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Biomedical subjects

M Khan

Publications and source records attributed to M Khan.

At least 91 records · Page 5Linked to original sources
PubMed2001

A national register for surveillance of inherited disorders: beta thalassaemia in the United Kingdom.

OBJECTIVE: To demonstrate the value of a national register for surveillance of services for an inherited disorder. METHODS: Data from the United Kingdom Thalassaemia Register and the United Kingdom Register of Prenatal Diagnosis for Haemoglobin Disorders were combined in a database; these registers include all fetuses known to have been diagnosed with beta thalassaemia major, beta thalassaemia intermedia, or haemoglobin E/beta thalassaemia in the United Kingdom. Data were extracted to show outcomes (selective abortion or live birth) of all fetuses and the status of those born with a disorder (alive, dead, successful bone marrow transplant, or lost to follow-up) by parents' region of residence and ethnicity. FINDINGS: At the end of 1999 the register included 1074 patients, 807 of whom were alive and residing in the United Kingdom. A successful bone marrow transplant has been performed for 117 out of 581 (20%) patients born since 1975. Residents of Pakistani origin are now the main group at risk in the United Kingdom, replacing residents of Cypriot origin. This has led to a marked shift in the need for services from the south-east of England to the Midlands and the north of England. Despite the acceptability of prenatal diagnosis, the proportion of affected births remains 50% higher than would be expected, reflecting a widespread failure to deliver timely screening and counselling to carriers. Even though effective treatment is available the annual number of deaths is rising, indicating that better tolerated treatments are needed. CONCLUSION: A national diagnosis register is a powerful instrument for monitoring the treatment and prevention of inherited disorders and for highlighting correctable shortcomings. In view of the increasing possibilities for genetic screening there is a strong case for central funding for such databases within modern health services.

Adolescent↗
PubMed2001

Bolitho--claimant's friend or enemy?

The aim of this paper is to consider whether the decision of the House of Lords in Bolitho v City and Hackney Health Authority [1997] 4 All.E.R. 771 has, in theory and practice, altered the English law on standard of care in clinical negligence cases to the benefit of claimants (patient/plaintiffs). The conclusion reached is that the current signs are very encouraging.

Child↗
PubMed2001

The increasing burden of tuberculosis in pregnant women, newborns and infants under 6 months of age in Durban, KwaZulu-Natal.

OBJECTIVES: In spite of the global epidemic of tuberculosis (TB) which has been exacerbated by HIV, the impact of these co-infections on maternal and perinatal health has been limited. We document new evidence from Durban, KwaZulu-Natal, on the increasing effects of TB in pregnant women, neonates and infants. METHOD: Women with TB were prospectively studied at the antenatal clinics and obstetric and labour wards at King Edward VIII Hospital, Durban, between 1996 and 1998. The incidence of TB was calculated, and the population-attributable fraction of TB due to HIV infection in pregnancy was estimated. Concurrently, culture-confirmed cases of Mycobacterium tuberculosis in neonates and infants under 6 months of age at the hospital were documented. RESULTS: One hundred and forty-six cases of maternal TB were detected. TB occurred in 0.1% and 0.6% of maternities in 1996 and 1998 respectively. Overall, TB rates for HIV non-infected maternities was 72.9/10(5), and for HIV-infected maternities, 774.5/10(5). The attributable fraction of TB related to HIV in pregnancy was 71.7%; 10.3% of these mothers died. There was a 2.2-fold increase in the caseload of culture-confirmed TB in neonates and young infants at the hospital. CONCLUSION: In regions where TB and HIV prevalence is high, efforts to improve maternal and perinatal health must include the detection of TB in pregnancy.

Age Factors↗
PubMed2000

Gene therapy for myocardial protection: transfection of donor hearts with heat shock protein 70 gene protects cardiac function against ischemia-reperfusion injury.

