Familial atrial fibrillation is a genetically heterogeneous disorder

OBJECTIVES: The aims of this study were to identify and characterize familial cases of atrial fibrillation (AF) in our clinical practice and to determine whether AF is genetically heterogeneous. BACKGROUND: Atrial fibrillation is not generally regarded as a heritable disorder, yet a genetic locus for familial AF was previously mapped to chromosome 10. METHODS: Of 2,610 patients seen in our arrhythmia clinic during an 18-month study period, 914 (35%) were diagnosed with AF. Familial cases were identified by history and medical records review. Four multi-generation families with autosomal dominant AF (FAF 1 to 4) were tested for linkage to the chromosome 10 AF locus. RESULTS: Fifty probands (5% of all AF patients; 15% of lone AF patients) were identified with lone AF (age 41 +/- 9 years) and a positive family history (1 to 9 additional relatives affected). In FAF 1 to 3, AF was associated with rapid ventricular response. In contrast, AF in FAF-4 was associated with a slow ventricular response and, with progression of the disease, junctional rhythm and cardiomyopathy. Genotyping of FAF 1 to 4 with deoxyribonucleic acid markers spanning the chromosome 10q22-q24 region excluded linkage of AF to this locus. In FAF-4, linkage was also excluded to the chromosome 3p22-p25 and lamin A/C loci associated with familial AF, conduction system disease, and dilated cardiomyopathy. CONCLUSIONS: Familial AF is more common than previously recognized, highlighting the importance of genetics in disease pathogenesis. In four families with AF, we have excluded linkage to chromosome 10q22-q24, establishing that at least two disease genes are responsible for this disorder.     

Twenty-four-hour secretion patterns of luteinizing hormone in mithuns (Bos frontalis)

A 24 h secretion pattern of luteinizing hormone (LH) was not available in mithun (Bos frontalis), a semi-wild ruminant. To characterize the 24 h LH profiles, six female mithun calves (age 7.8 +/- 0.5 months and 102.5 +/- 5.6 kg; group I) and six female mithuns averaging 25.4 months of age and 240 kg (group II) were selected from the National Research Centre on Mithun farm and were maintained in semi-intensive systems. Blood samples collected from all the animals at 30 min intervals for 24h were assayed for plasma LH. Plasma progesterone was also estimated in twice-a-week samples collected for 6-week period preceding each 24h sampling to assess whether any animal had begun ovarian cyclicity. The body weights of all animals were also recorded weekly during the 6-week period. LH patterns consisted of frequent pulses of varying amplitude. Luteinizing hormone pulses occurred at an average frequency of 0.28/h ( approximately 7 pulses/24 h) and 0.15/h ( approximately 3.5 pulses/24 h) for mithuns of groups II and I, respectively, the rate did not differ markedly among mithuns within each group but was significantly different between the groups. Similarly, the magnitude of LH secretory pulses did not vary among mithuns within the group but was significantly higher in group II than in group I animals. In group II, the LH peaks averaged 1.59 and 1.00 ng/ml in mithun having the highest and lowest LH peaks, respectively and the corresponding values for group I mithuns were 0.66 and 0.51ng/ml. Mithun with higher peak LH levels also had higher mean LH concentrations (P<0.05). The mithuns of group II had significantly higher plasma progesterone concentration (0.89 +/- 0.02 ng/ml) than those recorded in group I mithuns (0.26 +/- 0.01 ng/ml). Plasma progesterone profiles suggested that no animal reached puberty. In conclusion, there was higher LH secretion with higher pulsatility and greater amplitude in group II mithuns than exhibited in mithuns of group I and the prepubertal mithuns of group II were in approaching puberty, which were also indicated by their plasma progesterone profiles, critical body weight and age required to attain puberty, in addition to higher pulsatility of LH secretion.     

Meningoencephalitis associated with COVID-19: a systematic review

Journal of NeuroVirology - With the growing number of COVID-19 cases in recent times. significant set of patients with extra pulmonary symptoms has been reported worldwide. Here we venture out to...     

In Vitro Activity and Resistance Profile of Dasabuvir,a Nonnucleoside Hepatitis C Virus Polymerase Inhibitor

