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Biomedical subjects

A Islam

Publications and source records attributed to A Islam.

At least 19 recordsLinked to original sources

Relationship between visceral adiposity and intramyocellular lipid content in two rat models of insulin resistance.

High visceral adiposity and intramyocellular lipid levels (IMCL) are both associated with the development of type 2 diabetes. The relationship between visceral adiposity and IMCL levels was explored in diet- and glucocorticoid-induced models of insulin resistance. In the diet-induced model, lean and fa/fa Zucker rats were fed either normal or high-fat (HF) chow over 4 wk. Fat distribution, IMCL content in the tibialis anterior (TA) muscle (IMCL(TA)), and whole body insulin resistance were measured before and after the 4-wk period. The HF diet-induced increase in IMCL(TA) was strongly correlated with visceral fat accumulation and greater glucose intolerance in both groups. The increase in IMCL(TA) to visceral fat accumulation was threefold greater for fa/fa rats. In the glucocorticoid-induced model, insulin sensitivity was impaired with dexamethasone. In vivo adiposity and IMCL(TA) content measurements were combined with ex vivo analysis of plasma and muscle tissue. Dexamethasone treatment had minimal effects on visceral fat accumulation while increasing IMCL(TA) levels approximately 30% (P < 0.05) compared with controls. Dexamethasone increased plasma glucose by twofold and increased the saturated fatty acid content of plasma lipids [fatty acid (CH2)n/omegaCH3 ratio +15%, P < 0.05]. The lipid composition of the TA muscle was unchanged by dexamethasone treatment, indicating that the relative increase in IMCL(TA) observed in vivo resulted from a decrease in lipid oxidation. Visceral adiposity may influence IMCL accumulation in the context of dietary manipulations; however, a "causal" relationship still remains to be determined. Dexamethasone-induced insulin resistance likely operates under a different mechanism, i.e., independently of visceral adiposity.

Adipose Tissue↗

Lack of association of birth size with polymorphisms of two imprinted genes, IGF2R and GRB10.

Little is known about the determinants of birth size variability among individuals. Maternal and nutritional factors have been studied, but familial clustering suggests genetic factors as well. As a first step in testing this hypothesis, we examined common sequence variants in IGF2R and GRB10, two genes involved in the regulation of growth and subject to parental imprinting. The IGF2R gene was scanned with five polymorphisms spanning the coding and 3'-UTR for possible association with birth size in a set of 97 normal newborns in Greece. In addition, a silent SNP in GRB10 exon 2 was similarly tested as an exploratory first step. Birth weight and length were compared between groups of newborns divided according to which allele they had received from heterozygous parents. No significant differences were found between alleles in either gene, examined either by parental origin or in aggregate. Thus, we found no evidence that IGF2R variants modulate intrauterine growth within the normal range. If such variants exist in GRB10, they are not in linkage disequilibrium with the marker studied.

Alleles↗

Health-related millennium development goals: policy challenges for Pakistan.

OBJECTIVES: There are two objectives: (a) to clearly articulate the Millennium Development Goals (MDGs) adopted by the United Nations in 2000 and their implications for developing countries like Pakistan; and (b) to critically review the challenges faced by Pakistan in achieving the health-related MDGs. METHODS: A critical review of secondary data and information generated primarily by multilateral agencies and United Nations organizations. RESULTS: The MDGs represent a global consensus on the broad goals of development to be achieved by 2015. Of the eight Millennium Development Goals, three are specifically health related--reducing infant (under-5) and maternal mortality; and combating HIV/AIDS, tuberculosis, malaria and other significant communicable diseases. According to various studies, many developing countries will not achieve the MDGs without concerted efforts and commitment of additional resources. Like many other developing countries, Pakistan is also faced with an enormous challenge in reaching the Millennium Development Goals and targets set by the United Nations. For Pakistan, perhaps the most challenging MDG is that of reducing "by three-quarters the maternal mortality ratio." Maternal mortality is so intertwined with other "social" factors--including the status of women--that a comprehensive holistic approach is required. CONCLUSION: In order to achieve the MDGs, Pakistan would require a fundamental shift in its policy and strategic directions. Along with allocation of significant additional resources for health, it needs to review and reprioritize the use of existing resources, focusing more on primary health care. Pakistan must also adopt a holistic integrated approach that views health, education, and other social sector development as intrinsically interrelated and interwoven. Without such an integrated approach, achieving the health-related MDGs is likely to remain illusive for Pakistan. There is a critical need to foster a healthy debate on the health-related Millennium Development Goals in Pakistan so as to inform and, hopefully influence, public policy.