BACKGROUND: Heat shock protein 70 (HSP70) gene transfection has been shown to enhance myocardial tolerance after normothermic ischemia-reperfusion. We investigated the effect of HSP70 gene transfection on mechanical and endothelial function in a protocol mimicking clinical heart preservation. METHODS AND RESULTS: Rat hearts were infused ex vivo with Hemagglutinating Virus of Japan-liposome complex containing HSP70 gene (HSP, n=8) or no gene (CON, n=8), and heterotopically transplanted into recipient rats. Four days after surgery, transfected hearts were perfused on a Langendorff apparatus for 45 minutes, arrested with St Thomas' No. 1 cardioplegia for 4 hours at 4 degrees C, and reperfused for 1 hour. Mechanical and endothelial function was studied before and after ischemia. Creatine kinase was measured in reperfusion effluent. Hearts underwent Western blotting and immunohistochemistry to confirm HSP70 overexpression. Postischemic recovery of mechanical function (% preischemic+/-SEM) was greater in HSP versus CON: Left ventricular developed pressure recovery was 76.7+/-3.9% versus 60. 5+/-3.1% (P:<0.05); dP/dtmax recovery was 79.4+/-4.9% versus 56. 2+/-3.2% (P:<0.05); dP/dtmin recovery was 74.8+/-4.6% versus 57. 3+/-3.6% (P:<0.05). Creatine kinase release was attenuated in HSP versus CON: 0.22+/-0.02 versus 0.32+/-0.04 IU/min/g wet wt. (P:<0. 05). Recovery of coronary flow was greater in HSP versus CON: 76. 5+/-3.8% versus 59.2+/-3.2% (P:<0.05). Recovery of coronary response to 5-hydroxytryptamine (5 x 10(-)(5) mol/L) was 55.6+/-4.7% versus 23. 9+/-3.2% (P:<0.05); recovery of coronary response to glyceryltrinitrate (15 mg/L) was not different between HSP and CON: 87.4+/-6.9% versus 84.3+/-5.8% (NS). CONCLUSIONS: In a clinically relevant donor heart preservation protocol, HSP70 gene transfection protects both mechanical and endothelial function.

Animals↗
PubMed2000

Human mesothelioma samples overexpress both cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (NOS2): in vitro antiproliferative effects of a COX-2 inhibitor.

Accumulating data demonstrate overexpression of both inducible NO synthase (NOS2) and cyclooxygenase-2 (COX2) in many epithelial neoplasias. In addition, cyclooxygenase inhibitors have been shown to have antineoplastic and prophylactic efficacy against human colon cancer and in mouse models of this disease. Mesothelioma arises in a context of asbestos exposure and chronic inflammation, which would be expected to enhance the expression of these inducible enzymes. This study demonstrates that both inducible enzymes were expressed in 30 human mesothelioma tissues but were not detectable in nonreactive mesothelial tissues from the same individuals. In contrast, areas of reactive mesothelial cells stained positively for these enzymes. In vitro exposure of human mesothelioma cell lines to the COX2 inhibitor, NS398, revealed dose- and time-dependent antiproliferative activity, whereas the NOS2 inhibitor, 1400W, had no detectable inhibitory effect. Surprisingly, nonmalignant human mesothelial isolates expressed both NOS2 and COX2 in vitro at the same level as mesothelioma cell lines but were less sensitive to NS398 inhibition. This finding indicates that these nonmalignant isolates may retain properties of reactive mesothelial cells and suggests that targets in addition to COX2 may be involved in the antiproliferative response of mesothelioma cell lines. These results have clinical significance because of the selective activity of the drug coupled with the therapeutic resistance and poor prognosis of mesothelioma. The findings presented here suggest that further preclinical studies of these inhibitors in animal models of mesothelioma would be of great interest.

Adult↗
PubMed2000

Informed choice in genetic screening for thalassaemia during pregnancy: audit from a national confidential inquiry.

