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Biomedical subjects

R Bashir

Publications and source records attributed to R Bashir.

At least 19 recordsLinked to original sources
PubMed1999

The cellular immunology of multiple sclerosis.

Multiple sclerosis (MS) is a neurological disease that affects the central nervous system (brain and spinal cord) resulting in debilitating motor and sensory dysfunction. Its mean age of onset is 30 years and, with the exception of trauma, MS remains the most frequent cause of neurological disabilities for young adults. The disease is highly variable in its onset and progression. It may not be easily diagnosed, at least in its earliest stages. Significant disability is a hallmark of MS. Indeed, up to 50% of patients require walking aids and 10% are wheelchair-bound at 15 years after an initial diagnosis. Clinical features include deficits in sensory (parasthesias and numbness), motor (difficulties with fine movements and gait), balance, bladder, and sexual functions. Although the etiology for MS is not yet known, it is thought to be related to microbial, genetic, and/or environmental factors. Pathologically, MS is characterized by inflammation. An influx of mononuclear cells occurs through a disrupted blood-brain barrier into an immune-privileged central nervous system. The secretion of a variety of inflammatory cytokines and chemokines from glial cells leads to loss of myelin, disruption of oligodendrocyte integrity, and axonal loss. These events, in large measure, affect progressive neural atrophy. How brain inflammatory activities affect transendothelial migration of leukocytes into the brain and alter the process of myelination are the focal points for MS research activities.

Animals↗
PubMed1999

Merosin-positive congenital muscular dystrophy: a large inbred family.

Large families with congenital muscular dystrophy are rare. We report a clinical, histopathological, immunocytochemical, electrophysiological, radiological and genetic study of 10 cases affected by "pure" CMD belonging to two generations of a large inbred Palestinian family. The disease showed autosomal recessive inheritance. All patients had generalised muscular weakness and hypotonia at birth without arthrogryposis. They had a relatively benign clinical course with stabilisation of the clinical picture at different ages and at variable degrees of severity. The pattern of muscle weakness and wasting was more marked in the proximal upper limb-girdle and trunk muscles. Lower limb muscles were more mildly involved. Serum CK was normal or moderately increased. All patients had normal intelligence, normal computed tomography (CT) scans of the brain and normal somatosensory evoked potentials (SEP). Electromyography (EMG) and muscle biopsy showed morphological changes compatible with muscular dystrophy. Immunocytochemistry for dystrophin, laminin alpha 2 of merosin, and for alpha, beta, gamma sarcoglycans was normal. Linkage analysis excluded all the known loci for CMD, including laminin alpha 2 on chromosome 6q2, the Fukuyama congenital muscular dystrophy locus on 9q3, the integrin alpha 7 locus on chromosome 12q13 and the recently identified locus on 1p35-36. The family we present is clinically and genetically distinct from the already mapped forms of congenital muscular dystrophy. Genetic studies are in progress to localise the gene responsible for this condition.

Adolescent↗
PubMed1999

Dysferlin is a plasma membrane protein and is expressed early in human development.

Recently, a single gene, DYSF, has been identified which is mutated in patients with limb-girdle muscular dystrophy type 2B (LGMD2B) and with Miyoshi myopathy (MM). This is of interest because these diseases have been considered as two distinct clinical conditions since different muscle groups are the initial targets. Dysferlin, the protein product of the gene, is a novel molecule without homology to any known mammalian protein. We have now raised a monoclonal antibody to dysferlin and report on the expression of this new protein: immunolabelling with the antibody (designated NCL-hamlet) demonstrated a polypeptide of approximately 230 kDa on western blots of skeletal muscle, with localization to the muscle fibre membrane by microscopy at both the light and electron microscopic level. A specific loss of dysferlin labelling was observed in patients with mutations in the LGMD2B/MM gene. Furthermore, patients with two different frameshifting mutations demonstrated very low levels of immunoreactive protein in a manner reminiscent of the dystrophin expressed in many Duchenne patients. Analysis of human fetal tissue showed that dysferlin was expressed at the earliest stages of development examined, at Carnegie stage 15 or 16 (embryonic age 5-6 weeks). Dysferlin is present, therefore, at a time when the limbs start to show regional differentiation. Lack of dysferlin at this critical time may contribute to the pattern of muscle involvement that develops later, with the onset of a muscular dystrophy primarily affecting proximal or distal muscles.

