Exome sequencing identifies homozygous variants in MBOAT7 associated with neurodevelopmental disorder

Intellectual disability (ID) is a large group of neurodevelopmental disorders characterized by a congenital limitation in intellectual functioning (reasoning, learning, and problem solving), adaptive behavior (conceptual, social, and practical skills), originated at birth and manifested before the age of 18. By whole exome sequencing of five consanguineous Pakistani families presenting hallmark features of ID, global developmental delay, aggressive and self-injurious behaviors, microcephaly, febrile seizures and facial dysmorphic features, we identified three novel homozygous missense variants (NM_024298.5: c.588G > T; p.Trp196Cys, c.736 T > C; p.Tyr246His and c.524A > C; p. Asp175Ala) and one rare homozygous in-frame deletion variant (c.758_778del;p.Glu253_Ala259del) in membrane-bound O-acyltransferase family member 7 (MBOAT7) gene previously associated with autosomal recessive neurodevelopmental disorder. The segregation of the variants was validated by Sanger sequencing in all family members. In silico homology modeling of wild-type and mutated proteins revealed substantial changes in the structure of both proteins, indicating a possible effect on function. The identification and validation of new pathogenic MBOAT7 variants in five cases of autosomal recessive ID further highlight the importance of this genes in proper brain function and development.     

Genotype determination of hepatitis C virus from Northern India: Identification of a new subtype

Hepatitis C virus (HCV) shows substantial nucleotide sequence diversity distributed throughout the viral genome, with many variants showing only 68–79% overall sequence homology. This has led to problems in diagnosis of HCV using commercial immunoassays. Based on clustering of homologous sequences, various genotypes and subtypes of HCV have been described from different geographical regions. In the present study, 11 isolates from India were genotyped using sequence comparison for part of the nonstructural (NS5) and structural (core) regions. Parts of the genome covering 451 bp (nt 9-459) of the core gene and a 249 bp fragment (nt 7959-8207) of the NS5 gene were reverse transcribed and amplified using nested polymerase chain reaction (RT-PCR). The amplified fragments were cloned and sequenced. The classification into genotypes was done on the basis of phylogenetic analysis. Four isolates showed sequence homology to type 1b. Two of the isolates were classified as type 3a. One isolate was classified as type 3b and the remaining four isolates were found to be variants of type 3 but did not belong to any designated subtype. On the basis of phylogenetic analysis two of the unclassified isolates were put into a new subtype of 3 named as 3g. In one of these variants, parts of a 5′-noncoding (5′ NCR; 204 bp), envelope-E1 (435 bp), and NS3 (502 bp) regions were also amplified, cloned, and sequenced. This study demonstrates the type 3 variants including a new subtype (3g) to be the major cause of HCV infection in India. © 1996 Wiley-Liss, Inc.     

Berberis vulgaris root bark extract prevents hyperoxaluria induced urolithiasis in rats

Berberis vulgaris is a widely used plant for the treatment of urolithiasis. To evaluate its antiurolithic potential, the crude aqueous‐methanol extract of Berberis vulgaris root bark (Bv.Cr) was tested in an animal model of urolithiasis, developed in male Wistar rats by adding 0.75% ethylene glycol in drinking water. Bv.Cr (50 mg/kg) inhibited CaOx crystal deposition in renal tubules and protected against associated changes including polyuria, weight loss, impaired renal function and the development of oxidative stress in kidneys. Activity‐guided fractionation revealed the concentration of antiurolithic constituent(s) mainly in the aqueous fraction. These data, indicating the presence of antiurolithic activity in Berberis vulgaris root bark, rationalize its medicinal use for the treatment of urolithiasis. Copyright © 2010 John Wiley & Sons, Ltd.     

Evaluation of therapeutic control in a Pakistani population with hypertension

Rationale, aims and objectives Cardiovascular diseases (CVD) are increasing at an alarming rate in South Asia. High blood pressure is a modifiable risk factor for CVD. In this study, we evaluated the control of blood pressure and the prevalence of cardiovascular risk factors in patients with hypertension. Method A cross‐sectional study was conducted in 50 primary health care centres throughout Pakistan. Individuals with a documented history of hypertension, receiving pharmacological therapy, were enrolled and evaluated for the control of their blood pressure. Results The recommended therapeutic control of hypertension (systolic blood pressure <140 mmHg, diastolic blood pressure <90 mmHg) was seen in only 6.4% of the study participants. Values of both the mean systolic and diastolic blood pressures in all subjects were higher than the desired therapeutic levels (P < 0.001). There was a high prevalence in the study population of established but modifiable risk factors of CVD, such as smoking (30.5%), hypercholesterolemia (59.5%) and sedentary lifestyle (43.5%). Lack of therapeutic control of systolic blood pressure was found significantly associated with age, hypercholesterolemia and sedentary lifestyle (P < 0.05). Conclusions Patients being treated at primary health care centres in Pakistan have inadequate control of high blood pressure. Evidence‐based continuous education of primary health care physicians is a necessary intervention for optimizing treatment strategies and achieving better therapeutic control of hypertension in our population.     