OBJECTIVE: National audit of informed choice in antenatal screening for thalassaemia. DESIGN: Audit from the UK Confidential Enquiry into Counselling for Genetic Disorders. SETTING: Thalassaemia module of the UK Confidential Enquiry into Counselling for Genetic Disorders. SUBJECTS: 138 of 156 couples who had had a pregnancy affected by a major beta thalassaemia from 1990 to 1994. MAIN OUTCOME MEASURES: How and when genetic risk was identified for each couple, and whether and when prenatal diagnosis was offered. RESULTS: Risk was detected by screening before or during the first pregnancy in 49% (68/138) of couples and by diagnosis of an affected child in 28% (38/138) of couples. Prenatal diagnosis was offered in 69% (274/400) of pregnancies, ranging from 94% (122/130) for British Cypriots to 54% (80/149) for British Pakistanis and from 90% in the south east of England to 39% in the West Midlands. Uptake of prenatal diagnosis was 80% (216/274), ranging from 98% (117/120) among British Cypriots in either the first or second trimester to 73% (35/48) among British Pakistanis in the first trimester and 39% (11/28) in the second trimester. A demonstrable service failure occurred in 28% (110/400) of pregnancies, including 110 of 126 where prenatal diagnosis was not offered and 48 of 93 that ended with an affected liveborn infant. CONCLUSION: Although antenatal screening and counselling for haemoglobin disorders are standard practices in the United Kingdom, they are delivered inadequately and inequitably. An explicit national policy is needed, aiming to make prenatal diagnosis in the first trimester available to all couples and including ongoing national audit.

Choice Behavior↗
PubMed2000

Long-term effect of prospective detection of high genetic risk on couples' reproductive life: data for thalassaemia.

Prospective risk detection with availability of prenatal diagnosis is the best service currently available for couples at high genetic risk Here we describe the long term effect of this service on the reproductive life of 102 couples at risk of thalassaemia, whose risk was detected prospectively by carrier screening, who made use of prenatal diagnosis, and where the woman is now over 40. Overall outcome for couples is described in terms of number of favourable versus unfavourable pregnancy outcomes. (A favourable pregnancy outcome = unaffected livebirth, or affected livebirth resulting from informed parental choice.) The 102 couples had a total of 356 pregnancies, including 302 viable pregnancies, and 88% achieved a family unburdened by thalassaemia. 68% of viable pregnancies had a favourable outcome, but only 43% of couples had only favourable outcomes, and 26% lost two or more viable wanted pregnancies. When early losses are included 58% of pregnancies had a favourable outcome, but only 30% of couples had only favourable outcomes, and 41% lost two or more pregnancies. Even with the best available service, at risk couples remain victims of chance, and a significant minority experience great difficulty in obtaining even one healthy child. Research is needed on approaches that may allow couples better control of reproductive outcomes.

Adult↗
PubMed2000

Endotoxin induces structure-function alterations of rat liver peroxisomes: Kupffer cells released factors as possible modulators.

We report that endotoxin treatment results in decreased amounts of peroxisomes as well as changes in structure and function of peroxisomal membranes. Peroxisomes isolated from the liver of control and treated animals showed a marked decrease in total protein, but no significant alteration in the sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) protein profile. However, the Western blot study of the peroxisomal beta-oxidation enzymes and catalase showed an increase in those enzymes in the peroxisomal peak of normal density in endotoxin-treated rats. Disintegration of peroxisomal membranes by carbonate treatment from endotoxin-treated liver and change in the fluidity of peroxisomal membranes suggests alterations in peroxisomal membrane structure. No such alterations were found in mitochondrial or microsomal membranes of endotoxin-treated livers. The lipid analysis of these organelles showed that the only organelle affected was the peroxisome, with a significant decrease in the phospholipid and cholesterol concentrations. To understand the mechanism of endotoxin-mediated alterations in peroxisomes, we studied the possible role of Kupffer cell secreted soluble factors (tumor necrosis factor alpha [TNF-alpha]) on the peroxisomal structure/function. Inactivation/elimination of Kupffer cells by gadolinium chloride before endotoxin treatment did not normalize the overall peroxisomal protein amount and the lipid composition of isolated peroxisomes. However, the levels of individual protein amount in remaining peroxisomes were normalized. Endotoxin also decreased peroxisomal beta-oxidation, and this was partially restored with gadolinium treatment. These results clearly show that peroxisomes are severely affected by endotoxin treatment and suggest that the damage to this organelle may contribute, at least in part, to endotoxin-induced hepatic cytotoxicity.