Amino Acid Sequence↗
PubMed1999

Identical mutation in patients with limb girdle muscular dystrophy type 2B or Miyoshi myopathy suggests a role for modifier gene(s).

Limb girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM), a distal muscular dystrophy, are both caused by mutations in the recently cloned gene dysferlin, gene symbol DYSF. Two large pedigrees have been described which have both types of patient in the same families. Moreover, in both pedigrees LGMD2B and MM patients are homozygous for haplotypes of the critical region. This suggested that the same mutation in the same gene would lead to both LGMD2B or MM in these families and that additional factors were needed to explain the development of the different clinical phenotypes. In the present paper we show that in one of these families Pro791 of dysferlin is changed to an Arg residue. Both the LGMD2B and MM patients in this kindred are homozygous for this mutation, as are four additional patients from two previously unpublished families. Haplotype analyses suggest a common origin of the mutation in all the patients. On western blots of muscle, LGMD2B and MM patients show a similar abundance in dysferlin staining of 15 and 11%, respectively. Normal tissue sections show that dysferlin localizes to the sarcolemma while tissue sections from MM and LGMD patients show minimal staining which is indistinguishable between the two types. These findings emphasize the role for the dysferlin gene as being responsible for both LGMD2B and MM, but that the distinction between these two clinical phenotypes requires the identification of additional factor(s), such as modifier gene(s).

Base Sequence↗
PubMed1998

A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B.

The limb-girdle muscular dystrophies are a genetically heterogeneous group of inherited progressive muscle disorders that affect mainly the proximal musculature, with evidence for at least three autosomal dominant and eight autosomal recessive loci. The latter mostly involve mutations in genes encoding components of the dystrophin-associated complex; another form is caused by mutations in the gene for the muscle-specific protease calpain 3. Using a positional cloning approach, we have identified the gene for a form of limb-girdle muscular dystrophy that we previously mapped to chromosome 2p13 (LGMD2B). This gene shows no homology to any known mammalian gene, but its predicted product is related to the C. elegans spermatogenesis factor fer-1. We have identified two homozygous frameshift mutations in this gene, resulting in muscular dystrophy of either proximal or distal onset in nine families. The proposed name 'dysferlin' combines the role of the gene in producing muscular dystrophy with its C. elegans homology.

Adolescent↗
PubMed1998

Renal involvement in the systemic inflammatory reaction syndrome.

Uncontrolled infection quite often leads to systemic inflammatory reaction syndrome (SIRS) and multiorgan dysfunction (MOD) syndrome. Thirty-five consecutive patients (19 males) fulfilling strict diagnostic criteria for SIRS were enrolled in two multicenter prospective double-blind trials involving new therapies for SIRS. The patients were followed prospectively up to day 28 after the enrollment. In the 35 patients with SIRS, males predominated in the age group below 40 (10/12, 83%) compared to the older group (nine males out of 23, 39%). Out of 16 females presenting with SIRS, only two were below the age of 40. This distribution was statistically different than our general MICU population. The serum albumin in these patients was uniformly low, with a mean of 22.5 gm/L. The bulk of SIRS patients (22/35; 63%) went on to develop acute renal failure (ARF). Although statistically not different, skin and peritoneal infections were more common in ARF group while pulmonary infections in non-ARF group. The majority of blood-cultures grew gram-positive organisms. Resolution of SIRS occurred within first 3 days in greater number of non-ARF survivors than ARF survivors (6/9, 66.7% vs. 6/16, 37.5%). Of the 22 ARF patients, 17 showed improvement in their renal function; the five who did not, died before day 28. The overall mortality (about 32%) was similar in both groups. Patients who developed both ARF and ARDS did not survive. In conclusion. SIRS occurs mostly in elderly patients, almost always in patients with low albumin levels. Premenopausal women seem to be protected. Blood cultures isolated a gram-positive organism in the majority of cases. Improvement in serum creatinine suggests good prognosis. The mortality in ARF and non-ARF groups is similar.