Developing Countries↗

Incidence of bony secondary at presentation of breast carcinoma in our region.

Study is conducted to evaluate the incidence of bony secondary and to evaluate the need for routine bone scintigraphy at the time of presentation of breast carcinoma in this region. Of the total 130 patients evaluated by bone scan, sixty (n = 60, 46.15%) had secondary lesion in bone. Among the 54 preoperative patients, all with positive FNAC, twenty (n = 20, 37.03%) had bony metastases. Of the 76 post-operative patients, forty (n = 40, 52.63%) had secondary bone lesions. Single lesion was seen in only five (n = 5, 8.53%) cases. Rest fifty five (n = 55, 91.67%) had multiple bony secondaries. Most of the postoperative cases (n = 40, 52.63%) were invasive/infiltrative duct cell carcinoma. The very high incidence of bony secondary appears to be due to delayed presentation associated with poor socioeconomic condition, ignorance and also shyness. Bony metastases at the time of presentation suggests poor prognosis. As it can affect therapeutic management of these patients, routine bone scintigraphy at the time of presentation of breast carcinoma patients to a tertiary label hospital is proposed, against conflicting conclusion by papers in the developed countries.

Adult↗

Estrogen and progesterone treatment: effects on muscarinic M(4) receptor subtype in the rat brain.

We investigated the effect of ovariectomy (OVX) and hormonal treatment for 10 weeks by estradiol and progesterone on muscarinic M(4) receptor subtype in different brain areas of female rats. Moreover, motor activity of OVX and hormone-treated rats was measured by automated open field exploration boxes. Receptor quantification in the hippocampus, frontal cortex, parietal cortex, amygdala and hypothalamus was done by receptor autoradiography using a selective ligand for muscarinic M(4) receptors. Ovariectomy up-regulated M(4) receptors in the dentate gyrus, CA1, CA3, frontal cortex and hypothalamus whereas the estrogen treatment restored M(4) binding to that of the sham group. Progesterone treatment had no effect on the ovariectomy-induced up-regulation of M(4) receptors. Ovariectomy significantly decreased the exploratory activity of the rats compared to the sham group. Estrogen treatment restored the exploratory behavior of the ovariectomized rats to that of the sham group whereas the progesterone-treated rats were less alert to the surrounding when compared to the sham and estrogen supplemented rats. The effect of estrogen on the hippocampal muscarinic M(4) receptor subtype is a novel finding and may have functional significance for cholinergic receptors especially in relation to postmenopausal memory problems and neurodegenerative disease like Alzheimer's disease.

Amygdala↗

Strengthening primary health care and family planning services in Pakistan: some critical issues.

OBJECTIVE: The Lady Health Workers (LHWs) under the Ministry of Health and the Village-based Family Planning Workers (VBFPWs) under the Ministry of Population Welfare are mandated to bring services to the people and are often the only health care resource available particularly for women. This study was conducted to understand the problems faced by the LHWs and VBFPWs in their routine work. STUDY DESIGN: A situational analysis followed by focus group discussions conducted with a cross-section of LHWs and VBFPWs in four districts, one from each province. RESULTS: Findings reveal that LHWs and VBFPWs are faced with a number of problems that severely limit their effectiveness. Findings suggest that the population/health worker ratios vary considerably from one district to another. Moreover, these two categories of workers differ considerably in terms of level of education, training and skills. There is lack of well-designed client record cards, proper training and backup support, including emergency obstetric care, to cover the range of essential services demanded by the consumers and a lack of information feedback. CONCLUSION: These issues need to be recognized and addressed to further strengthen primary health care and family planning services in the country. The paper presents some of the important findings of the survey and focus group discussions conducted by the Community Health Sciences Department of the Aga Khan University as part of a broader study funded by the United Nations Population Fund. These findings have serious implications for future primary health care and family planning policies in Pakistan.

Delivery of Health Care↗

Health sector reform in Pakistan: why is it needed?

