Latent class analysis of attention and white matter correlation in children with attention-deficit/hyperactivity disorder.

This study aimed to explore attentional patterns among children with inattentive attention-deficit/hyperactivity disorder (ADHD-I) and children with typical development (TD), using a latent class analysis (LCA). Patterns of brain connectivity were also explored. The sample comprised 29 ADHD-I and 29 TD matched children. An LCA was conducted to reclassify subjects according to their attentional performance, considering cognitive measures of attention and behavioral symptoms, regardless of group of origin. The new clusters were then compared in respect to brain white matter measurements (extracted from diffusion tensor imaging). Participants were rearranged in 2 new latent classes, according to their performance in an attention task and the results of behavioral scales, resulting in groups with more homogeneous attentional profiles. A comparison of the 2 new classes using the white matter measurements revealed increased fractional anisotropy in the left inferior fronto-occipital fasciculus and left inferior longitudinal fasciculus for the class composed by participants with a higher risk of attentional problems. The findings indicated that it was possible to observe variability regarding neuropsychological profile, accompanied by underpinning neurobiological differences, even among individuals with the same disorder subtype - inattentive ADHD. This specific data-driven clustering analysis may help to enhance understanding of the pathophysiology of the disorder's phenotypes.

Latent class analysis of attention and white matter correlation in children with attention-deficit/hyperactivity disorder

This study aimed to explore attentional patterns among children with inattentive attention-deficit/hyperactivity disorder (ADHD-I) and children with typical development (TD), using a latent class analysis (LCA). Patterns of brain connectivity were also explored. The sample comprised 29 ADHD-I and 29 TD matched children. An LCA was conducted to reclassify subjects according to their attentional performance, considering cognitive measures of attention and behavioral symptoms, regardless of group of origin. The new clusters were then compared in respect to brain white matter measurements (extracted from diffusion tensor imaging). Participants were rearranged in 2 new latent classes, according to their performance in an attention task and the results of behavioral scales, resulting in groups with more homogeneous attentional profiles. A comparison of the 2 new classes using the white matter measurements revealed increased fractional anisotropy in the left inferior fronto-occipital fasciculus and left inferior longitudinal fasciculus for the class composed by participants with a higher risk of attentional problems. The findings indicated that it was possible to observe variability regarding neuropsychological profile, accompanied by underpinning neurobiological differences, even among individuals with the same disorder subtype - inattentive ADHD. This specific data-driven clustering analysis may help to enhance understanding of the pathophysiology of the disorder's phenotypes.

Acute renal failure with sodium-glucose-cotransporter-2 inhibitors: Analysis of the FDA adverse event report system database.

BACKGROUND AND AIMS: Sodium-glucose-cotransporter-2 (SGLT2) inhibitors have recently been approved for the treatment of type II diabetes mellitus (T2DM). It has been proposed that these agents could induce acute renal failure (ARF) under certain conditions. This study aimed to evaluate the association between SGLT2-inhibitors and ARF in the FDA adverse event report system (FAERS) database. METHODS AND RESULTS: We analyzed adverse event cases submitted to FAERS between January 2013 and September 2016. ARF cases were identified using a structured medical query. Medications were identified using both brand and generic names. During the period evaluated, 18,915 reports (out of a total of 3,832,015 registered in FAERS) involved the use of SGLT2-inhibitors. SGLT2-inhibitors were reportedly associated with ARF in 1224 of these cases (6.4%), and were defined as the "primary" or "secondary" cause of the adverse event in 96.8% of these cases. The proportion of reports with ARF among reports with SGLT2 inhibitor was almost three-fold higher compared to reports without these drugs (ROR 2.88, 95% CI 2.71-3.05, p < 0.001). The proportion of ARF reports among cases with SGLT2-inhibitors was significantly greater than the proportion of ARF among cases with T2DM without SGLT2-inhibitors (ROR 1.68, 95% CI 1.57-1.8, p < 0.001). Among the SGLT2-inhibitors, canagliflozin was associated with a higher proportion of reports of renal failure (7.3%), compared to empagliflozin and dapagliflozin (4.7% and 4.8% respectively, p < 0.001). CONCLUSION: SGLT2-inhibitors are associated with an increase in the proportion of reports of ARF compared to other medications. SGLT2-inhibitor agents may differ from one another in their respective risk for ARF.

Genetic variation in the alpha1B-adrenergic receptor and vascular response.

