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.

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 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.

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.

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.

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.

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.

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.

Corticosteroid-induced glaucoma attributable to an adrenocorticotropin-secreting malignant carcinoid tumor of the thymus.

PURPOSE: To describe the clinical and histopathologic findings in a patient with corticosteroid-induced open-angle glaucoma attributable to an adrenocorticotropin-secreting malignant carcinoid of the thymus. METHODS: Case report. In a 33-year-old man, the clinical course, laboratory findings, and imaging results as well as the histopathologic findings are described. RESULTS: Increased intraocular pressure in this patient represented a manifestation of severe hypercortisolism attributable to a malignant adrenocorticotropin-secreting carcinoid tumor. Surgical removal resulted in return of the intraocular pressure values to normal levels. CONCLUSION: Thymic carcinoid is a rare cause of Cushing syndrome, which can lead to increased intraocular pressure.

Ticlopidine-induced thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) occurs in association with a wide variety of disorders including infections, connective tissue diseases, and solid organ tumors. It also may coincide with administration of drugs such as mitomycin, metronidazole, oral contraceptives, cyclosporine, and many others. We report the occurrence of TTP in a patient shortly after the initiation of ticlopidine.

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.

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%).

[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.

[Sickle cell anemia: cerebral angiography changes]. / Anemia falciforme: alterações angiográficas cerebrais.

Two cases of sickle cell disease with neurological complications are described. Cerebral angiograms were performed and a characteristic moyamoya-like angiographic pattern was demonstrated. This pattern results from a compensatory vascularization which may follow occlusion of the arteries at the base of the brain in several diseases. The risks of angiography and appropriate precautions are emphasized.

[Headache in childhood: diagnosis and therapy. A prospective study of 77 cases]. / Cefaléia na infância: diagnóstico e terapêutica. Estudo prospectivo de 77 casos.

Seventy seven cases of migraine in children were studied. Age average was 9 years +/- 2; there were any sex differences. The frontal localization was found in roughly 49% of cases, whereas hemicrania was just found in 9% of cases. The most frequent factors associated were nausea, vomiting and dizziness. The most common triggering factor was the stress. Family history of migraine occurred in 76.5%. Out of 36 patients suffering migraine, 31 underwent a prophylactic treatment with pizotifen or propranolol. There was satisfactory clinical responses in roughly 90% of cases.

[Sexual differences in functional hemispheric asymmetry: verbal tachistoscopic evaluation using microcomputers]. / Diferenças sexuais na assimetria funcional hemisférica. Avaliação taquistoscópica verbal utilizando microcomputador.

Study of sexual differences for the hemispheric prevalence on visual verbal stimuli using a microcomputer-based tachistoscope technic. Seventeen right-handed individuals, 10 males and 7 females (mean age 32 years old), without neurological or visual abnormalities were studied. The subjects performed a verbal trigram tachistoscope test, using a IBM PC microcomputer compatible. The trigram consists of 80 consonant-vowel-consonant pairs of stimuli presented randomly to right and left visual fields. The evaluation was made through two conditions: T1 and T2. In T1 Experiment stimuli exposition time was 260 ms, and in T2 Experiment the stimuli exposition time was 160 ms. In T1 Experiment 80% of females showed a Right Hemispherical Preference while 100% of males showed a Left Hemispherical Preference. In T2 Experiment, both sexes showed Left Hemispheric Preference. A close relationship between sexual difference and hemispheric preference was found. We point out the importance of stimuli exposition time in determination of sexual differences in lateral hemispherical asymmetry.

[Rolandic epilepsy: report of 53 cases]. / Epilepsia rolândica: relato de 53 casos.

The clinical and EEG features of 53 out-patients with benign partial epilepsy of childhood with rolandic spikes were studied. The age mean (years) of seizures onset was 5.5 +/- 3.2. Simple partial seizures with speech arrest were more frequent than other seizure types. In seven cases (13.2%) cognitive disabilities were present. In the left-side foci a expected correlation between the interictal EEG focus and clinical lateralization of seizure was observed; in the right-side foci, the right-side interictal focus was correlated with ipsilateral seizures.

[Analysis of functional hemispheric asymmetry in children with partial epilepsy and normal IQ by performance in WISC subtests]. / Análise da assimetria funcional hemisférica de criancas com epilepsia parcial e QI normal pelo desempenho nos subtestes do WISC.

We studied 87 normal IQ children, 26 partial epileptic (epileptic group) and 61 non-epileptic children (control group) with mean age of 9 years in relation to cognitive performance in Wechsler Infant Scale for Children (WISC) battery. The epileptic group showed lower score in IQ performance and in three verbal subtests (Information, Digit span, Arithmetic) and three performance subtests (Block Design, Object Assembly and Coding). Patients with right hemisphere EEG focus showed low score in subtests related to spatial ability and non-verbal attention, whereas patients with left hemisphere EEG focus showed low score only in Digit span subtest (related to immediate memory and verbal attention). The authors suggest that cognitive deficits in partial non-lesional epileptic children is related to the side of EEG interictal abnormalities, even in children with normal IQ.

[Temporal lobe epilepsy. Surgical treatment]. / Epilepsia do lobo temporal. Tratamento cirúrgico.

The authors report the surgical management of 32 patients with medically intractable seizures. In all cases the epileptiform focus present in the temporal region was demonstrated by electroencephalography. Our report was made up of 14 male patients and 18 female patients. Their ages ranged from 9 to 62 years. The material was divided into two groups. The first, with eighteen patients with cerebral lesion (like gliomas, arteriovenous malformation, epidermoid tumor) demonstrated on the CT scan and MR imaging underwent to lesion resection: in some cases with adjacent irritative area (guided by electrocorticography) out of eloquent zone, the removal of this irritative area was done. The second, with fourteen patients without cerebral expansive lesion; the MR imaging showed mesial temporal sclerosis in eight cases; all the patients of this group underwent to temporal lobectomy; the histopathologic exam showed temporal sclerosis in nine cases and normal brain in five. The postoperative follow-up showed better results in the cases with expansive cerebral lesion (83.4% seizure free) than the cases without that lesion (71.4% seizure free).