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Biomedical subjects

I H Khan

Publications and source records attributed to I H Khan.

At least 37 records · Page 2Linked to original sources
PubMed1998

Role of the SH3-ligand domain of simian immunodeficiency virus Nef in interaction with Nef-associated kinase and simian AIDS in rhesus macaques.

The nef gene of the human and simian immunodeficiency viruses (HIV and SIV) is dispensable for viral replication in T-cell lines; however, it is essential for high virus loads and progression to simian AIDS (SAIDS) in SIV-infected adult rhesus macaques. Nef proteins from HIV type 1 (HIV-1), HIV-2, and SIV contain a proline-Xaa-Xaa-proline (PxxP) motif. The region of Nef with this motif is similar to the Src homology region 3 (SH3) ligand domain found in many cell signaling proteins. In virus-infected lymphoid cells, Nef interacts with a cellular serine/threonine kinase, designated Nef-associated kinase (NAK). In this study, analysis of viral clones containing point mutations in the nef gene of the pathogenic clone SIVmac239 revealed that several strictly conserved residues in the PxxP region were essential for Nef-NAK interaction. The results of this analysis of Nef mutations in in vitro kinase assays indicated that the PxxP region in SIV Nef was strikingly similar to the consensus sequence for SH3 ligand domains possessing the minus orientation. To test the significance of the PxxP motif of Nef for viral pathogenesis, each proline was mutated to an alanine to produce the viral clone SIVmac239-P104A/P107A. This clone, expressing Nef that does not associate with NAK, was inoculated into seven juvenile rhesus macaques. In vitro kinase assays were performed on virus recovered from each animal; the ability of Nef to associate with NAK was restored in five of these animals as early as 8 weeks after infection. Analysis of nef genes from these viruses revealed patterns of genotypic reversion in the mutated PxxP motif. These revertant genotypes, which included a second-site suppressor mutation, restored the ability of Nef to interact with NAK. Additionally, the proportion of revertant viruses increased progressively during the course of infection in these animals, and two of these animals developed fatal SAIDS. Taken together, these results demonstrated that in vivo selection for the ability of SIV Nef to associate with NAK was correlated with the induction of SAIDS. Accordingly, these studies implicate a role for the conserved SH3 ligand domain for Nef function in virally induced immunodeficiency.

Animals↗
PubMed1997

Scleroderma, D-penicillamine treatment, and progressive renal failure associated with positive antimyeloperoxidase antineutrophil cytoplasmic antibodies.

Progressive renal failure in patients with scleroderma is a sinister development that is usually attributed to impaired renal blood flow. In some exceptional cases, the underlying pathology is a crescentic glomerulonephritis, which has been associated with positive antineutrophil cytoplasmic antibodies, and in particular antimyeloperoxidase antibodies. The prognosis in such cases has been very poor. We report such a patient whose renal function has improved and stabilized on immunosuppressive therapy.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1997

Characterization of flagella genes of Agrobacterium tumefaciens, and the effect of a bald strain on virulence.

Agrobacterium tumefaciens produces flagella that are arranged circumthecally near one end of the bacilliform cell. The flagella are required for motility to facilitate reaching the root surface, and possibly aid in orientating the bacterial cells at various sites for infection. We have identified three flagella genes designated flaA, flaB, and flaC. Mutations in flaA, flaB and flaC result in abberant swimming behaviour. Electron microscopic examination of these mutants revealed the defective flagella. A non-motile, bald mutant strain was generated by deleting all three fla genes. Nucleotide sequencing of flaA, flaB, and flaC showed that they have a potential coding capacity for polypeptides of 307, 321, and 314 amino acid residues, respectively. The predicted amino acid sequences of the A. tumefaciens FlaA and FlaB proteins are similar (66% average identity) to the FlaA and FlaB proteins encoded by flaA and flaB genes, respectively, in Rhizobium meliloti. There was no counterpart FlaC protein reported in R. meliloti, but the A. tumefaciens FlaC is similar in amino acid sequence to the R. meliloti FlaA (59.8% identity) and FlaB (66.7% identity). Distinct from FlaA and FlaB of R. meliloti is the absence of histidine and cysteine residues and their shorter length (by 88 amino acid residues fewer than FlaA and FlaB of R. meliloti). The transcriptional start sites of each fla gene determined by primer extension revealed consensus-sequence boxes representing potential binding sites for sigma 28 RNA polymerase (RNAP) upstream of the transcriptional start of each fla gene. Besides the potential sigma 28-binding site upstream of flaC, also present are additional putative conserved sequences, GC at -11 and GG at -21 from the transcriptional start, that resemble potential binding motifs for sigma 54. Because the sigma 54 promoter is associated with genes regulated by physiological changes in various bacteria, the flaC gene might be similarly regulated in response to A. tumefaciens responding to host plant stimuli. Virulence studies showed that the bald strain was consistently reduced in virulence below that of the parental wild-type strain by at least 38%. The difference is statistically significant and suggests that the flagella may play a role in facilitating virulence.

