic glomeruli, 60 kDa heat shock protein (Hsp60) was significantly upregulated on the endothelial lining cells of aneurysm and vascular cyst. Hsp60 increase may be related to endothelial cell damage due to its intracellular protective role. Blood urea nitrogen and creatinine levels remained within their normal range indicating well-functioning renal reserve function. In conclusion, high dosed PN may affect the endothelium leading to inability of vascular permeability and consequence to mesangiolysis. Our results suggest that only a high dose of chronic oral administration of PN is relatively toxic in association with mesangiolysis. The NOAEL was determined to be 100 mg/kg/day.
1. Introduction
Mesangiolysis is a harmful glomerular process leading to necrosis of mesangial cells and/or endothelial cells within the glomeruli. Several conditions are known causes of mesangiolysis, such as toxic glomerulopathy from Habu snake venom [1], circulatory disturbance from congenital heart disease [2], microangiopathy from hemolytic uremic syndrome [3], glomerulonephritis from anti-thymocyte-1 antibody [4], focal glomerulosclerosis [5], transplantation [6], radiation [7], diabetes mellitus [8, 9], amyloidosis [10], and monoclonal Ig deposition disease [11]. However, mesangiolysis is rarely found in preclinical toxicity studies [12], and herb extraction induced mesangiolysis has not yet been reported.
Herbal and natural products are commonly prescribed as alternative medicine in developing countries especially Thailand. Like Phikud Navakot (PN), major ingredients of Yahom Navakot are composed of nine Thai herbal plant species, Anacyclus pyrethrum, Angelica dahurica, Angelica sinensis, Atractylodes lancea, Artemisia annua, Ligusticum sinense, Picrorhiza kurroa, Saussurea lappa, and Terminalia chebula. PN has a long tradition of use in Thailand to alleviate hyperlipidemia, cardiovascular diseases, cerebrovascular diseases, asthma, diabetes mellitus, and some kinds of cancer [13–20]. However the purified extraction of this herb has not been investigated for chronic oral toxicity. Therefore, repeated doses of its aqueous extracts were evaluated in Sprague Dawley rats. At the end of the study, hematology, blood clinical chemistry, and histopathology studies were examined.
In addition, to identify the pathogenesis of considered histopathological changes especially mesangiolysis, two proteins thought to be involved in this mechanism were selected for immunohistochemical study. Aquaporins (AQPs), membrane-inserted water channel proteins, play a highly important role in the reabsorption of water and homeostasis of the vascular system [21]. 60 kDa heat shock protein (Hsp60), mitochondrial chaperone, is involved in stress response and apoptosis inhibition [22, 23]. The results of this study provide new insights into the effects and the precautions required to appropriately consume PN.
2. Materials and Methods
2.1. Animal Husbandry
Animal studies were performed in accordance with the Mahidol University policy for the care and use of animals for scientific purposes and approved by the institutional animal ethics committee (Animal Welfare assurance number: RA2011.03). Healthy eight-week-old Sprague Dawley rats from the National Laboratory Animal Center, Mahidol University, Thailand, were used. All rats were housed in an environment of 23 ± 2°C, 55 ± 15% relative humidity, 10–15 air change per hour ventilation, and 12:12 hours of dark and light cycle and provided with pasteurized standard diet and 7–10 ppm chlorinated water ad libitum.
2.2. Test Article
The extracts of PN were kindly prepared by Associated Professor Dr. Uthai Sotanaphun, Department of Pharmacognosy, Faculty of Pharmacy, Silpakorn University, Nakorn Pathom, Thailand. Raw materials of the nine herbs were mixed and ground into a powder. The powder was immersed in 80% ethanol overnight, then boiled for 3 hours, and filtered to remove the residue. Next, the aqueous extracts were repeatedly boiled for 3 hours and filtrated. The aqueous extracts were spray-dried to remove trace solvent.
2.3. Chronic Toxicity Test
Male and female rats were administered daily oral doses of 10, 100, and 1,000 mg/kg of the extract for 12 months ( rats/group) while the control group was given water at the same volume as the tested extracts. During the period of the study, all rats were daily observed for mortality and clinical signs of toxicity.
2.4. Hematology and Blood Clinical Chemistry
At the end of the study, the rats were euthanized by overdose inhalation of carbon dioxide. Blood samples were collected by cardiac puncture and rats were humanly killed by exsanguinations. Hematological and blood clinical chemistry tests were conducted by an ABBOTT CELL-DYN 3500 system (ABBOTT Laboratories, IL, USA) and a Hitachi 902 automated blood analyzer (Hitachi Science Systems Ltd., Ibaraki, Japan).
2.5. Histopathology
All tested rats were subjected to gross necropsy. All gross pathological changes were microscopically examined. The heart, liver, lung, kidney, and spleen were removed and then were fixed in 10% neutral buffer formalin. Fixed specimens underwent standard processing and were embedded in paraffin wax. Sections (5 µm) were mounted on glass slides for staining by hematoxylin and eosin (H&E). All instances of histopathological change were examined. Overall histopathological appearances were scored as 0 = absent, +1 = mild (<25%), +2 = moderate (25–50%), and +3 = severe (>50%).
For mesangiolysis, the glomerulus was examined at least 50 glomeruli/rat then the prevalence of mesangiolysis was calculated. The severity was simultaneously scored as follows: 0 = absent, +1 = mild glomerular endothelial swelling to generalized capillary aneurysm (Figures 1(g)–1(i)), +2 = developed glomerular cyst which is <50% of glomerular area (Figures 1(d)–1(f)), and +3 = developed glomerular cyst which is >50% of glomerular area (Figures 1(a)–1(c)).