The alpha1B (α1B)-adrenergic receptors contribute to vasoconstriction in humans. We tested the hypothesis that variation in the ADRA1B gene contributes to interindividual variability and ethnic differences in adrenergic vasoconstriction. We measured dorsal hand vein responses to increasing doses of phenylephrine in 64 Caucasians and 41 African Americans and genotyped 34 ADRA1B variants. We validated findings in another model of catecholamine-induced vasoconstriction, the increase in mean arterial pressure (ΔMAP) during a cold pressor test (CPT). One ADRA1B variant, rs10070745, present in 14 African-American heterozygotes but not in Caucasians, was associated with a lower phenylephrine ED50 (geometric mean (95% confidence interval), 144 (69-299) ng ml-1) compared with 27 African-American non-carriers (208 (130-334) ng ml-1; P=0.015) and contributed to the ethnic differences in ED50. The same variant was also associated with a greater ΔMAP during CPT (P=0.008). In conclusion, ADRA1B rs10070745 was significantly associated with vasoconstrictor responses after adrenergic stimulation and contributed to the ethnic difference in phenylephrine sensitivity.

Genetic variation in the α1A-adrenergic receptor and phenylephrine-mediated venoconstriction.

There is large interindividual variability and ethnic differences in phenylephrine-mediated vasoconstriction. We tested the hypothesis that genetic variation in ADRA1A, the α1A adrenergic receptor gene, contributes to the variability and ethnic differences. We measured local dorsal hand vein responses to increasing doses of phenylephrine in 64 Caucasians and 42 African-Americans and genotyped for 32 ADRA1A single nucleotide polymorphisms. The ED50 ranged from 11 to 5442 ng min(-1), and the Emax ranged from 13.5-100%. The rs574647 variant was associated with a trend towards lower logED50 in each race and in the combined cohort (P=0.008). In addition, rs1079078 was associated with a trend to higher logED50 in each race and in the combined cohort (P=0.011). Neither variant accounted for the ethnic differences in response. None of the ADRA1A haplotypes was associated with the outcomes. In conclusion, ADRA1A variants do not contribute substantially to the marked interindividual variability or ethnic differences in phenylephrine-mediated venoconstriction.

Population pharmacokinetic analysis of the active product of dipyrone.

OBJECTIVE: Pharmacokinetics of 4-methyl-amino-antipyrine (MAA), the active metabolite of the nonsteroidal anti-inflammatory agent dipyrone, whose time course correlates to the therapeutic effect of the drug, are studied. STUDY DESIGN AND SETTING: 153 patients hospitalized in the Department of Medicine at the Hadassah University Hospital, Jerusalem, Israel. INTERVENTION: Patients receiving dipyrone for the treatment of fever or pain were asked to participate in the study. Pharmacokinetics and statistical analysis: Using the population approach based on a formerly developed experimental model, the relationships between pharmacokinetic parameters and demographic and physiological covariates are explored. RESULTS: The results of the analysis show considerable variability in pharmacokinetics across the study population, and a significant decrease in clearance with age. CONCLUSION: A population pharmacokinetic analysis of MAA, the active product of dipyrone, reveals that age is a significant predictor of MAA disposition. Covariates that measure hepatic and renal function do not appear to be good predictors of the rate of MAA disposition.

CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study.

Warfarin anticoagulation effect is characterized by marked variability, some of which has been attributed to CYP2C9 polymorphisms. This study prospectively examines whether a priori knowledge of CYP2C9 genotype may improve warfarin therapy. Patients were randomly assigned to receive warfarin by a validated algorithm ("control", 96 patients) or CYP2C9 genotype-adjusted algorithms ("study", 95 patients). The first therapeutic international normalized ratio and stable anticoagulation were reached 2.73 and 18.1 days earlier in the study group, respectively (P<0.001). The faster rate of initial anticoagulation was driven by a 28% higher daily dose in the study group (P<0.001). Study group patients spent more time within the therapeutic range (80.4 vs 63.4%, respectively, P<0.001) and experienced less minor bleeding (3.2 vs 12.5%, P<0.02, respectively). In conclusion, CYP2C9 genotype-guided warfarin therapy is more efficient and safer than the "average-dose" protocol. Future research should focus on construction of algorithms that incorporate other polymorphisms (VKORC1), host factors, and environmental influences.

Interethnic differences in drug response: the contribution of genetic variability in beta adrenergic receptor and cytochrome P4502C9.

Ethnic differences in drug response have been extensively reported, and ethnicity has been suggested to be useful clinically as a predictor of drug response. Genetic polymorphisms in the genes encoding beta(1) adrenergic receptor (AR) and beta(2) AR, targets of beta AR antagonists, and in cytochrome P4502C9, the enzyme involved in warfarin metabolism, have the potential to explain some of the observed ethnic variability in drug response and to improve clinical practice.