OBJECTIVE: The health care system in Pakistan is beset with numerous problems--structural fragmentation, gender insensitivity, resource scarcity, inefficiency and lack of accessibility and utilization. Moreover, Pakistan is faced with a precarious economic situation, burdened by heavy external debt and faltering productivity and growing poverty. These circumstances, on the one hand, underscore the need for innovative health sector reform and, on the other, indicate the complexity of the task involved. The recently announced Devolution Plan of the Government of Pakistan (GOP) that seeks to introduce elected district level local bodies, offers an opportunity to assess the existing publicly funded health care system and introduce far-reaching reforms to make it more efficient and effective. STUDY DESIGN: Based on a critical analysis of secondary data from the public domain as well as from various research projects undertaken by the Aga Khan University, the paper intends to present convincing arguments for fundamental health sector reform in Pakistan. PRINCIPLE CONCLUSIONS: (a) All factors point to the need for a fundamental reform of the health sector in Pakistan; and (b) the Devolution Plan presents an unique opportunity that must be seized to reshape the health care system and make it more efficient and effective.

Developing Countries↗

Health sector reform in Pakistan: future directions.

The health care system in Pakistan is beset with numerous problems--structural fragmentation, gender insensitivity, resource scarcity, inefficiency and lack of functional specificity and accessibility. Faced with a precarious economic situation characterized by heavy external debt and faltering productivity, Pakistan's room to maneuver with health sector reform is quite limited. Although the recently announced Devolution Plan provides a window of opportunity, it must go beyond and introduce far-reaching changes in the health and social sectors. Regionalization of health care services in an integrated manner with functional specificity for each level of care is an essential step. Integration of current vertical programs within the framework of a need-based comprehensive primary health care system is another necessary step. Most importantly, fostering a public-private partnership to share the cost of basic primary health care and public health services must be an integral part of any reform. Pakistan must also make the health care system more gender sensitive through appropriate training programs for the service providers along with wide community participation in decision-making processes. Relevant WHO/World Bank/UNDP developed tools could be extremely useful in this respect. The article is based on a critical analysis of secondary data from the public domain as well as from various research projects undertaken by the Aga Khan University. It also draws from the experiences of health sector reform carried out in other countries, particularly those in the Asia-Pacific region. The purpose is to inform and hopefully influence, public policy as the country moves towards devolution.

Health Care Reform↗

Dye sensitization of nanocrystalline titanium dioxide with square planar platinum(II) diimine dithiolate complexes.

A series of platinum-based sensitizers of the general type Pt(NN)(SS), where NN is 4,4'-dicarboxy-2,2'-bipyridine (dcbpy) or 4,7-dicarboxy-1,10-phenanthroline (dcphen) and SS is ethyl-2-cyano-3,3-dimercaptoacrylate (ecda), quinoxaline-2,3-dithiolate (qdt), 1,2-benzenedithiolate (bdt), or 3,4-toluenedithiolate (tdt), that have various ground-state oxidation potentials has been synthesized and anchored to nanocrystalline titanium dioxide electrodes for light-to-electricity conversion in regenerative photoelectrochemical cells with an I(-)/I(-)(3) acetonitrile electrolyte. The intense mixed-Pt/dithiolate-to-diimine charge-transfer absorption bands in this series could be tuned from 440 to 580 nm by choosing appropriate dithiolate ligands, and the highest occupied molecular orbitals varied by more than 500 mV. Spectrophotometric titration of the Pt(dcphen)(bdt) complex exhibits a ground-state pK(a) value of 3.2 +/- 0.1, which can be assigned to the protonation of the carboxylate group of the dcphen ligand. Binding of Pt(dcbpy)(qdt) to porous nanostructured TiO(2) films was analyzed using the Langmuir adsorption isotherm model, yielding an adsorption equilibrium constant of 4 x 10(5) M(-1). The amount of dye adsorbed at the surface of TiO(2) films was 9.5 x 10(-8) mol/cm(2), which is ca. 50% lower than the full monolayer coverage. The resulting complexes efficiently sensitized TiO(2) over a notably broad spectral range and showed an open-circuit potential of ca. 600 mV with an impressive fill factor of > 0.70, making them attractive candidates for solar energy conversion applications. The visible spectra of the 3,4-toluenedithiol-based sensitizers showed an enhanced red response, but the lower photocurrent efficiency observed for these sensitizers stems in part from a sluggish halide oxidation rate and a fast recombination of injected electrons with the oxidized dye.