Agrobacterium tumefaciens↗
PubMed1997

Acute renal failure: factors influencing nephrology referral and outcome.

We investigated the incidence, factors affecting referral and outcome of acute renal failure (ARF), in an unselected (predominantly Caucasian) population in the Grampian region of Scotland served by a single renal unit. Case-notes were examined for all patients with a serum creatinine > or = 300 mumol/l. ARF (311 patients) was defined as a temporary rise in serum creatinine > or = 300 mumol/l, or, if the patient died during the acute illness, clinical features indicating acute deterioration of previously normal renal function. Advanced ARF at presentation (51 of the 311 with ARF) was defined as a first recorded serum creatinine > or = 500 mumol/l. Patients were classified into low-, medium-, and high-risk groups according to presence of comorbidity and age. The annual incidence of ARF was 620/million population (pmp), that of advanced ARF 102 pmp. The age-related incidence of ARF ranged from 30 pmp in the age group (0-19 years) to 4266 pmp in the age group > 80 years. Overall, 22% were referred to a nephrologist (34% after excluding those with advanced cancer and age > 80 years). Referral of patients decreased from 100% in the age group 0-19 to 5% in those > 80 years. Referrals in the low-, medium- and high-risk groups were 75%, 30% and 14%, respectively. Patient survival at 2 years was 80%, 42% and 19% for low-, medium-, and high-risk groups, respectively (86%, 44% and 32% for referred patients). Referral and outcome in patients with ARF were significantly influenced by age and presence of comorbidity at presentation.

Acute Kidney Injury↗
PubMed1997

The effect of exercise training on physical fitness and plasma lipids in young Chinese men and women.

BACKGROUND: The mortality from coronary heart disease (CHD) has been steadily increasing in many parts of the world. Measures to reduce the incidence of CHD were initially addressed mainly to middle aged and elderly population groups, but for effective prevention of CHD, measures addressed to younger age groups are also necessary. Moreover, differences between male and female plasma lipid changes after exercise training are not known exactly. METHODS: The concentrations of plasma lipids, before and after regular physical exercise training for 12 weeks, were analyzed in 25 male and 25 female medical students of the same age group. Physical fitness was evaluated by the measurement of maximum oxygen uptake. RESULTS: Results indicated that plasma tri-glyceride, HDL-cholesterol, LDL-cholesterol and VLDL-cholesterol differences between the before-and-after exercise were significant (p < 0.05) in males while the differences of plasma total cholesterol were found to be insignificant. In females there were no significant changes in the plasma lipids levels. In both males and females, the marked increase in maximal O2 uptake after exercise training indicated an improvement in physical fitness. CONCLUSIONS: This study concludes that a short-term exercise program can improve plasma lipid and lipoprotein patterns more in males than in females. It also suggests that daily physical exercise may be an important prevention for cardiovascular diseases in later life, so it is essential to establish a life style with optimum nutrition and physical activity in both the young and in adults of all ages.

Adult↗
PubMed1997

Monthly measurements of intraocular pressure in normal, ocular hypertensive, and glaucoma male subjects of same age group.