2.6. Immunohistochemistry
Polyclonal rabbit antiaquaporin 1 (AQP1) (Millipore, USA, AB3272-200UL) and polyclonal rabbit anti-60 kDa heat shock protein (Hsp60) (Bioss, USA, 900291W) were used as indicators of the vascular system and endothelial cell anomaly. Five micron thick sections from the paraffin blocks were cut and placed on precoated immunohistochemistry slides, then dried overnight at 56°C, and then allowed to cool. The sections were deparaffinized in xylene and rehydrated prior to immunostaining. Heat-induced antigen retrieval with citrate buffer (pH 6) was used to unmask the antigen from all antibodies. Endogenous peroxidase was quenched with 3% v/v hydrogen peroxide in methanol after sections were cooled. The sections were washed with 0.2% v/v Tween in phosphate buffered saline (PBS) and blocked with protein block serum-free (Dako, Denmark, X0909) for 10 min. Sections were incubated in primary antibody diluted in PBS with 1% v/v normal goat serum (NGS, Vector, USA, S1000). The sections were washed and incubated at room temperature for 30 min with labeled polymer HRP anti-mouse/rabbit EnVision kit (Dako, Denmark, K5007) and visualized with diaminobenzidine (DAB, Dako, Denmark, K3468). The slides were counterstained with hematoxylin before permanent mounting with Permount.
Fifty intact and mesangiolytic glomeruli were randomly examined and images were captured at 400x magnification. Immunohistochemical expression of AQP1 and Hsp60 was then analyzed using ImageJ, NIH [24]. Color images were first converted to 8 bits in gray scale. Adjusted images were transformed by threshold mode to locate the area of interest. The polygon selection mode was used to draw a line over the area of glomerulus. The area of positive reaction was estimated by the number of black pixels with measure mode as percentage area of expression/glomerular area.
2.7. Statistical Analysis
Quantitative results were expressed as mean ± standard deviation. Qualitative results were expressed as prevalence. Data were statistically analyzed with IBM SPSS statistical software version 20. One way analysis of variance (ANOVA) and Levene's test were used to differentiate the difference of mean and variance among groups. Multiple comparison, Bonferroni test, or Dunnett test was performed for equal and nonequal variance assumption. Pearson Chi-square test was used to differentiate the proportion among groups.
3. Results
3.1. Survival and Clinical Signs
76 rats (total ) survived to the end of the study. The cause of death was considered to be related to gavage technical error which was histopathologically presented by aspirated pneumonia. There was no toxicity-related mortality. Treatment and concurrent control groups were similar in clinical manifestations.
3.2. Hematology and Blood Clinical Chemistry
Mean hematological and blood clinical chemistry parameters are shown in Tables 1 and 2. All of these parameters in both treatment and concurrent control groups were similar. No remarkable changes were observed in hematologic and clinical chemistry parameters.
3.3. Histopathology
There was no toxicity-related gross in the hearts, livers, lungs, and spleens at any tested dosages. Histopathological findings are shown in Table 3. Most were similar prevalence when comparing the treatment and concurrent control groups. In the kidney, we found toxicity-related lesion at the highest dose of PN. Both sides of the kidney exhibited the prevalence of mesangiolysis which significantly differed from those of 10, 100 mg/kg/day dosages and the control group. However its prevalence did not vary according to side or sex of any group. The mean severity score in all groups was also similar. The lesions were ranked from dissolution of the mesangial cells, glomerular endothelial swelling, fully developed capillary aneurysm (Figures 1(g)–1(i)), and glomerular cyst (Figures 1(a)–1(f)). A glomerular cyst is a large vascular space arising by the merger of the dilated mesangium and adjoined capillary. Microangiopathy, glomerulosclerosis, glomerulonephritis, amyloidosis, lamellate nodule, fibrin deposit, and leukocyte accumulation were not seen in these mesangiolytic glomeruli. Additional notable lesions related to nontreatment-related response were pelvis calcification and transitional cell hyperplasia (Figure 2) which were significantly higher in the control group than the others (Table 3).
3.4. Immunohistochemistry
In general, AQP1 is expressed on endothelial cells [25–27], red blood cells, and proximal tubules [28]. Hsp60 is expressed on both the renal cortex and medulla [29], particularly in the cytoplasm and mitochondria of any cell [30]. In this study, we compared their expression in the glomeruli and our results indicate that AQP1 was expressed on red blood cells (Figures 3(a)–3(f)). In the mesangiolytic glomeruli, Hsp60 was highly expressed on endothelial lining cells of the capillary aneurysm (Figure 3(h)), large aneurysm, and glomerular cyst (Figures 3(g) and 3(i)) while the expression on intact glomeruli was faint (Figures 3(j)–3(l)).
The image analysis demonstrated that AQP1 expression in the mesangiolytic glomeruli was significantly lower when compared to the intact glomeruli (1.45 ± 0.01% and 8.93 ± 0.09%, value = 0.004). In contrast to Hsp60, the expression in the mesangiolytic glomeruli was significantly higher than in intact glomeruli (13.76 ± 0.02% and 0.65 ± 0.01%, value = 0.000).