Animals↗
PubMed2000

Lovastatin therapy for X-linked adrenoleukodystrophy: clinical and biochemical observations on 12 patients.

X-linked adrenoleukodystrophy (X-ALD) is a progressive demyelinating disorder whose neurological signs and symptoms can manifest in childhood as cerebral ALD or in adulthood in the form of a progressive myelopathy (AMN). The consistent metabolic abnormality in all forms of X-ALD is an inherited defect in the peroxisomal beta-oxidation of very long chain (VLC) fatty acids (>C(22:0)) which may in turn lead to a neuroinflammatory process associated with demyelination of the cerebral white matter. The current treatment for X-ALD with Lorenzo's oil aims to lower the excessive quantities of VLC fatty acids that accumulate in the patients' plasma and tissues, but does not directly address the inflammatory process in X-ALD. We have previously demonstrated that lovastatin and other 3-HMG-CoA reductase inhibitors are capable of normalizing VLC fatty acid levels in primary skin fibroblasts derived from X-ALD patients. Lovastatin can block the induction of inducible nitric oxide synthase and proinflammatory cytokines in astrocytes, microglia, and macrophages in vitro. In a preliminary report, we demonstrated that lovastatin therapy can normalize VLC fatty acids in the plasma of patients with X-ALD. Here we report our clinical and biochemical observations on 12 patients with X-ALD who were treated with lovastatin for up to 12 months. Our results show that the high plasma levels of hexacosanoic acid (C(26:0)) showed a decline from pretreatment values within 1 to 3 months of starting therapy with 40 mg of lovastatin per day and stabilized at various levels during a period of observation up to 12 months. The percentage decline from pretreatment values varied and did not correlate with the type of ALD gene mutation (point mutation versus gene deletion). In 6 patients, in whom red cell membrane fatty acid composition was studied, a mean correction of 50% of the excess C(26:0) was observed after 6 months of therapy suggesting sustained benefit. In a few patients who discontinued lovastatin therapy plasma C(26:0) levels reverted to pretreatment values suggesting a cause and effect relationship between these events. Two patients dropped out of the study claiming no clinical benefit, 1 was withdrawn due to adverse effects, and an adult patient with cerebral involvement died during the study. A 10-year-old boy with severe cerebral involvement showed worsening of his neurological status. All patients with AMN remained neurologically stable or showed modest subjective improvement. All patients who did not have Addison's disease at the time of enrollment maintained normal adrenal function throughout the study. The implications of our findings for developing an effective therapy for X-ALD are discussed.

Adrenoleukodystrophy↗
PubMed2000

Identification of the pathway of alpha-oxidation of cerebronic acid in peroxisomes.

Cerebronic acid (2-hydroxytetracosanoic acid), an alpha-hydroxy very long-chain fatty acid (VLCFA) and a component of cerebrosides and sulfatides, is unique to nervous tissues. Studies were carried out to identify the pathway and the subcellular site involved in the oxidation of cerebronic acid. The results from these studies revealed that cerebronic acid was catabolized by alpha-oxidation to CO2 and tricosanoic acid (23:0). Studies with subcellular fractions indicated that cerebronic acid was alpha-oxidized in fractions having particulate bound catalase and enzyme systems for the beta-oxidation of VLCFA (e.g., lignoceric acid), suggesting peroxisomes as the subcellular organelle responsible for alpha-oxidation of cerebronic acid. Etomoxir, an inhibitor of mitochondrial fatty acid oxidation, had no effect on cerebronic acid alpha-oxidation. Further, cerebronic acid oxidation was found to be dependent on the presence of NAD+ but not FAD, NADPH, ATP, Mg2+, or CoASH. Intraorganellar localization studies indicated that the enzyme system for the alpha-oxidation of cerebronic acid was associated with the peroxisomal limiting membranes. Studies on cultured fibroblasts from normal subjects and patients with peroxisomal disorders indicated an impairment of alpha-oxidation of cerebronic acid in cell lines that lack peroxisomes [e.g., Zellweger syndrome (ZS)]. On the other hand, alpha-oxidation of cerebronic acid was found to be normal in cell lines from X-linked adrenoleukodystrophy, adult Refsum disease, and rhizomelic chondrodysplasia punctata. Our results clearly demonstrate that alpha-oxidation of alpha-hydroxy VLCFA (cerebronic acid) is a peroxisomal function and that this oxidation is impaired in ZS. Furthermore, this alpha-oxidation enzyme system is distinct from the one for the alpha-oxidation of beta-carbon branched-chain fatty acids (e.g., phytanic acid).