APACHE↗
PubMed1998

Staphylococcus capitis causing aortic valve endocarditis.

Coagulase-negative staphylococci have been implicated in certain human infections but are generally considered to be contaminants. Although their clinical significance has been questioned, rare species of coagulase-negative staphylococci such as Staphylococcus capitis and Staphylococcus ludgunensis have recently emerged which cause endocarditis with high morbidity and mortality rates. We report a case of severe aortic valve endocarditis with conduction delays due to S. capitis infection which was treated successfully with antibiotics.

Aged↗
PubMed1997

Use of the 25 mm flanged esophageal Z stent for malignant dysphagia: a prospective multicenter trial.

BACKGROUND: An initial multicenter study using a 21 mm flanged esophageal Z stent demonstrated excellent palliation but an 11% immediate complication rate at placement and a 27% migration rate at 1 month. This North American multicenter trial prospectively studied a 25 mm flanged Z stent to define its palliative ability and whether the increased diameter affected placement or migration problems. METHODS: Fifty patients who had esophageal Z stents at seven university or regional referral hospitals were prospectively studied. Indications for prosthesis placement, previous therapy, patient demographics, incidence of concomitant tracheoesophageal fistula, and degree of dysphagia were defined, as were procedural and subsequent stent-related problems, survival times, the ability to occlude a tracheoesophageal fistula, and subsequent degree of dysphagia. RESULTS: Twenty-four patients had infiltrating malignancy (16 exophytic and 10 extrinsic), 9 of whom had concomitant tracheoesophageal fistulas. Ten patients (20%) had misplaced stents requiring retrieval and replacement, 12 patients (24%) had subsequent stent-related problems including exsanguination (2), aspiration (3), tumor overgrowth (3), and postplacement migration (4) (8%). There was statistically significant improvement in prestent versus poststent dysphagia and two thirds of patients had complete occlusion of their tracheoesophageal fistula. CONCLUSIONS: Redesign of the esophageal Z stent has decreased the migration rate without increasing placement or subsequent erosion problems. Its efficacy appears comparable to the currently marketed Z stent for the palliation of malignant dysphagia and occlusion of tracheoesophageal fistula.

Aged↗
PubMed1996

Aup1, a novel gene on mouse chromosome 6 and human chromosome 2p13.

We have cloned a novel mouse cDNA, Aup1, encoding a predicted protein of 410 amino acid residues. The 1.5-kb Aup1 transcript is ubiquitously expressed in mouse tissues. An evolutionary relationship to the Caenorhabditis elegans predicted protein F44b9.5 is indicated by the 35% identity and 53% conservation of the amino acid sequences. Nineteen related human ESTs spanning 80% of the protein have also been identified, with a predicted amino acid sequence identity of 86% between the human and the mouse proteins. The gene has been mapped to a conserved linkage group on human chromosome 2p13 and mouse Chromosome 6. Aup1 was eliminated as a candidate gene for two closely linked disorders, human LGMD2B and mouse mnd2.

Amino Acid Sequence↗
PubMed1996

Genetic and physical mapping at the limb-girdle muscular dystrophy locus (LGMD2B) on chromosome 2p.