Dasabuvir (ABT-333) is a nonnucleoside inhibitor of the RNA-dependent RNA polymerase encoded by the hepatitis C virus (HCV) NS5B gene. Dasabuvir inhibited recombinant NS5B polymerases derived from HCV genotype 1a and 1b clinical isolates, with 50% inhibitory concentration (IC₅₀) values between 2.2 and 10.7 nM, and was at least 7,000-fold selective for the inhibition of HCV genotype 1 polymerases over human/mammalian polymerases. In the HCV subgenomic replicon system, dasabuvir inhibited genotype 1a (strain H77) and 1b (strain Con1) replicons with 50% effective concentration (EC₅₀) values of 7.7 and 1.8 nM, respectively, with a 13-fold decrease in inhibitory activity in the presence of 40% human plasma. This level of activity was retained against a panel of chimeric subgenomic replicons that contained HCV NS5B genes from 22 genotype 1 clinical isolates from treatment-naive patients, with EC₅₀s ranging between 0.15 and 8.57 nM. Maintenance of replicon-containing cells in medium containing dasabuvir at concentrations 10-fold or 100-fold greater than the EC₅₀ resulted in selection of resistant replicon clones. Sequencing of the NS5B coding regions from these clones revealed the presence of variants, including C316Y, M414T, Y448C, Y448H, and S556G, that are consistent with binding to the palm I site of HCV polymerase. Consequently, dasabuvir retained full activity against replicons known to confer resistance to other polymerase inhibitors, including the S282T variant in the nucleoside binding site and the M423T, P495A, P495S, and V499A single variants in the thumb domain. The use of dasabuvir in combination with inhibitors targeting HCV NS3/NS4A protease (ABT-450 with ritonavir) and NS5A (ombitasvir) is in development for the treatment of HCV genotype 1 infections.     

Identification of Metal Dithiocarbamates as a Novel Class of Antileishmanial Agents

Dithiocarbamates have emerged as potent carbonic anhydrase (CA) inhibitors in recent years. Given that CAs are important players in cellular metabolism, the objective of this work was to exploit the CA-inhibitory property of dithiocarbamates as a chemotherapeutic weapon against the Leishmania parasite. We report here strong antileishmanial activity of three hitherto unexplored metal dithiocarbamates, maneb, zineb, and propineb. They inhibited CA activity in Leishmania major promastigotes at submicromolar concentrations and resulted in a dose-dependent inhibition of parasite growth. Treatment with maneb, zineb, and propineb caused morphological deformities of the parasite and Leishmania cell death with 50% lethal dose (LD₅₀) values of 0.56 μM, 0.61 μM, and 0.27 μM, respectively. These compounds were even more effective against parasites growing in acidic medium, in which their LD₅₀ values were severalfold lower. Intracellular acidosis leading to apoptotic and necrotic death of L. major promastigotes was found to be the basis of their leishmanicidal activity. Maneb, zineb, and propineb also efficiently reduced the intracellular parasite burden, suggesting that amastigote forms of the parasite are also susceptible to these metal dithiocarbamates. Interestingly, mammalian cells were unaffected by these compounds even at concentrations which are severalfold higher than their antileishmanial LD₅₀s). Our data thus establish maneb, zineb, and propineb as a new class of antileishmanial compounds having broad therapeutic indices.     

Incidence of and Risk Factors for Hospital-Acquired Diarrhea in Three Tertiary Care Public Hospitals in Bangladesh

During April 2007–April 2010, surveillance physicians in adult and pediatric medicine wards of three tertiary public hospitals in Bangladesh identified patients who developed hospital-acquired diarrhea. We calculated incidence of hospital-acquired diarrhea. To identify risk factors, we compared these patients to randomly selected patients from the same wards who were admitted > 72 hours without having diarrhea. The incidence of hospital-acquired diarrhea was 4.8 cases per 1,000 patient-days. Children < 1 year of age were more likely to develop hospital-acquired diarrhea than older children. The risk of developing hospital-acquired diarrhea increased for each additional day of hospitalization beyond 72 hours, whereas exposure to antibiotics within 72 hours of admission decreased the risk. There were three deaths among case-patients; all were infants. Patients, particularly young children, are at risk for hospital-acquired diarrhea and associated deaths in Bangladeshi hospitals. Further research to identify the responsible organisms and transmission routes could inform prevention strategies.     

Electrochromic Os-based metallo-supramolecular polymers: electronic state tracking by in situ XAFS,IR, and impedance spectroscopies

In this study, the electronic states of Os-based metallo-supramolecular polymers (poly(OsL)²⁺) during electrochromism were tracked by in situ X-ray absorption fine structure (XAFS), infrared (IR), and impedance spectroscopies. The XAFS spectra suggested electronic charge migration in the polymer, and the in situ spectra revealed reversible changes caused by electrochemical redox reactions. The IR spectra of the polymers showed an IVCT band, and we also confirmed the reversible changes by applying a voltage to the redox cell. During the impedance measurements, we found a drastic decrease in the charge transfer resistance (R_CT) of the polymer films near the electrochemical redox potential.

In this study, the electronic states of Os-based metallo-supramolecular polymers (poly(OsL)²⁺) during electrochromism were tracked by in situ X-ray absorption fine structure (XAFS), infrared (IR), and impedance spectroscopies.