4. Discussion
PN is listed in the National Public Health Ministry of Thailand's list of herbal medical products. Our previous studies have revealed the efficacy and safety of PN. An experimental study demonstrated that PN reduces dizziness and fainting due to its vasorelaxation property [31], increases mean arterial and diastolic blood pressure, and increases tail blood flow [32]. In vitro studies also demonstrated that PN ameliorates endothelial stress due to its synergistic antioxidant property [33], attenuates oxidative stress-induced apoptotic cell death, inhibits platelet aggregations, and relates to glucose catabolism [32]. Acute and subchronic toxicity studies revealed that single and repeated oral administration of PN is relatively nontoxic with high dosage contraindication for serum uric acid elevation [34]. The present study demonstrated chronic oral toxicity effects of the extracts from herbs in PN. In each group, hematology and blood clinical chemistry values remained within the normal range. A histopathological study revealed that almost all observed lesions in liver, heart, lung, spleen, and kidney were not related to toxicological effect from PN. Rather, they were associated with physiological changes, aging lesions, and oral gavage induced lesions [24]. The only histopathological change related to toxicological effect from chronic ingestion of high dosed PN is mesangiolysis.
Based on mode of origin and morphological features, there are three types of recognizable mesangiolysis [35]. The first is the severe form with glomerular cyst formation indicating primary mesangial injury [36]. The second type is characterized by extensive widening of subendothelial space as a consequence to endothelial injury. The third type is associated with lamellate nodules caused by persistent endothelial and mesangial cell damage. In this study, the mesangiolysis caused by chronic oral administration of high-dosed PN is likely type 1 and 2 depending on morphology. The histopathological study revealed that half of the counted glomeruli showed two patterns of mesangiolysis, which is characterized by small to large aneurysm and cystic mesangiolysis. The glomerular architecture did not show evidence of thrombotic microangiopathy, glomerulonephritis, or glomerulosclerosis.
The mechanism of mesangiolysis has been discussed in many studies relevant to marked inability of vascular permeability, local intravascular coagulation, or direct effect on the mesangial cells [37]. Examples of mesangiolysis due to primary mesangial injury are Habu venom nephropathy [1], anti-thymocyte-1 antibody [4], and mitomycin C [37]. Other conditions related to endothelial cell injury are secondary mesangiolysis [2, 3, 5, 7–11]. One study postulated the mechanisms of mesangiolysis are both direct and indirect. Glycol ethers could be a direct toxicity on mesangial cells or indirect toxicity leading to hemolysis and possibly microangiopathy [38].
AQP1 in red blood cells is downregulated in some renal diseases, which is relevant to the imbalance of the vascular system and endothelial cells such as uremic syndrome [39]. Unfortunately, there have been no reports about AQP1 alteration related to glomerular diseases in rats. However, our study showed a reduction of AQP1 immunolabelling in the mesangiolytic glomeruli. This decline is characterized by decreasing numbers of glomerular red blood cells with normal expression on their surface. This reduction may indicate an inability of vascular permeability and glomerular circulation due to vascular defects which correlate to aneurysm and cystic formation in the mesangiolytic glomeruli.
There are many reports describing the relationship between the role of Hsp60 and kidney diseases. Generally they conclude that overexpression of Hsp60 enhances cytoprotective function and is induced by cellular stress processes such as chronic kidney disease [40], diabetic nephropathy (hyperglycemia and glomerular hypertension) [41], and renal failure [42]. These studies concluded that Hsp60 expression usually increases in mesangial cells and podocytes, probably due to their susceptibility to injury.
AQP1 alteration is the most important evidence from our study to support that PN induced mesangiolysis may be associated with vascular permeability imbalance or endothelial cell alteration. This is in agreement with upregulation of Hsp60 on endothelial lining cells of aneurysm and vascular cyst which indicate an injury or stress condition. Like those mentioned studies, high dosed PN may affect the endothelium and its closet neighbor cells, leading to mesangiolysis.
In addition, toxicological studies of herbs that affect glomeruli have been limited. Few reports investigate the adverse effects of herbs on renal tissues, for instance, interstitial edema and tubular necrosis in Phyllanthus amarus toxicity [43], high dosed Labisia pumila induces multiple foci of necrosis and focal pyelitis [44], and Chinese-herb containing aristolochic acid enhances urothelial atypia and transitional cell carcinoma [45]. Therefore, this study is the first report highlighting that extracts from herbs in PN affect glomeruli and can induce mesangiolysis.
The association between renal phenotypes of blood chemistry and mesangiolysis is limited. Most of the study reported that blood urea nitrogen (BUN) and creatinine levels were markedly raised in mesangiolysis with other pathological lesions, particularly advanced or end-stage renal diseases, endarteritis like lesions, cellular proliferation, glomerular enlargement, and endothelial or mesangial cell swelling [46–48]. In our study, both hematological and clinical chemistry values stayed within the normal range even with 1,000 mg/kg/day dosages including BUN and creatinine. These indicate that renal function is still preserved. It showed that mesangiolysis alone, without any pathological change, cannot alter renal function parameters.
One more interesting pathological finding in this study is transitional cell hyperplasia which was not considered to be toxic-related response. It is noted that urothelial or transitional cell hyperplasia is an important pathologic appearance of urothelial change in renal papillae which occurs as a response to bacterial infection, urinary tract toxins, carcinogens, and calculi and in association with renal papillary necrosis [12]. In the present study, transitional cell hyperplasia in the control rats was correlated to high prevalence of renal pelvis calcification (Table 3) which may relate to their physiological changes.
5. Conclusions
In conclusion, this work evaluates chronic toxicity of extracts from nine herbs in PN. The investigation demonstrated that they are relatively safe, as they did not cause any lethality nor produced any remarkable physiological, behavioral, hematological, blood clinical chemistry, and anatomical adverse effects of chronic toxicity in rats. The NOAEL was determined to be 100 mg/kg/day. However the contraindication of the prolonged usage for high dose oral administration should be considered remarkable mesangiolysis.
Conflict of Interests
All authors declare that there is no conflict of interests regarding the publication of this paper.