A common beta1-adrenergic receptor polymorphism (Arg389Gly) affects blood pressure response to beta-blockade.

BACKGROUND: A common polymorphism of the beta(1)-adrenergic receptor Arg389Gly markedly affects function in vitro, but little is known about its in vivo significance. METHODS AND RESULTS: Resting and exercise hemodynamic responses were measured in subjects homozygous for Arg389 (n = 21) or Gly389 (n = 13) alleles before and 3 hours after administration of a beta-blocker, atenolol. Demographic characteristics and atenolol concentrations were similar in the two genotypic groups. Genotype had a marked effect on resting hemodynamic responses to atenolol, with Arg389-homozygous subjects having a larger decrease in resting systolic blood pressure (8.7 +/- 1.3 mm Hg versus 0.2 +/- 1.7 mm Hg, P < .001) and mean arterial blood pressure (7.2 +/- 1.0 mm Hg versus 2.0 +/- 1.7 mm Hg, P = .009). Attenuation of exercise-induced hemodynamic responses by atenolol was not affected by genotype. CONCLUSIONS: There is reduced sensitivity of Gly389 homozygotes to a beta-adrenergic receptor antagonist, and this polymorphism may be an important determinant of variability in response to beta-blockade.

Use of complementary alternative medicine in patients admitted to internal medicine wards.

OBJECTIVE: To evaluate rate and type of complementary alternative medicine (CAM) use in patients admitted to a medical ward. To identify demographic and disease or treatment-related factors associated with CAM use in these patients. To evaluate the awareness of physicians regarding this practice and whether CAM use had contributed to hospital admission. METHODS: This study is based on consecutive interviews and chart reviews of 180 patients admitted to the Department of Internal Medicine, Hadassah Hebrew University Hospital in Jerusalem, Israel. 29 patients were excluded due to impaired cognitive state and 2 patients refused to participate in the study. Patients were asked questions concerning sociodemographic characteristics and CAM use: type, time, duration of use, causes, outcomes and communication about CAM use with their hospital and family physicians. Information about background diseases, acute diagnoses that led to hospitalization, symptoms on admission, drugs taken at home prior to admission was provided by chart reviews. RESULTS: 26% of patients reported a lifetime history of CAM use and 11% during the month prior to admission. Younger age, higher education and Israeli, USA or European origin was associated with more frequent CAM use. Hospital physicians were informed only about 12% of the CAM courses in the month prior to admission, whereas family physicians were aware of about half of them. No direct or indirect harmful effects of CAM were noticed in this study. No essential changes in the regimen of drugs or other conventional treatments due to CAM use were found. If the condition deteriorated, patients did not defer their visit to hospital because of CAM use. CONCLUSIONS: With reservations due to small sample size, it appears that CAM use was not an important factor influencing hospital admissions to a medical ward. Awareness of the hospital physicians regarding CAM use in their patients during the month prior to admission was much lower than that of the family physicians (12% vs. 51.3%).

Post-partum hypocalcemia: idiopatic hypoparathyroidism manifested early in lactation.

Hypocalcemia associated with labor and lactation is a rare condition reported previously in patients with hypovitaminosis D. We here describe a case of a young woman in whom symptomatic severe hypocalcemia appeared after her second delivery, early in lactation. At the end of lactation the condition worsened. We review all previously reported cases and suggest a possible physiologic explanation for the association between pregnancy, lactation and the appearance of symptomatic hypocalcemia.

[Eletroencephalographic ambulatory monitoring in refractory epilepsies in childhood]. / Monitorização eletroencefalográfica ambulatorial na epilepsia de difícil controle da infância.

The objective of our study was, by means of continuous prolonged ambulatory electroencephalographic monitoring, to analyze the temporal distribution of paroxysmal discharges during sleep and awake in children and adolescents with refractory epilepsies. Twenty-one patients in the 4-to-17 year age bracket with refractory epilepsies, with 52.3% (n=11) male and 47.6% (n=10) female from the Discipline of Neurology of the Universidade Federal de São Paulo (Federal University of São Paulo). Cerebral Holter was carried out with Bioware EEG-2008 of prolonged ambulatory electroencephalographic monitoring equipment. We observed greater frequency of isolated and grouped epileptic discharges in day and in night sleep in relation to awake; day and night sleep led to activation of epileptic discharges, both isolated and grouped. The cerebral Holter was more effective in detecting epileptiform discharges than the routine EEG in 33.33% of the patients. The cerebral Holter proved a useful and precise method in detecting epileptic discharges, as an aid in the assessment of the fluctuations in frequency of paroxysmal activity in children with refractory epilepsies, both in relation to activities in daily life, and to the relation to the biological cycle of sleep and awake.