The limb-girdle muscular dystrophies (LGMD) are a genetically heterogeneous group of disorders, different forms of which have been mapped to at least six distinct genetic loci. We have mapped an autosomal recessive form of LGMD (LGMD2B) to chromosome 2p13. Two other conditions have been shown to map to this region or to the homologous region in mouse: a gene for a form of autosomal recessive distal muscular dystrophy, Miyoshi myopathy, shows linkage to the same markers on chromosome 2p as LGMD2B, and an autosomal recessive mouse mutation mnd2, in which there is rapidly progressive paralysis and muscle atrophy, has been mapped to mouse chromosome 6 to a region showing conserved synteny with human chromosome 2p12-p13. We have assembled a 6-cM YAC contig spanning the LGMD2B locus and have mapped seven genes and 13 anonymous polymorphic microsatellites to it. Using haplotype analysis in the linked families, we have narrowed our region of interest to a 0-cM interval between D2S2113 and D2S2112/D2S145, which does not overlap with the critical region for mnd2 in mouse. Use of these most closely linked markers will help to determine the relationship between LGMD2B and Miyoshi myopathy. YACs selected from our contig will be the starting point for the cloning of the LGMD2B gene and thereby establish the biological basis for this form of muscular dystrophy and its relationship with the other limb-girdle muscular dystrophies.

Animals↗
PubMed1996

The phenotype of chromosome 2p-linked limb-girdle muscular dystrophy.

This study reports on a detailed clinical, electrophysiological, muscle computed tomography (CT) and laboratory investigation carried out on five families with definite linkage to chromosome 2p. Some clinical and laboratory features were common to most of the patients, such as the very high serum creatine kinase (CK) levels (mean 43.70 times the normal). The onset was most frequently in the late teens or early twenties with weakness and wasting of the pelvic girdle muscles. All patients had normal motor milestones and had not complained of any symptoms of muscle disease in early childhood. The clinical course was variable both between and within some families, but was most often slowly progressive. Some variability in the pattern of muscle involvement between the different families has also been observed.

Adolescent↗
PubMed1996

Limb-girdle muscular dystrophy: a follow-up study of 79 patients.

The limb-girdle muscular dystrophies (LGMD) are autosomally inherited neuromuscular diseases. Recently six different loci for LGMD have been reported: 5q (LGMD1A), 15q (LGMD2A), 2p (LGMD2B), 13q (LGMD2C), 17q (LGMD2D) and 4p-14-q21.2 (LGMD2E) respectively. We have studied 79 patients affected by LGMD during the period 1976 to 1995. All patients were examined clinically, and various investigations, including genetics were performed. According to their data we divided them as follow: 1) Cases with autosomal recessive inheritance (34.19%) of these two families are linked to chromosome 2p and the others were subdivided according to the age at onset into childhood LGMD and juvenile-adult LGMD; 2) Cases with dominant inheritance (13.92%); 3) Sporadic cases (51.89%). Onset of symptoms occurs from the first to the third decade. The clinical course varies considerably, as does the degree of disability. Our study allowed to identify two different groups of patients who relatively homogeneous with respect to their clinical and laboratory characteristics.

Adolescent↗
PubMed1996

Main clinical features of the three mapped autosomal recessive limb-girdle muscular dystrophies and estimated proportion of each form in 13 Brazilian families.

Autosomal recessive limb-girdle muscular dystrophies (AR LGMD) represent a group of muscle diseases with a wide spectrum of clinical signs, varying from very severe to mild. Four different loci that when mutated cause the AR LGMD phenotype have been mapped or cloned or both: in two of them the linked families seem to have a relatively mild phenotype (LGMD2a and LGMD2b), in the third one the reported linked families show a more severe clinical course (LGMD2c), while mutations in the fourth locus may cause severe or mild phenotypes (LGMD2d). The relative proportion of each of these genetic forms among the LGMD families and whether there are other genes that when mutated cause this phenotype is unknown. The closest available informative markers for each of the mapped AR LGMD genes have been tested in 13 Brazilian families with at least three affected patients. The findings from the present report confirm non-allelic heterogeneity for LGMD and suggest that in our population about 33% of the LGMD families are caused by mutations in the 15q gene, 33% in the 2p gene, 17% by mutations in the adhalin gene, and less than 10% may be by mutations at the 13q locus. They also suggest that there is at least one other gene responsible for this phenotype. In addition, the main clinical features of the different forms are discussed.