This study was supported by the National Laboratory Animal Center, Mahidol University, Faculty of Tropical Medicine, Mahidol University, and the National Research Council of Thailand (NRCT) under the project, namely, Development of Standardized Extracts from Herbs in Phikud Navakot.
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Join CDEA as we celebrate the wide variety of CA dance! We are excited to announce our second annual all sector dance festival performance showcase. The performance is February 9th, 2019 at 8pm at the Portola High School Performing Arts Center in Irvine (Southern CA).
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allow me to start by thanking the Lord for all his blessings and to continue praying for the nation's prosperity and well-bei.
Ward, and the gospel stylings of Memphis's Stax Music Academy, The King opens the door to a deeper, more complex discourse on.
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able to hear God's beating in the heart of the men an women of our nations. Mary, "teacher of the Gospel," walked and sang th.
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When Jesus was born in Bethlehem of Judea," reads the Gospel for the feast of the Epiphany. where the first U.S. president.
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A well-known preacher, in an attempt to make the gospel more plausible to folks who have limited. Then with Abraham, you read about the promise of a nation from which this child will come. With Mos.
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Learn and Pray for the World. Select any country from the list below to see fuel for prayer and country information including maps, flags, e-Prayer cards and prayer videos.
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Neurodevelopmental Disorder
Methylphenidate for ADHD Treatment May Be Associated With Low BMINovember 06, 2018
The relationship between ADHD, MPH use, and growth appears complex, given that a consistent effect could not be observed across all ADHD conditions.
Certain Lots of Quillivant XR May Potentially Have Quality/Efficacy IssuesOctober 25, 2018
Quillivant XR, a central nervous system stimulant, is indicated to treat ADHD in patients aged 6 years and older.
Anatomical Patterns Present in Childhood ADHD May Predict Phenotypic VariationOctober 17, 2018
The authors identified 4 anatomical patterns in participants with attention-deficit/hyperactivity disorder associated with head size, delayed development, symptoms of attention-deficit/hyperactivity disorder, and cognitive performance.
History of ADHD Associated With Increased Risk for Basal Ganglia and Cerebellum DisordersOctober 17, 2018
Patients with ADHD may require careful monitoring to permit early detection and treatment of disorders of the basal ganglia or cerebellum.
ADHD Symptom Aggression Not Mediated by Clinical AnxietyOctober 03, 2018
These results do not support existing hypotheses on the role of anxiety as either an exacerbating or protective factor for ADHD-related aggression.
Smaller Brain Regions Associated With ADHD, Conduct Disorder Symptoms in AdolescentsOctober 02, 2018
Researchers analyzed neuroimaging data from a group of 1093 adolescents from the IMAGEN project.
Cesarean Delivery, Early Childhood Antibiotic Use Not Associated With Risk for ADHDSeptember 24, 2018
This research rejects any association between increased risk for ADHD and changes in children's microbiota related to cesarean delivery or antibiotic use.
Improving Medication Adherence in ADHD Lowers Risk for Oppositional Defiant Disorder, Conduct Disorder in AdulthoodSeptember 21, 2018
Researchers found that children who were compliant with drug therapy had a significantly lower risk for oppositional defiant disorder or conduct disorder than those who were noncompliant.
High Suicidality Among Children With ADHD Mediated by Family Functioning, Psychiatry ComorbiditiesSeptember 21, 2018
Clinicians may find these data useful in considering the mediating effects of family function and psychiatric comorbidities among patients with ADHD.
Attention-Deficit/Hyperactivity Disorder Increasing Among US Children and AdolescentsSeptember 20, 2018
This increase may be the result of expanded continuing medical education regarding ADHD that has raised physician awareness, as well as modifications in diagnostic criteria.
Differences in Efficacy and Tolerability of ADHD Medications Across Age GroupsSeptember 12, 2018
Guidelines on which ADHD medications should be preferred across different age groups are unclear, and the safety and benefits of these medications remain controversial.
Adult Smoking and Depression Are Contributing Factors to ADHD in Children and AdolescentsSeptember 07, 2018
The authors argue that, given the findings of this study, the awareness of the detrimental effects of both smoking and depression upon children should be raised among parents.
Last 20 Years Saw Increase in Prevalence of ADHD in ChildrenSeptember 06, 2018
From 1997-1998 to 2015-2016, there was an increase in the prevalence of ADHD among children.
FDA Rejects ADHD Drug NDA Citing Need for More DataSeptember 05, 2018
The FDA stated that the dasotraline NDA cannot be approved in its current form and is requiring additional data to further assess the efficacy and tolerability of the drug.
Children With Subsyndromal ADHD Have Significant Morbidity and DisabilityAugust 31, 2018
Compared with controls, those with subthreshold ADHD experienced greater impairments in social functioning and had higher rates of requiring extra help in school.
Methylphenidate Good First-Choice Pediatric ADHD DrugAugust 21, 2018
Methylphenidate should be considered as a first choice for the treatment of ADHD in children and adolescents.
ADHD Medications Compared for Efficacy, Tolerability in Children and AdultsAugust 14, 2018
The 7 treatments included in the study were amphetamines (including lisdexamfetamine), atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil.
Jornay PM Approved for the Treatment of ADHDAugust 09, 2018
Jornay PM utilizes the proprietary Delexis drug delivery platform which consists of 2 functional film coatings: the first layer delays the initial drug release for up to 10 hours and the second layer helps control the release rate of the active ingredient throughout the day.
Digital Media Engagement Associated With ADHD Symptoms in AdolescentsJuly 30, 2018
These results indicate an association between adolescent engagement in digital media activities and subsequent ADHD symptoms.
High Frequency of Digital Media Use Linked to ADHD SymptomsJuly 23, 2018
There is a modest, but statistically significant, association between higher frequency of digital media use and subsequent symptoms of ADHD among adolescents.