Compound cardiac toxicity of oral erythromycin and verapamil.

OBJECTIVE: To report a case of complete atrioventricular (AV) block and QTc prolongation following coadministration of high-dose verapamil and erythromycin. CASE SUMMARY: A 79-year-old white woman was admitted to the hospital due to extreme fatigue and dizziness. On admission, heart rate was 40 beats/min and blood pressure was 80/40 mm Hg. An electrocardiogram showed complete atrioventricular (AV) block, escape rhythm of 50 beats/min, and QTc prolongation 583 msec. This event was attributed to concomitant treatment with verapamil 480 mg/d and erythromycin 2,000 mg/d, which was prescribed one week before admission. DISCUSSION: This is the first case published describing complete AV block and prolongation of QTc following coadministration of erythromycin and verapamil. CYP3A4 is the main isoenzyme responsible for metabolism of erythromycin and verapamil. Both drugs are potent inhibitors of CYP3A4 and of P-glycoprotein; this may be the basis for the pharmacokinetic interaction between erythromycin and verapamil. In addition to being a woman, our patient had other risk factors for QT prolongation: slow baseline heart rate (probably induced by verapamil), left-ventricular hypertrophy, and possibly ischemic heart disease. CONCLUSIONS: This life-threatening arrhythmia was probably the result of a pharmacokinetic and/or pharmacodynamic interaction of high-dose verapamil and erythromycin.

Phenytoin metabolic ratio: a putative marker of CYP2C9 activity in vivo.

CYP2C9 mediates the oxidative metabolism of approximately 10% of drugs, some of which are characterized by a narrow therapeutic index. We aimed to validate genotype method and phenotype methodology, for evaluation of CYP2C9 activity in vivo. Thirty-one healthy subjects (22 male) received a single 300 mg dose of phenytoin. Blood was drawn periodically and urine was collected at intervals for 96 h. Plasma phenytoin and 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) and urine S and R enantiomers of p-HPPH were determined by high-performance liquid chromatography. CYP2C9 genotyping was obtained by polymerase chain reaction followed by digestion with Sau96I and StyI for the identification of CYP2C9*2 and CYP2C9*3, respectively. Eighteen subjects were CYP2C9*1 homozygous, seven were CYP2C9*2 heterozygous, four were CYP2C9*3 heterozygous, one was CYP2C9*2 homozygous and one was compound CYP2C9*2/CYP2C9*3 heterozygous. The allele frequencies of CYP2C9*1, CYP2C9*2 and CYP2C9*3 were 0.76 [95% confidence interval (CI) 0.73-0.79], 0.16 (95% CI 0.13-0.19) and 0.08 (95% CI 0.05-0.11), respectively. The CYP2C9-mediated production of (S)-p-HPPH represented the major metabolic pathway of phenytoin biotransformation as its excretion accounted for 95.6 + 0.9% of 'total' p-HPPH excretion over the 96 h collection interval. Phenytoin metabolic clearance to produce (S)-p-HPPH (PMC), correlated significantly with (S)-p-HPPH (or 'total' p-HPPH) content in 0-8, 0-12 and 0-24 urine collections (r = 0.88, 0.85 and 0.89, respectively) and with phenytoin metabolic ratio (PMR) defined as the ratio of urine (S)-p-HPPH (or 'total' p-HPPH) to mid-interval plasma phenytoin (r = 0.90, 0.88 and 0.94, respectively). PMC and PMR exhibited a gene-dose effect so that the highest and lowest values were noted in homozygous subjects CYP2C9*1 and subjects carrying two defective alleles, respectively, whereas heterozygous subjects had intermediate values. CYP2C9 genotyping and several phenytoin metabolic indices are correlated with CYP2C9 activity in vivo. The utility of phenytoin to predict the metabolism of other CYP2C9 substrates justifies further evaluation.

The evaluation of pleural effusions in patients with heart failure.

PURPOSE: To determine the causes of pleural effusions in patients with heart failure, and the association of the characteristics of these statistics with the use of diuretics. SUBJECTS AND METHODS: Eighty-one patients with a definite diagnosis of heart failure who underwent thoracentesis were evaluated. Fluids were classified as transudates or exudates using Light's criteria. RESULTS: Forty-one effusions (in 34 patients) were transudates, and 54 (in 47 patients) were exudates. A specific cause was found for 32 of the exudates (27 patients); except for heart failure, no obvious cause was found for the remaining 22 fluids (20 patients). Exudates with a specific cause for an exudate were more likely to have at least two of Light's criteria (18 of 27 [67%]) than did exudates without a known cause (2 of 21 [10%]). Intravenous diuretic therapy in the 24 hours before thoracentesis was significantly more common among patients with exudates without a specific cause. CONCLUSIONS: Patients with heart failure may have exudative pleural effusions without an obvious cause except heart failure.