Intravitreal steroids may facilitate treatment of Eales' disease (idiopathic retinal vasculitis): an interventional case series

PURPOSE: Eales' disease is an idiopathic peripheral perivasculitis leading to proliferative vascular retinopathy, recurrent vitreous haemorrhages, and tractional retinal detachment. It is an elusive cause of blindness in young, otherwise healthy individuals. We studied the effects of intravitreal triamcinolone acetonide (IVTA) in patients of Eales' disease, which may eventually reduce the side effects and cost of management, with results equivalent to or better than oral steroids. METHODS: Ethics approval and prior patient consent were obtained. Fluorescein fundus angiograms (FFAs) of 12 eyes of 12 Eales' disease patients were taken before enrolment. These patients received 0.1 ml of 40 mg/ml (4 mg) intravitreal triamcinolone through pars plana under topical anaesthesia. Regular weekly follow-ups were initiated to ascertain Snellen visual acuity, intraocular pressure (IOP) with Goldman tonometer, and triple mirror examination. Fluorescein fundus angiography was again performed in the 8th week to monitor response to treatment. Decrease in areas of late perivascular dye extravasation on fluorescein angiography was used as marker for improvement. RESULTS: Ten out of a total of 12 (83.33%) eyes treated with IVTA showed significant reduction of late leakage from retinal vessels on fluorescein fundus angiography. Two out of 12 eyes (16.67%) did not show considerable decrease in late perivascular fluorescein dye leakage after 8 weeks of intravitreal triamcinolone injection. Two patients (16.67%) had a significant rise in IOP after IVTA. CONCLUSION: Intravitreal steroids may be advocated for management of idiopathic retinal vasculitis without complications of systemic steroids, and minimize need for more invasive procedures.     

Magnetic resonance imaging of liver lesions: exceptions and atypical lesions

On state-of-the-art magnetic resonance imaging, most lesions can be detected and characterized with confidence according to well-known criteria. However, atypical characteristics in some common lesions and the incidental encounter with rare lesions may pose diagnostic difficulties. In this article, six challenging hepatic lesions will be discussed and evaluated on the most important magnetic resonance imaging sequences, with histological correlation when available. In addition, the background information concerning these lesions will be described based on the most recent available literature. By reading this article, the reader will be able to (1) categorize the lesion in solid and fluid-containing lesions, based on the T2 signal intensity; and (2) define the benign or malignant nature of the lesion, in relation to the signal intensity and dynamic enhancement pattern, despite the presence of atypical characteristics of some lesions.     

Liver imaging at 3.0 T: diffusion-induced black-blood echo-planar imaging with large anatomic volumetric coverage as an alternative for specific absorption rate-intensive echo-train spin-echo sequences: feasibility study

Institutional Review Board approval and signed informed consent were obtained by all participants for an ongoing sequence optimization project at 3.0 T. The purpose of this study was to evaluate breath-hold diffusion-induced black-blood echo-planar imaging (BBEPI) as a potential alternative for specific absorption rate (SAR)-intensive spin-echo sequences, in particular, the fast spin-echo (FSE) sequences, at 3.0 T. Fourteen healthy volunteers (seven men, seven women; mean age +/- standard deviation, 32.7 years +/- 6.8) were imaged for this purpose. Liver coverage (20 cm, z-axis) was always performed in one 25-second breath hold. Imaging parameters were varied interactively with regard to echo time, diffusion b value, and voxel size. Images were evaluated and compared with fat-suppressed T2-weighted FSE images for image quality, liver delineation, geometric distortions, fat suppression, suppression of the blood signal, contrast-to-noise ratio (CNR), and signal-to-noise ratio (SNR). An optimized short- (25 msec) and long-echo (80 msec) BBEPI provided full anatomic, single breath-hold liver coverage (100 and 50 sections, respectively), with resulting voxel sizes of 3.3 x 2.7 x 2.0 mm and 3.3 x 2.7 x 4.0 mm, respectively. Repetition time was 6300 msec, matrix size was 160 x 192, and an acceleration factor of 2.00 was used. b Values of more than 20 sec/mm(2) showed better suppression of the blood signal but b values of 10 sec/mm(2) provided improved volume coverage and signal consistency. Compared with fat-suppressed T2-weighted FSE, the optimized BBEPI sequence provided (a) comparable image quality and liver delineation, (b) acceptable geometric distortions, (c) improved suppression of fat and blood signals, and (d) high CNR and SNR. BBEPI is feasible for fast, low-SAR, thin-section morphologic imaging of the entire liver in a single breath hold at 3.0 T.     