BACKGROUND: Recently it has been shown that environmental conditions have a significant influence on intraocular pressure (IOP). Due to differences in inherent constitution, diet and environmental conditions, there is a clear need for well collected IOP data in different countries and ethnic groups. The seasonal variation of IOP has never been described in Pakistani subjects. METHODS: IOP was measured each month over the course of 12 months with the Goldmann applanation tonometer in normal, ocular hypertensive, and glaucoma male subjects. RESULTS: In all groups, the average intraocular pressures in the winter months were highest, while lowest in summer months. The intraocular pressures of spring and autumn months were nearly the same. The intraocular pressure levels in these seasons were between the IOP levels in summer and winter seasons. The difference between highest and lowest IOP was 1.4 +/- 0.2, 3.1 +/- 1.4, and 2.3 +/- 1.1 mmHg, in normal, ocular hypertensive, and glaucoma subjects, respectively. The ups and downs of intraocular pressure were greater in the ocular hypertensive subjects than in the glaucoma patients. CONCLUSIONS: This study confirms that season influences IOP, and concludes that seasonal influence is highest in ocular hypertensive than in normal and glaucoma subjects. As compared to other nations, effect of seasons on IOP seems to be somewhat less pronounced in Pakistan.

Glaucoma↗
PubMed1996

Activation of PAK by HIV and SIV Nef: importance for AIDS in rhesus macaques.

BACKGROUND: The primate lentiviruses, human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) and simian immunodeficiency virus (SIV), encode a conserved accessory gene product, Nef. In vivo, Nef is important for the maintenance of high virus loads and progression to AIDS in SIV-infected adult rhesus macaques. In tissue culture cells expressing Nef, this viral protein interacts with a cellular serine kinase, designated Nef-associated kinase. RESULTS: This study identifies the Nef-associated kinase as a member of the p21-activated kinase (PAK) family of kinases and investigates the role of this Nef-associated kinase in vivo. Mutants of Nef that do not associate with the cellular kinase are unable to activate the PAK-related kinase in infected cells. To determine the role of cellular kinase association in viral pathogenesis, macaques were infected with SIV containing point-mutations in Nef that block PAK activation. Virus recovered at early time points after inoculation with mutant virus was found to have reverted to prototype Nef function and sequence. Reversion of the kinase-negative mutant to a kinase-positive genotype in macaques infected with the mutant virus preceded the induction of high virus loads and disease progression. CONCLUSIONS: Nef associates with and activates a PAK-related kinase in lymphocytes infected in vitro. Moreover, the Nef-mediated activation of a PAK-related kinase correlates with the induction of high virus loads and the development of AIDS in the infected host. These findings reveal that there is a strong selective pressure in vivo for the interaction between Nef and the PAK-related kinase.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Survival on renal replacement therapy in Europe: is there a 'centre effect'?

OBJECTIVE: Survival is the ultimate outcome measure in renal replacement therapy (RRT) and may be used to compare performance among centres. Such comparison, however, is meaningless if the influences of comorbidity, age and early deaths are not considered. We therefore studied survival rates on RRT in seven centres in Europe after taking into account the influence of age, early deaths, primary renal diagnoses, and comorbidity. DESIGN: A retrospective survival analysis was carried out on 1407 patients who commenced RRT in seven centres across five European countries during a 7-year period. Patients were stratified into low-, medium- and high-risk groups based mainly on comorbidity and to a lesser extent on age at commencement of RRT. Kaplan-Meier survival and Cox's proportional hazards model were used to compare survival. RESULTS: Before risk stratification overall 2-year survival across the seven centres ranged from 60.2 to 85.3% (69.3-89.9%) after excluding early deaths) masking a range of survivals of 27.4% for the high-risk group with the worst survival to 100% in the low-risk group with the best survival. After excluding early deaths 2-year survival in the low risk groups (n=622) was greater than 90% in all centres. Multivariate analysis showed that the mortality risk increased four fold from low- to medium- and a further 1.6-fold from medium- to high-risk group. However, despite this adjustment for comorbidity and age there still remained a significant difference in survival among some centres, i.e. a 'centre effect' which ranked the centres. CONCLUSION: Risk stratification diminishes the variance in survival between centres but a centre effect remains despite adjusting for age and comorbidity. Multicentre prospective studies are urgently required to identify the reasons for this apparent centre effect.

Adult↗
PubMed1996

The epidemiology of chronic renal failure and provision of renal services in Albania.