Younger Gestational Age Associated With Symptoms of ADHD in ChildrenJuly 12, 2018
These findings illustrate potential gains of reducing the number of preterm births and the importance of providing custom support to children born preterm to prevent neurodevelopmental problems.
Nonstimulants May Be an Appropriate Alternative to Stimulants for Treating ADHDJuly 10, 2018
Nonstimulants may be an appropriate alternative in cases in which co-occurring conditions might prevent the administration of stimulants.
In Children, Food Insecurity Tied to Behavior, CognitionJuly 06, 2018
Food insecurity may be linked to behavioral problems and poorer cognitive performance in children.
Chromosome 22q11.2 Rearrangements May Predispose Individuals to Autism, ADHDJune 28, 2018
The high risk for several neuropsychiatric and developmental disorders supports more extended use of genetic testing in child and adolescent psychiatry.
Early Preterm Birth Linked to Increased ADHD SymptomsJune 27, 2018
Early preterm birth is associated with a higher level of ADHD symptoms in preschool children.
Influence of Psychostimulants on BMI and Height in Youth With ADHDJune 19, 2018
Investigators conducted a retrospective observational study to assess the impact of psychostimulant medication on BMI and height in a group of children and adolescents with ADHD.
Predictors of Long-term Medication Adherence in Children With ADHDJune 15, 2018
Medication continuity in youth with ADHD is affected by several potentially modifiable factors that could be productive targets of intervention for pediatricians.
Exposure to Maternal Hypertension May Up Risk for ASD, ADHD in ChildJune 15, 2018
Exposure to hypertensive disorders of pregnancy may be associated with an increase in the risk for ASD and ADHD in offspring.
Promising Screening Tool for Impulsive Behaviors in Children: Short UPPS-P-C ScaleJune 08, 2018
These findings offer preliminary evidence of the validity of the short UPPS-P-C to screen for impulsivity traits in both typically developing children and in those with ADHD.
Brain Volume, ADHD Symptoms May Be Affected by Childhood StressorsJune 07, 2018
While the authors discovered no "sensitive period," the number of stressful events was moderately associated with the severity of attention-deficit/hyperactivity disorder symptoms.
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Psychiatry Advisor Articles
- Characteristics of Unipolar Mania, Distinct from Bipolar Disorder, Described
- Social Anxiety in Schizophrenia: An Overlooked Problem
- Challenging Stigma: Should Psychiatrists Disclose Their Own Mental Illness?
- Aspirin, N-Acetylcysteine Effective Adjunctive Treatments in Bipolar Depression
- Interview-Only Version of Yale-Brown Obsessive-Compulsive Scale Effective for OCD Monitoring in Youth
- Part 1: Adolescent Tech Use and Mental Health: Expert Roundtable
- Challenging Stigma: Should Psychiatrists Disclose Their Own Mental Illness?
- Social Anxiety in Schizophrenia: An Overlooked Problem
- Inflammation: Is It the Link Between Rheumatoid Arthritis and Depression?
- Interview-Only Version of Yale-Brown Obsessive-Compulsive Scale Effective for OCD Monitoring in Youth
- Childhood Physical Violence Associated With Decreased Total Cholesterol
- How the Government Shutdown Affects FDA Activities
- The Robot Will See You Now: The Increasing Role of Robotics in Psychiatric Care
- Extended-Release Naltrexone Improves Psychiatric Disorders During Addiction Therapy
- Infections, Antibiotics Associated With Subsequent Increased Risk for Mental Disorders in Youth


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More than 225 Dentons lawyers recognised across 99 categories of The Legal 500 UK 2018
Dentons is pleased to announce that the Firm has been ranked in 99 categories in the 2018 edition of The Legal 500 UK, and a total of 226 Dentons lawyers have been recognised across their respective practice areas.
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When a cancellation isn't a cancellation: Cancelling an insurance policy under the Alberta Insurance Act
When it comes to cancelling an insurance policy, both insurers and insureds need to complete the mandated steps.
"Gay marriage" cake: refusal to supply was not discriminatory
In Lee v. Ashers Baking Company Limited and Others, the Supreme Court considered whether a bakery's refusal to supply a cake with a slogan supporting gay marriage was discriminatory on the grounds of sexual orientation or political opinion
Federal autonomous vehicle legislation could get a lame-duck boost
Should Democrats take control of the US House of Representatives, the effort to pass federal autonomous vehicle legislation may be kicked into overdrive.
IRS issues cost of living adjustments to retirement plan limits
The IRS has issued its 2019 cost of living adjustments to retirement plan limits.
Starting your career as a student at Dentons exposes you to a world of experience and opportunities
With 174 locations in 78 countries, Dentons is home to top-tier talent that is found at the intersection of geography, industry knowledge and substantive legal experience. Working with Dentons, you will have the opportunity to learn from the best lawyers in the industry at the largest law firm in the world.
Dentons ranked across 66 practice areas in Chambers UK 2019 with leading individuals recognised in 110 categories
Dentons is pleased to announce that it has been recommended across 66 different practice areas by Chambers & Partners in the Chambers UK 2019 guide.
Dentons launches Market Insights publication: "Digital Transformation and the Digital Consumer"
Dentons, the world's largest law firm, has launched a new Market Insights publication entitled "Digital Transformation and the Digital Consumer", which examines the legal implications of the online economy.
Dentons celebrates successful first year following merger with Maclay Murray & Spens
Dentons is pleased to celebrate the first anniversary of the Firm's combination with Maclay Murray & Spens, creating a UK footprint of six offices: three in England (London, Milton Keynes and Watford) and three in Scotland (Glasgow, Edinburgh and Aberdeen).