Adolescent↗
PubMed1996

T-cell infiltration of primary CNS lymphoma.

We stained 13 primary CNS lymphomas (PCNSLs) (six from patients with AIDS, seven from immunocompetent patients) with a panel of antibodies to T cells (pan T cell [CD3], T helper cell [CD4], T suppressor cell [CD8], delta/delta cell [CD4-8-]), B cells (CD20), hematopoietic cells (T200), and NK cell (CD56). We estimated the percentage of tumor cells staining with each antibody. All tumors were B-cell lymphomas. The non-AIDS tumors showed a significant infiltration with CD3+ cells (mean of 10.82% of total cells). The AIDS patients' tumors showed a smaller percentage of CD3+ infiltrating cells (mean, 4.88% of total cells) (p<0.01). CD4+ cells were 9.11% of the total hematopoietic cells in the non-AIDS patients and 3.13% in AIDS patients (p<0.01). AIDS patients showed some CD8+ cells (0.3%), which was significantly higher than in immunocompetent patients (0%) (p<0.05). Very few tumor cells stained with the NK cell and delta/delta cell markers. Both immunocompetent and AIDS patients with PCNSL exhibit significant CD3+ and CD4+ cell infiltration of their tumors; this infiltration is significantly lower in AIDS patients. AIDS patients show a minor CD8+ cell infiltration of their tumors. These results on PCNSL are different from systemic lymphomas, which show a higher CD4 and CD8 cell infiltration, and may offer insights into the more aggressive nature of AIDS-related PCNSL.

Antigens, CD↗
PubMed1996

Angiographically documented coronary artery disease in asymptomatic middle aged men suspected of silent ischaemic heart disease.

One hundred and fourteen asymptomatic middle aged men, with a positive stress test, underwent coronary angiography at Armed Forces Institute of Cardiology/National Institute of Heart Diseases (AFIC/NIHD), Rawalpindi. Of these, 66 (58%) were found to have significant disease (> 50% luminal narrowing in at least one of the major epicardial arteries) while 48 (42%) had normal coronary arteries. Of the former, 27 (41%) had 1-vessel CAD, 18 (27%) had 2-vessel CAD and 21 (32%) had 3-vessel CAD. There were significantly more hypertensives, hyperlipidaemics and diabetics in CAD group, while other risk factors were the same. The overall risk factor prevalence was low. The major reasons for performing coronary angiography were a positive stress test done as part of routine annual medical checkup and resting ECG changes of enough significance to warrant further investigations. It is concluded that the presence of significant coronary artery disease can be silent in a large number of asymptomatic middle aged men, especially those who have conventional risk factors.

Adult↗
PubMed1995

Confirmation of the 2p locus for the mild autosomal recessive limb-girdle muscular dystrophy gene (LGMD2B) in three families allows refinement of the candidate region.

The mild autosomal recessive limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of muscle diseases. The first gene to be mapped and associated with this phenotype was a locus on 15q based on linkage analysis in families from a French geographic isolate. These results have been confirmed in other populations, but it was shown that there is genetic heterogeneity for this form of LGMD. Recently, a second locus has been mapped to chromosome 2p. The confirmation of the mapping of this second locus in LGMD families from different populations is of utmost importance for the positional cloning of this gene (HGMW-approved symbol LGMD2B). In this publication, haplotypes generated from five chromosome 2 markers from all of the known large families linked to chromosome 2p are reported together with the recombinants that show the current most likely location of the LGMD 2B gene.

Chromosome Mapping↗