Tirana, the only dialysis facility in Albania (pop 4 million), has a stock of 12 patients and three haemodialysis machines. To determine the need for renal services in Albania we studied the incidence and outcome of patients with chronic renal failure (CRF) referred to the renal service in Tirana (pop 300 000) over 1 year. Case-notes of all patients with a serum creatinine concentration > or = 300 mumol/l during the study period (1992) were examined and outcome at 2 years recorded for each patient. In all, 84 patients (mean age 41.6 +/- 17.5 years, 56% male) were referred to nephrologists of whom 35 (42%) came from Tirana, giving an annual incidence of 116 per million pop. 77% were under 40 and had no co-morbid illness. Glomerulonephritis, the most common renal diagnosis, affected 26% patients. 22% patients (mean age 38 +/- 18.1) died within 2 years and only 5% received dialysis. The mean age of those who received dialysis was 29 +/- 8.3 compared with those who were not dialysed (42 +/- 18.0). The 59 patients (24 from Tirana i.e. 80 per million) who were alive with advanced CRF (creatinine > 500) had a mean creatine of 623 +/- 93 mumol/l and would be candidates for dialysis. Patients with progressive renal failure in Albania are regularly followed and treated with antihypertensives and dietary modification. The need for RRT, however, is not being met even for young patients with no co-morbidity.

Adult↗
PubMed1995

Death during the first 90 days of dialysis: a case control study.

Comparison of survival data among centers may be used to assess performance, but may be influenced by the number of patients who die during the first 90 days of renal replacement therapy (RRT). Data published by registries in Europe do not detail these deaths, and US data generally exclude them from analysis for financial reasons. To study factors influencing such deaths we compared 42 patients who died within 90 days of first commencing RRT in one Scottish renal unit (group A) between 1971 and 1992 with 42 age- and sex-matched controls who started RRT over the same period and survived longer (group B). Patients who died within 90 days of RRT ranged in age from 25.3 to 83.7 years and had a mean age of 65.2 (SEM, 1.6; 95% confidence interval, 61.9 to 68.4). The proportion of patients who died during the first 90 days of RRT increased from 2% of all patients treated before 1981 to 12% in subsequent years. Thirty-three patients in group A received emergency dialysis via temporary venous access compared with only nine in group B (P < 0.055). There were more patients in group A with a diagnosis of arteriosclerotic renal artery stenosis (14 v 1) and with a history of smoking (15 v 2) than in group B (P < 0.0005). Median renal or nonrenal follow-up before RRT was 1.1 month in group A and 10.6 months in group B (P < 0.0001). Fewer patients in group A had no coexisting disease (1 v 17; P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Patients' perception of health on renal replacement therapy: evaluation using a new instrument.

Patients' perception of their health is an important outcome measure in the management of chronic disease. Comparing that perception from patients receiving different forms of renal replacement therapy (RRT) with data from the general population could be used to monitor the effectiveness of treatment. The short form 36 (SF-36) questionnaire is a general measure of health status which has been validated in the UK and uses eight health scales comprising physical function, social function, role limitation (physical and emotional), mental health, energy, pain and overall health. Using the SF-36 questionnaire, the perception of health of patients receiving RRT was compared with data from healthy control subjects. One hundred and seventy-two of 185 (93%) patients receiving RRT--transplant (n = 102), haemodialysis (n = 43), and peritoneal dialysis (n = 27) completed the questionnaire; scores were compared with those from 542 healthy control subjects. The perception of health of haemodialysis and peritoneal dialysis patients was significantly worse than transplanted patients and controls in six of the eight scales (P < 0.05 dialysis versus transplant and controls). That of transplanted patients was worse in only two and better in one of the eight scales compared with the general population (P < 0.05). Patients were also stratified into low, medium, and high-risk groups based on age and comorbidity and were analysed irrespective of treatment modality. Scores were significantly different across the risk groups in five of the eight scales. We conclude that the SF-36 questionnaire is acceptable to patients on RRT and enables the perception of health of patients receiving RRT to be compared with that of the general population.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Membranous nephropathy and granulomatous interstitial nephritis in sarcoidosis.

A 56-year-old woman developed nephrotic syndrome in association with pulmonary sarcoidosis. Renal biopsy revealed both granulomatous interstitial nephritis and membranous nephropathy. Treatment with steroids resulted in a decrease in proteinuria and there was no deterioration in renal function over a subsequent period of 10 months. This case provides further evidence that secondary membranous nephropathy associated with sarcoidosis should be treated with steroids.

Female↗