Claire Maddox is a member of Dentons' Litigation and Dispute Resolution, Competition and Antitrust, and Intellectual Property and Technology practices. An experienced litigator, Claire has represented clients in complex matters involving federal and state antitrust and unfair competition law, trade secret misappropriation, trademark infringement, copyright infringement, patent infringement, breach of contract, and business torts. Claire has also advised clients on antitrust compliance, issues relating to joint ventures and competitor collaborations, and responding to government antitrust investigations, including international cartel investigations.
Claire has litigated in both federal and state courts and in all phases of litigation, from initial pleadings through resolution, including trial. She has served on several trial teams, argued matters in federal court, handled all facets of discovery (including international discovery issues), and worked closely with experts in large, multi-party cases. Claire has also worked with clients to address and resolve business disputes outside of litigation.
Claire works with clients across a wide range of industries, including manufacturing, technology, health care, and defense. Claire has represented both U.S. and international clients in her matters, and she is experienced in managing relationships with foreign clients. She also has counseled national trade associations on antitrust issues.
Claire is on the DC Bar Litigation Community's Steering Committee and serves as the Committee's community outreach coordinator. She also has been an active member of both Dentons' firmwide Associates Committee, which she co-chaired from 2010 to 2011, and the Washington, DC, Associates Committee, which she chaired from 2009 to 2011. She has done pro bono work for the American Cancer Society's Cancer Action Network, which presented her with an award in 2011 in recognition of her efforts in support of the organization's Judicial Advocacy Initiative. Claire has organized and run a donated-items drive benefiting local charitable organizations, and has performed pro bono work for the Catholic Charities Archdiocesan Legal Network.
In 2011, the District of Columbia Access to Justice Commission and the DC Bar Pro Bono Program established the Capital Pro Bono Honor Roll to recognize the pro bono contributions of DC Bar members. In 2014, Claire registered for the High Honor Roll (100+ hours of pro bono services) and, in 2011 and 2012, she registered for the Honor Roll (50+ hours).
Prior to joining Dentons, Claire served as a judicial intern for the Honorable Charles E. Poston of the Norfolk [VA] Circuit Court, and interned for the Office of the Public Defender in Portsmouth, Virginia. During law school, she served on the William & Mary Bill of Rights Journal; was a board member of the Moot Court Team and the National Trial Team; and served for two years as a teaching assistant for her school's Legal Skills Program. At graduation, she was admitted to the Order of the Barristers and received the William B. Spong Professionalism Prize.
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Www.rovinfest.com - Southern New England Telephone Directory. Summer months is here, which means some time has arrive at pay attention to excellent tunes at a few of the festivals worldwide. Before you pack up for that working day and head out for the festival, take a instant to understand some suggestions so you're able to have the most enjoyable doable. Find out how you can possess a terrific time devoid of any of your stresses that can feature an all-day or multi-day summer time new music pageant.
In the event you concur that nothing could be better than being outside, making new friends, and earning some money as your own boss then you are prepared to develop into a holiday vendor. Learning to be a festival seller can be easy or difficult; it really depends upon the festival you want to sell your wares at.
Relevant to Southern New England Telephone Directory, A community festival is an event that's more usually than not organised and staged by a local community to celebrate or highlight a more unique component of itself same community.See Also: Angola Prison Arts And Crafts Festival
The Pageant year is on us and it is time to grab your Hunter Wellingtons for one more wild audio tour. You are going to obtain magazines full of pageant strategies, however they can be extremely impractical - all sandals and maxi attire. This can be attire is okay for anyone who is Kate Moss with all your very individual shower and VIP area but when you are going to any United kingdom Festivals and you simply do not provide the luxurious of employed assist, then rain combined with mud, are basically a presented.
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Gibson Les Paul Custom Antique Natural
MODE D'EMPLOI: Cet argus est une orientation sur les tendances des quotations maximum utilisées pour des questions d'assurances et autres évaluations de collection.
gibson melody maker 1964 usa made( not for sale) here we have a balst of the past vintage gibson 1964 melody maker. guitar is all original,its shows lots of natural aged finish cracks all over the body,this is a true relic,nothing artificial,1 single coil pickup,wrap around bridge,its a shortscale,it plays very nice,and sound really great.
1975 Gibson bass guitar catalogue see also 1976 Gibson Ripper 1977 Fretless Gibson Ripper 1978 Gibson Ripper. The earlier, wider, slab-bodied version of the Gibson Ripper was produced from the model's inception in 1973, through 1974. Compare this body shape, particularly the bevelling around the horns, with a later 1978 Gibson Ripper – these later Rippers have a far more sculptured look about.
Black Strat Relic Cute Debut Souvenirs Join us this Thanksgiving for the Annual Macy's Thanksgiving Day Parade! You'll find everything about the balloons,
Shut that gene off and you stop aging; accidents and disease are still a problem, but you've cured death by natural causes. Some people are just awesome at being old. They have custom canes and smo.
Over the past 50 or 60 years, a few solidbody electric guitar models have established themselves as must-have "standards" for guitar players. A great example is the venerable Gibson Les Paul – even non-guitar players are familiar with the iconic shape and name of this guitar. There are few.
Arlington Designs Luster Ceramic Bead Rimmed Cake Stand Antique Leaves Pink For Sale. Find Antique Leaves Pink In Stock Now. Silver Plate Home, Wholesale Various High Quality Silver
In 1816, a second specimen was found by Alexander Francois Barbie du Bovage at Nogentles-les-Vierges. This time. Squier then crossed the Atlantic and took the skull to Paul Broca, a leading anthrop.