Co-occurrence of hepatocellular carcinoma and lymphoma in patients with hepatitis C virus cirrhosis.

The association of hepatitis C virus (HCV) with neoplasia is not completely understood. Hepatitis C virus is hepatolymphotrophic. It is considered an inducing factor of hepatocellular carcinoma (HCC) and is associated with various types of lymphomas. We describe a patient with HCV cirrhosis who developed gastric lymphoma and HCC, and we review the current data and theories about the oncogenesis of HCV.

Glucose-6-phosphate dehydrogenase deficiency is associated with increased initial clinical severity of acute viral hepatitis A.

BACKGROUND AND AIM: In glucose-6-phosphate dehydrogenase (G6PD) deficiency, the enzyme is deficient in liver cells as well as in erythrocytes. It has been suggested that this may be associated with a more severe clinical presentation of acute viral hepatitis A. The aim of this study is to determine the severity of liver disease in patients with viral hepatitis and G6PD deficiency. METHODS: Eighteen patients with diagnosed G6PD deficiency and acute hepatitis A were compared with 18 matched control patients with hepatitis A in a university hospital for liver disease severity and clinical outcome. RESULTS: Two of 18 patients with G6PD deficiency had neurological deterioration. Patients with G6PD deficiency had a mean peak prothrombin time (PT) that was significantly prolonged as compared with the control group (15.5 +/- 3.7 vs 12.9 +/- 2.0 s, respectively, P < 0.02), and a significantly higher proportion had an abnormal PT (PT > 13.3 s): 61 versus 11% (P < 0.0001). Hemolysis occurred in 44% of the G6PD deficiency patients. Total and direct bilirubin were significantly higher in all patients with G6PD deficiency, including patients without hemolysis. There was no significant difference in liver enzyme levels between the two groups. Patients with G6PD deficiency had a longer average hospital stay (9.5 +/- 4.8 vs 3.4 +/- 0.8 days, respectively, P < 0.001). There was no difference in the final clinical outcome between the two groups, and recovery of liver function was seen in all patients. CONCLUSIONS: Glucose-6-phosphate dehydrogenase deficiency in patients with hepatitis A causes a more severe initial clinical presentation, but does not alter the final clinical outcome.

Mefloquine-induced acute hepatitis.

Mefloquine is an effective drug for prophylaxis and treatment of malaria caused by Plasmodium falciparum. It is generally well tolerated with few side effects. Minimal elevation of liver function tests has been reported after exposure to mefloquine, especially in susceptible individuals with prior abnormal liver function tests. Our patient, who had had elevated liver function tests attributed to heart failure, experienced an acute elevation of liver transaminases 6 weeks after exposure to mefloquine 250 mg/week. Cessation of the drug caused test results to return to normal. Mefloquine should be prescribed cautiously in patients with liver disease.

Safety of low dose methotrexate in elderly patients with rheumatoid arthritis.

Weekly low dose methotrexate is an established treatment for rheumatoid arthritis, but its use in elderly people has not been adequately examined. The aim of this study was to evaluate its safety in elderly patients with rheumatoid arthritis. A retrospective review of the clinical records of rheumatoid arthritis patients over the age of 65 attending a rheumatology unit was conducted. Eligible patients were followed for at least two years and treated with methotrexate in a dose of 7.5 mg/week while being maintained on concurrent treatment. Thirty three patients were studied. Their mean age was 78.8 years; 32 were female and one was male. Treatment was discontinued in four patients, two because of raised serum liver enzymes and two because of gastrointestinal irritation. No serious adverse events were reported. After two years, haemoglobin levels increased from a mean (SD) of 12.4 (1.3) g/dl to 13.0 (1.1) g/dl (r = 0.226, p < 0.005). The white blood count was significantly reduced from 7.9 (1.8) x 10(9)/l to 6.8 (1.7) x 10(9)/l (r = 0.184, p < 0.05). No episodes of neutropenia or agranulocytosis were observed. There was a non-significant decrease in platelet count. The erythrocyte sedimentation rate decreased from 56.8 (30.8) to 35.2 (24.6) mm/h (r = 0.246, p < 0.01). In conclusion, low methotrexate treatment in elderly patients appears to be safe. Routine determination of serum liver enzymes and renal function may reduce individual risk.