Journal Article↗

Evidence against GRB10 as the gene responsible for Silver-Russell syndrome.

Recent evidence shows that Silver-Russell syndrome (SRS), the major functional deficit of which is limited growth, both intrauterine and postnatal, is due to a double dose of a gene within 7p11.2-p13 that is normally expressed exclusively from the maternal copy. Of the several growth-related genes in this chromosomal region, only GRB10 has been demonstrated to be imprinted; however, imprinting was limited to brain and muscle and was incomplete. Using reverse-transcript PCR, we now confirm GRB10 imprinting in these two tissues is isoform-specific and, more importantly, demonstrate absence of imprinting in growth plate cartilage, the tissue most directly involved in linear growth. Thus, it is unlikely that GRB10 is the gene responsible for SRS.

Aged↗

Vasomax for the treatment of male erectile dysfunction.

This paper reviews laboratory and clinical data concerning oral phentolamine mesylate, Vasomax, an alpha-1, alpha-2 adrenergic receptor antagonist developed specifically for treatment of erectile dysfunction. A contemporary view of the neurovascular mechanisms in penile erection includes the effects of both smooth muscle relaxation and contraction. Contraction of the cavernosal arteries and trabecular smooth muscle appears to be predominantly under the control of alpha-adrenergic innervation. Conversely, adrenergic blockade of alpha-1 and alpha-2 receptors has been shown to facilitate penile erection in both animal and human models. The pharmacokinetic profile of Vasomax appears well suited for an oral erectogenic agent. Vasomax is rapidly absorbed and eliminated in normal males. Peak plasma concentrations are achieved in 30-60 min, and the half-life approximates 5-7 h. Food decreases the rate, but not the extent of bioavailability. Vasomax has low protein binding and is excreted primarily via urine and feces. There is a strong dose-response relationship in maximum plasma concentration (Cmax) and area under the curve (AUC), and there are no clear age-related differences in absorption or elimination rates. Efficacy of Vasomax has been systematically evaluated in two (ZON300, ZON301) large-scale, placebo-controlled trials, in addition to two long-term open-label studies. In both studies, Vasomax was associated with significant improvements in the erectile function domain scores of the International Index of Erectile Function (IIEF). Further improvements were noted as the duration of treatment and dose level were increased. The percentage of successful penetration attempts was also significantly improved with Vasomax compared to placebo. For patients who continued in open-label treatment with Vasomax, efficacy was generally well maintained. Vasomax was well tolerated by the majority of patients. The most common side effects observed were nasal congestion (10%), headache (3%), dizziness (3%), tachycardia (3%) and nausea (1%). Side effects were generally dose-related and in the mild-to-moderate range in all three studies. Furthermore, side effects seldom resulted in treatment discontinuation. Very few serious adverse events were observed in these trials. In summary, Vasomax appears to be effective in the treatment of male erectile dysfunction and well-tolerated by the majority of patients. The drug has a satisfactory side effect profile, without significant risk of cardiovascular effects. Results of clinical trials with Vasomax support the concept of adrenergic-blockade as a clinically relevant mechanism in the control of penile erection.

Adrenergic alpha-Antagonists↗

Neonatal morbidity and care-seeking behaviour in rural Bangladesh.

The present study was undertaken to assess the pattern of reported neonatal morbidity and the care-seeking behaviour for neonates in rural Bangladesh. Data were collected from 1511 women who had live births during January 1996-August 1998 in four rural subdistricts, which are the field sites of the Operations Research Project of the International Centre for Diarrhoeal Disease Research, Bangladesh. A structured questionnaire was used to collect information from the mothers who were interviewed in their homes. Forty-nine per cent of the neonates were reported to have suffered from some kind of morbidity. Fever was the most common morbidity reported in the study population (21 per cent), followed by breathing difficulty (11 per cent). Birth order, complications during pregnancy, and/or delivery and death of a sibling were found to be significantly associated with reported neonatal morbidity. Eighty-seven per cent of the mothers sought care for their newborns. Some were taken to several different providers, the commonest being homeopaths (38 per cent) and village doctors (37 per cent). Seventeen per cent were taken to trained providers, and only 5 per cent to government health facilities. Seeking care from trained providers was found to be associated with the gender of the neonate, birth order, antenatal care of the mother from trained providers, father's education and monthly expenditure of the family. The results of this study suggest that efforts should be made to raise community awareness regarding neonatal morbidity, the importance of seeking care from trained personnel and the availability of services for these conditions.