Hier finden sie einen kleinen Auszug unseres riesigen Angebots an E-Gitarren verschiedenster Marken.
The Les Paul All Wood celebrates its organic beauty like no Les Paul you've ever seen. While the non-wood components of any great Les Paul are kept to a minimum, and purely decorative, The Les Paul All Wood takes this thinking to the extreme, crafting every component that's conceivably possible from luscious, resonant, hand-selected tonewood.
Vintage Dune Buggy For Sale Awesome prices on and related listings. Shop in stock right now! We may have the rolling frame, parts and engine
Main St., next to STASH includes local art, vintage clothing, plants ready for purchase and. These join RCB Bamnk, Flaunt and Amour Nails & Spa. Brookfield Custom Homes LLC received an occupancy pe.
2 Florida Museum of Natural History, University of Florida, Gainesville, FL 32611–7800, USA. 3 Division of Paleontology, American Museum of Natural History, 79th Street and Central Park West, New York.
The Gibson Les Paul is a solid body electric guitar that was first sold by the Gibson Guitar Corporation in 1952. The Les Paul was designed by guitarist/inventor Les Paul along with Gibson president Ted McCarty, factory manager John Huis and their team.
If yes to all the above, don't fret, head over today to the Chesapeake Conference Center, 700 Conference Center Drive in Greenbrier for the East Coast Guitar Expo from 10 a.m. to 4 p.m. The event prom.
The Gibson Les Paul debuted in 1952 as a Goldtop. Les Paul himself wanted a gold finish as "it looks expensive."
More on the Gibson raids via New Jersey's Star-Ledger. Here's Gibson's most-famous player, Les Paul, with Mary Ford, singing "Song in Blue": Les Paul, incidentally, was one of Reason's 35 Heroes of Fr.
The Gibson Les Paul Custom is a higher end variation of the Gibson Les Paul guitar. It was developed in 1953 after Gibson had introduced the Les Paul model in 1952.
2. KOUING AMAN BREAD PUDDING, LES MADELEINES // SALT LAKE CITY, UTAH Simon Gibson, Flickr // CC BY-NC-ND 2.0 Once featured on The Best Thing I Ever Ate, the French-inspired pastries from Les Madeleine.
Kant thought talent was an integral ingredient of the emergence of greatness, as geniuses use their natural talents to produce something original and exemplary (Kant, 1790/1952). According to Kant, si.
479 Cedar Lane, Teaneck, NJ 07666 201-287-1959 201-287-1957(fax) www.larkstreetmusic.com
Browse Gibson products and enjoy free shipping on thousands of Gibson gear & 30 day returns.
1 Centre for GeoGenetics, Natural History Museum of Denmark, 1350K Copenhagen, Denmark. 2 Laboratoire d'Anthropobiologie Moléculaire et d'Imagerie de Synthèse UMR 5288, Université de Toulouse, CNRS, U.
Epiphone's Zakk Wylde Bullseye Les Paul Custom has been the choice of shredders for years. And now, Epiphone and Zakk step it up a notch with the addition of Zakk Wylde EMG-81/85 active humbucker pickups.
Rare Guitars – part of my Collection: 1984 Gibson Flying V Custom-so fabulous to play:Guild S300A-D a real rocker-supposedly once owned by Dave Hill of Slade:2003 Hamer Studio Mint Unplayed-two Seymour Duncan '59 pickups
gibson melody maker 1964 usa made( not for sale) here we have a balst of the past vintage gibson 1964 melody maker. guitar is all original,its shows lots of natural aged finish cracks all over the body,this is a true relic,nothing artificial,1 single coil pickup,wrap around bridge,its a shortscale,it plays very nice,and sound really great.
They produce the cheaper versions of Gibson guitars, and this Slash signature model. If you've got your heart set on learning on a Les Paul-style guitar, this vintage sunburst piece is the one for.
Buy Gibson USA LPTDM15ANNH1 Les Paul Traditional Mahogany Top Solid-Body Electric Guitar, Antique Natural: Solid Body – Amazon.com FREE DELIVERY possible on eligible purchases
The company's struggles may initially come as a surprise to observers who see vintage Gibsons selling for six figures on instrument sites — indeed, a 1960 Gibson Les Paul Standard could be yours today.
Single coil pickup Gibson part number 13570. Launched in 1971, the SB-300 bass and SB-400 bass were the first Gibson basses to have single coil pickups. These units were also used in the following Gibson guitars: SG-100, SG-200, SG-250, ES-320. They clearly borrowed stylistically from the Les Paul low-impedance pickups (above) that had first appeared on a production bass in 1969.
Born in the early '50s, the Les Paul really began taking shape in the mid-50s. Gibson was upgrading many aspects of their trusty axe, including the addition of the Tune-o-matic ABR-1 bridge to the Les Paul.
Is Solid Waste Collection And Disposal Effective –(BUSINESS WIRE)–The Broward County Commission today awarded Wheelabrator Technologies an exclusive, five-year contract for disposal of the county's municipal solid
Alice In Wonderland 2 Midnight Souvenirs Nineteen-year-old Alice returns to the magical world from her childhood adventure, where she reunites with her old friends and learns
Cute Debut Souvenirs Join us this Thanksgiving for the Annual Macy's Thanksgiving Day Parade! You'll find everything about the balloons, route, time, history
Consideration of the bill will take place about a year after federal agents raided the Gibson Guitar company of Tennessee. those penalties by merely owning or traveling with a vintage musical instr.
The keyboard allows for dolphins to teach humans as much as the humans teach the dolphins. Furthermore, the matched whistle will allow for a more natural integration of communication into the dolphin'.