Tc-99m-methoxy isobutyl isonitrile scintimammography: imaging postexcision biopsy for residual and multifocal breast tumor

OBJECTIVES: The interpretation of mammogram in a postsurgical breast can be extremely complex and difficult because masses, calcifications, and architectural distortion can mimic cancer. Scintimammography has been proposed because it is not affected by these morphological changes and can potentially be used in patients after excision biopsy to assess any residual tumor, other foci of disease (multifocal disease). MATERIALS AND METHODS: The population comprised of 21 patients (mean age: 47.80 years, median age: 50 years, and age range: 26-77 years) evaluated for suspected residual breast cancer after excision biopsy. All patients received a 740-1000 MBq bolus IV injection of Tc-99m-methoxy isobutyl isonitrile (MIBI) preferably in pedal vein. At 5-10 min after injection, planar images were obtained in prone lateral and supine anterior positions using dual head gamma camera. MIBI uptake was scored as follows: 1 - as normal uptake (compared with contralateral side), 2 - focal low-intense uptake (equivocal), and 3 - focal high-intense uptake (positive). All patients had histopathology for tissue diagnosis. RESULTS: Of the 21 patients evaluated, scintimammography planar was found true positive in 13 and true negative in six. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 92.85, 85.71, 92.85, 85.71, and 90.47%, respectively (P<0.001). Scintimammography detected 2/2 multifocal disease. CONCLUSION: In patients after excision biopsy, scintimammography with Tc-99m-MIBI is valuable in assessing residual or multifocal disease. Scintimammography has high positive predictive value and may influence planning further management.     

Risk factors for breast cancer in Pakistani women aged less than 45 years

BACKGROUND: There has been an increase in the incidence of breast cancer in previously low-risk Asian countries. It is important to identify the risk factors for Asian women, as little information currently exists for this population. AIM: The objective of the study was to determine risk factors for breast cancer among Pakistani women. SUBJECTS AND METHODS: 498 cases younger than 45 years were interviewed from 1 July 1997 to 31 December 1998 at two major cancer hospitals. Age-matched population-based controls were selected from two cities and two villages to represent urban and rural areas. For the variables under study, cases and controls were compared by t-test. Conditional multiple logistic regression models were applied to the data set. RESULTS: Women with BMI >or= 30, with a family history of breast cancer and who were parous were at increased risk. Among parous women risk factors included BMI >or= 30, being in a consanguineous marriage, later age at menarche, later age at first full-term pregnancy, high parity and a history of abortion. CONCLUSION: The risk factors identified for Pakistani women below 45 years were similar to those observed in other studies. However, obesity in pre-menopausal women and late menarche were not protective and consanguinity was identified as a risk.     

Blocking key mutated hotspot residues in the RBD of the omicron variant (B.1.1.529) with medicinal compounds to disrupt the RBD-hACE2 complex using molecular screening and simulation approaches

A new variant of SARS-CoV-2 known as the omicron variant (B.1.1.529) reported in South Africa with 30 mutations in the whole spike protein, among which 15 mutations are in the receptor-binding domain, is continuously spreading exponentially around the world. The omicron variant is reported to be highly contagious with antibody-escaping activity. The emergence of antibody-escaping variants is alarming, and thus the quick discovery of small molecule inhibitors is needed. Hence, the current study uses computational drug screening and molecular dynamics simulation approaches (replicated) to identify novel drugs that can inhibit the binding of the receptor-binding domain (RBD) with hACE2. Screening of the North African, East African and North-East African medicinal compound databases by employing a multi-step screening approach revealed four compounds, namely (−)-pipoxide (C1), 2-(p-hydroxybenzyl) benzofuran-6-ol (C2), 1-(4-hydroxy-3-methoxyphenyl)-2-{4-[(E)-3-hydroxy-1-propenyl]-2-methoxyphenoxy}-1,3-propanediol (C3), and Rhein (C4), with excellent anti-viral properties against the RBD of the omicron variant. Investigation of the dynamics demonstrates stable behavior, good residue flexibility profiles, and structural compactness. Validation of the top hits using computational bioactivity analysis, binding free energy calculations and dissociation constant (K_D) analysis also indicated the anti-viral properties of these compounds. In conclusion, this study will help in the design and discovery of novel drug therapeutics, which may be used against the emerging omicron variant of SARS-CoV-2.

A new variant of SARS-CoV-2 known as the omicron variant (B.1.1.529) reported in South Africa with 30 mutations in the whole spike protein, among which 15 mutations are in the receptor-binding domain, is continuously spreading exponentially around the world.