Adult↗

P53 mutations in carcinoma breast--a clinicopathological study.

OBJECTIVES: To find out the incidence of p53 mutations and their possible correlation with clinicopathological presentation in females with breast carcinoma. SETTINGS: Department of Surgery, Pakistan Institute of Medical Sciences, Islamabad. PATIENTS AND METHODS: Seventy four patients with operable carcinoma breast that underwent mastectomy were included in this prospective study. Tumour tissue specimens and peripheral blood samples were examined for p53 mutations. Age, tumour size, nodal status and histopathology was assessed in patients with and without p53 mutations. RESULTS: Ten (13.5%) patients showed p53 mutations in their tumour specimens while 64 (86.48%) had normally functioning p53 gene. Patients were divided into two groups, A (normally functioning p53), and B (mutated p53). Intraductal carcinoma was the most frequent histological variant(A = 57, B = 10), while lymph nodes were involved in 67.19% (A = 47) and 60% (B = 6) cases respectively. The age of patients and clinical parameters (tumour size, nodal status and histopathological diagnosis) were compared between the two groups and no statistically significant correlation between p53 mutations and clinicopathological parameters was found. CONCLUSIONS: It was concluded that p53 mutation is present in carcinoma breast in Pakistani population but there was no significant correlation between p53 mutation and tumour aggressiveness (size, nodal status and histopathology).

Breast Neoplasms↗

Role of traditional birth attendants in improving reproductive health: lessons from the family health project, Sindh.

OBJECTIVE PURPOSE OF THE STUDY: Despite strenuous efforts, the maternal mortality rate in Pakistan remains high. The national figure of 340 maternal deaths per 100,000 live births tends to hide the fact that in some rural areas it is as high as 700 per 100,000 live births. Not surprisingly, in Pakistan only 20% of births are attended by a trained health professional. In most rural areas, home to almost 70% of the population, traditional birth attendants (TBAs) deliver 90% of the births. TBAs, therefore, play a crucial role in the delivery of maternal health care in Pakistan. Realizing the importance of TBAs, the Family Health Project (FHP) of the Department of Health Sindh, financed by the World Bank, tried to enhance their knowledge and skills through comprehensive training programs. FHP provided training to 650 TBAs in 10 districts. The training was provided by the Department of Community Health Sciences (CHS) of the Aga Khan University (AKU) who acted as technical consultant to the project. STUDY DESIGN: A community-based qualitative post-intervention survey. RESULTS: Post-intervention survey of this seven-year project (1992-1999) revealed that (a) the training enhanced the knowledge and skills of the TBAs, (b) the trained TBAs provide more broader health care services and (c) they enjoy greater community acceptance and provide greater consumer satisfaction. It also showed that the TBAs remain the most available and accessible health resource in most rural settings. CONCLUSION: It is imperative that TBAs and their continuing training should remain central to any reproductive health intervention along with an effective referral system linking them to well-equipped emergency obstetric care facilities. However, the assessment clearly demonstrated that an integrated referral system backed by effective emergency obstetric care is essential to the success of the TBA training program.

Humans↗

Identification and characterization of a 500-kb homozygously deleted region at 1p36.2-p36.3 in a neuroblastoma cell line.