Two windows and a dedicated in-store display of the Berlin Prada shop located on Kurfuerstendamm 186 are currently showing off a selection from the set of custom-made suitcases. leather to create a.
The two-hour cruise will explore the shores of Lake Arthur to observe and/or photograph birds and waterfowl in their natural habitat. A continental breakfast will be served during the cruise. The cost.
In 2016, Gibson introduced another Pete Townshend Gibson Les Paul Deluxe series, based on Pete's 1976 Gibson Les Paul Deluxe Gold Top that he smashed at the Boston Gardens on 1 April 1976, and is now displayed at the Victoria & Albert Museum, London.This new series follows on the original Pete Townshend Signature Gibson Les Paul Deluxe series of three in 2005.
Gibson Montana have announced a limited edition replica of Elvis Presley's personal J200 to honour the 70th anniversary of his birth. The customized 1956 J200 remained one of Elvis' favourite guitars.
Repair estimates indicated that the storm would almost certainly rank among the nation's costliest natural disasters, despite packing a lighter punch than initially feared. Of the 11 towns that had be.


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Drake Shows His Love For New Orleans in His 'In My Feelings' Video Featuring Big Freedia & Lil Wayne [Watch]
Drake new song "In My Feelings" has been a viral sensation over the past few weeks. The song created a viral trend, the "Shiggy Challenge," and has pretty much been everywhere since it's release. But after
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SRK to Big B: Celebrities Congratulate Indian Women's Cricket Team
Bollywood supported Indian women's cricket team in finals, though they lost by 9 runs against England.
Getty Images
Though India lost by nine runs after looking good for major part of their 229-run chase, celebrities have shown their love, support and admiration for the team.
Here's what they tweeted:
Amitabh Bachchan: Until you lose, you shall never know the joy of victory! Well played ladies. Bhartiya Nari Zindabad!
T 2494 - Until you loose, you shall never know the joy of victory ! Well played ladies .. Bhartiya Nari Zindabad !! WWC17 pic.twitter.com/Ghxkou5Nn4— Amitabh Bachchan (@SrBachchan) July 23, 2017
Shah Rukh Khan: I wish I was there to give the lovely ladies a hug. Be proud girls. We have achieved greatness today. BCCI women, you've made all Indians proud.
I wish I was there to give the Lovely Ladies a hug. Be proud girls we have achieved greatness today. @BCCIWomen u made all Indians proud.— Shah Rukh Khan (@iamsrk) July 23, 2017
Akshay Kumar: Even broken hearts can laugh! These women have started a revolution and I couldn't be more proud.
Even Broken Hearts Can Laugh!!— Akshay Kumar (@akshaykumar) July 23, 2017
These Women have started a revolution & I couldn't be more proud 👊🏽 #WWC17Final pic.twitter.com/gVfHI08XHi
Priyanka Chopra: Well played women in blue. It's been an incredible journey and you will always be an inspiration for girls across India.
Well played #WomenInBlue, it's been an incredible journey and you will always be an inspiration for girls across India... #WWC17Final 🇮🇳— PRIYANKA (@priyankachopra) July 23, 2017
Shahid Kapoor: This team has woken us all up to women's cricket in India. Great game girls. Almost had it. Proud.
This team has woken us all up to women's cricket in india. Great game girls. Almost had it. #proud— Shahid Kapoor (@shahidkapoor) July 23, 2017
Shraddha Kapoor: It's okay team India. You girls made it to the finals! That in itself is such a proud moment. Womens' World Cup 2017. Girl power all the way.
It's OK team India. You girls made it to the finals!!! That in itself is such a proud moment. #WomensWorldCup2017 Girl power all.the.way ❤— Shraddha (@ShraddhaKapoor) July 23, 2017
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When you are renting a 5, 10, 15, 20, 30 or 40 yard dumpster, you want a company you can trust with prices that make you smile. Give us a call today and see the difference we can make in your next construction or clean out project.
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Most cities or municipalities do not have many regulations regarding dumpster rental as long as you keep the dumpster entirely on your own property during the rental period. If you need to place your container on the street in any way, you will likely have to obtain a permit from the appropriate building permit office in your town. You can check with your local public works department to be sure.
Most Angola dumpster rental companies will take care of securing this permit for you if you rent from them. Make sure that if you're planning to put the dumpster on the street, the company has made the appropriate arrangements. You should also ensure that you get the permit in a timely manner and at the correct cost. If you thought the dumpster company was getting a permit and they did not, you will be the one who will have to pay the fine that is issued by the authorities.
As you're booking some sort of dumpster or 2, consider regardless of whether you need a mobile sanitation device. This can be crucial, especially if restrooms are being remodeled and the house being done is outside of a city. This is not the common as well as garden variety of portable John, but the form used while special events along with venues, through celebrities as well as the public. Speak about streamlining -- anyone will be comfortable, working in direction of being "green" as they possibly, and saving you time and money.
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A junk piled up for period of time may pollute the earth, invite penalty from the project owner, be given complaints via neighbors intended for spoiling the surroundings and degrades each side your job spot, so junk removal features turned up in a major headaches for most with the project managers.
One aspect that customer features to be more cautious before hiring a dumpster is all about location with the dumpster in the employment site. The particular dumpster requires a place double their size. The nearby of that region should be retained to ensure that these animals and subjects do not get into the pot. You have to seek advice from the 20 Yard Dumpster Rentals in Angola, LA supplier beforehand in regards to the kind of junk accepted through them. Getting rid of unaccepted trash to the dumpster will ask penalty. You'll an additional demand for junk disposed to the dumpster above the limitations.
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Please use the form below to contact us. We look forward to working with you and will get back to you as soon as possible. All fields are required