Animals↗
PubMed2000

Effect of soil on microbial responses to metal contamination.

An experiment was conducted to investigate microbial responses to metal inputs in five soils with varying clay and organic contents; one soil had also a higher pH. These soils were treated with a low metal, sewage sludge control or with this sludge contaminated to achieve Cu=112, Ni=58 and Zn=220 mg kg(-1) in medium and Cu=182, Ni=98 and Zn=325 mg kg(-1) in high metal soils. CO(2) evolution rates were measured at 1 week and at 4-5-day intervals thereafter until the end of the incubation (7 weeks). Extractable metals (CaCl(2) and water), biomass C, metabolic quotient, ergosterol, bacterial-fungal phospholipid fatty acid (PLFA-3 weeks only) ratio and mineral N were measured at 3 and 7 weeks. Metal inputs caused a marked increase in metal availability in the slightly acidic sandy loams, a smaller increase in slightly acidic clays and had little effect in the alkaline loam. After an initial increase in CO(2) evolution with metal inputs in all soils, the high metal treatment alone caused a significant decrease at later stages, mainly in sandy loams. Although biomass C and metabolic quotient decreased in all soils with higher metal inputs, the effect was more pronounced in the sandy loams. Metal inputs increased ergosterol and decreased bacterial-fungal PLFA ratios in most soils. Larger mineral N contents were found in all high metal soils at 3 weeks but, after 7 weeks, metals caused a significant decrease in sandy loams. CaCl(2) and water-extractable Cu, Ni and Zn contents were closely correlated with microbial indices in sandy loam but not in clay soils. Overall, the effect of treatments on microbial and extractable metal indices was greater in loams. Within a single series, higher organic soils showed less pronounced responses to metal inputs, although this trend was not always consistent.

Journal Article↗
PubMed2000

Sensitization to aeroallergens among patients with allergic rhinitis in a desert environment.

BACKGROUND: The causative allergens of allergic rhinitis in desert environments are uncertain. OBJECTIVE: To determine the sensitizing aeroallergens in patients with allergic rhinitis in Kuwait, a desert country. METHODS: A total of 706 patients aged 6 to 64 years (mean 34.3 years) with allergic rhinitis were studied. Sera from the patients were screened for specific IgE to 14 inhalant allergens by the CAP-RAST method. RESULTS: Specific IgE to any allergen was detected in 86.3% of patients. The prevalence rates for allergen groups were: pollens (77.3%), house dust (62.3%), and molds (14.7%). The individual allergens with the highest positive rates were pollens of the weed Chenopodium (64.3%); Bermuda grass (55.0%), and Prosopis tree (50.3%). These plants were all imported and cultivated for the purpose of "greening" the desert. German cockroach (48.2%) and house dust mites (32.4% to 39.2%) were the most prevalent indoor sensitizers. With the exception of the molds, sensitization rates were higher for males than females. The youngest age group (6 to 17 years) had significantly higher sensitization rates than the older ones, particularly with respect to the molds (P < .01 to .001). Severe sensitization was more common with Alternaria than the other allergens and in general mold sensitization was more frequently associated with severe symptoms. Polysensitization was very common, with 81.8% of all sensitized patients positive to more than one allergen. CONCLUSIONS: Pollens of the local horticultural plants are the main sensitizing allergens among patients with allergic rhinitis in this desert environment. The practices that "green" the desert seem to also encourage allergen sensitization.

Adolescent↗