Loss of heterozygosity of the distal region of chromosome 1p where tumor suppressor gene(s) might harbor is frequently observed in many human cancers including neuroblastoma (NBL) with MYCN amplification and poor prognosis. We have identified for the first time a homozygously deleted region at the marker D1S244 within the smallest region of overlap at 1p36.2-p36.3 in two NBL cell lines, NB-1 and NB-C201 (MASS-NB-SCH1), although our genotyping has suggested the possibility that both lines are derived from the same origin. The 800-kb PAC contig covering the entire region of homozygous deletion was made and partially sequenced (about 60%). The estimated length of the deleted region was 500 kb. We have, thus far, identified six genes within the region which include three known genes (DFF45, PGD, and CORT) as well as three other genes which have been reported during processing our present project for the last 3(1/2) years (HDNB1/UFD2, KIAA0591F/KIF1B-beta, and PEX14). They include the genes related to apoptosis, glucose metabolism, ubiquitin-proteasome pathway, a neuronal microtubule-associated motor molecule and biogenesis of peroxisome. At least three genes (HDNB1/UFD2, KIAA0591F/KIF1B-beta, and PEX14) were differentially expressed at high levels in favorable and at low levels in unfavorable subsets of primary neuroblastoma. Since the 1p distal region is reported to be imprinted, those differentially expressed genes could be the new members of the candidate NBL suppressor, although RT-PCR-SSCP analysis has demonstrated infrequent mutation of the genes so far identified. Full-sequencing and gene prediction for the region of homozygous deletion would elucidate more detailed structure of this region and might lead to discovery of additional candidate genes. Oncogene (2000) 19, 4302 - 4307

Carrier Proteins↗

Anilides of (R)-trifluoro-2-hydroxy-2-methylpropionic acid as inhibitors of pyruvate dehydrogenase kinase.

The optimization of a series of anilide derivatives of (R)-3,3, 3-trifluoro-2-hydroxy-2-methylpropionic acid as inhibitors of pyruvate dehydrogenase kinase (PDHK) is described that started from N-phenyl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide 1 (IC(50) = 35 +/- 1.4 microM). It was found that small electron-withdrawing groups on the ortho position of the anilide, i.e., chloro, acetyl, or bromo, increased potency 20-40-fold. The oral bioavailability of the compounds in this series is optimal (as measured by AUC) when the anilide is substituted at the 4-position with an electron-withdrawing group (i.e., carboxyl, carboxyamide, and sulfoxyamide). N-(2-Chloro-4-isobutylsulfamoylphenyl)-(R)-3,3, 3-trifluoro-2-hydroxy-2-methylpropionamide (10a) inhibits PDHK in the primary enzymatic assay with an IC(50) of 13 +/- 1.5 nM, enhances the oxidation of [(14)C]lactate into (14)CO(2) in human fibroblasts, lowers blood lactate levels significantly 2.5 and 5 h after oral doses as low as 30 micromol/kg, and increases the ex vivo activity of PDH in muscle, kidney, liver, and heart tissues. However, in contrast to sodium dichloroacetate (DCA), these PDHK inhibitors did not lower blood glucose levels. Nevertheless, they are effective at increasing the utilization and disposal of lactate and could be of utility to ameliorate conditions of inappropriate blood lactate elevation.

Anilides↗

High expression of Survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma.

Survivin (SVV) is a family member of inhibitor of apoptosis proteins (IAPs) and its expression is cell cycle regulated. The gene is mapped to chromosome 17q25, the region of which is frequently gained in advanced stages of neuroblastoma (NBL). However, the role of SVV in NBL is poorly understood. Here we studied the clinical and biological role of SVV in NBL. A 1.9 kb SVV transcript was expressed in all of 9 NBL cell lines at higher levels than those in adult cancer cell lines. In 34 primary NBLs, high levels of SVV expression was significantly associated with age greater than 12 months (two sample t-test: P= 0.0003), advanced stages (P = 0.0136), sporadic tumors (P= 0.0027) and low levels of TrkA expression (P = 0.0030). In NBL cell lines, SVV mRNA expression was dramatically down-regulated in CHP134 and IMR32 cells undergoing apoptosis after treatment with all-trans retinoic acid (RA) or serum deprivation. It was only moderately decreased in cells (SH-SY5Y and CHP901) undergoing RA-induced differentiation. On the other hand, in proliferating NBL cells or RA-treated SK-N-AS line which is refractory to RA, the SVV mRNA remained at steady state levels or rather up-regulated. Furthermore, transfection of SVV into CHP134 cells induced remarkable inhibition of the RA-induced apoptosis. Collectively, our results suggest that high expression of SVV is a strong prognostic indicator for the advanced stage neuroblastomas, and that it could be one of the candidate genes for the 17q gain.

Apoptosis↗