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Islamabad, Pakistan

Paracha R.Z.,National University of Sciences and Technology | Ali A.,National University of Sciences and Technology | Ahmad J.,National University of Sciences and Technology | Hussain R.,Shifa Tameer e Millat University | And 2 more authors.
Computational Biology and Chemistry

A number of diseases including sepsis, rheumatoid arthritis, diabetes, cardiovascular diseases and hyperinflammatory immune disorders have been associated with Toll like receptor (TLR) 2 and TLR4. Endogenous adaptor protein known as MyD88 adapter-like protein (MAL) bind exclusively to the cytosolic portions of TLR2 and TLR4 to initiate downstream signalling. Brutons tyrosine kinase (BTK) and protein kinase C delta (PKCδ) have been implicated to phosphorylate MAL and activate it to initiate downstream signalling. BTK has been associated with phosphorylation at positions Tyr86 and Tyr106, necessary for the activation of MAL but definite residual target of PKCδ in MAL is still to be explored. To produce a better understanding of the functional domains involved in the formation of MAL-kinase complexes, computer-aided studies were used to characterize the protein-protein interactions (PPIs) of phosphorylated BTK and PKCδ with MAL. Docking and physicochemical studies indicated that BTK was involved in close contact with Tyr86 and Tyr106 of MAL whereas PKCδ may phosphorylate Tyr106 only. Moreover, the electrostatics charge distribution of binding interfaces of BTK and PKCδ were distinct but compatible with respective regions of MAL. Our results implicate that position of Tyr86 is specifically phosphorylated by BTK whereas Tyr106 can be phosphorylated by competitive action of both BTK and PKCδ. Additionally, the residues of MAL which are necessary for interaction with TLR2, TLR4, MyD88 and SOCS-1 also play their roles in maintaining interaction with kinases and can be targeted in future to reduce TLR2 and TLR4 induced pathological responses. © 2014 Elsevier Ltd. All rights reserved. Source

Ayub Q.,Wellcome Trust Sanger Institute | Mezzavilla M.,Wellcome Trust Sanger Institute | Mezzavilla M.,University of Trieste | Pagani L.,Wellcome Trust Sanger Institute | And 6 more authors.
American Journal of Human Genetics

The Kalash represent an enigmatic isolated population of Indo-European speakers who have been living for centuries in the Hindu Kush mountain ranges of present-day Pakistan. Previous Y chromosome and mitochondrial DNA markers provided no support for their claimed Greek descent following Alexander III of Macedon's invasion of this region, and analysis of autosomal loci provided evidence of a strong genetic bottleneck. To understand their origins and demography further, we genotyped 23 unrelated Kalash samples on the Illumina HumanOmni2.5M-8 BeadChip and sequenced one male individual at high coverage on an Illumina HiSeq 2000. Comparison with published data from ancient hunter-gatherers and European farmers showed that the Kalash share genetic drift with the Paleolithic Siberian hunter-gatherers and might represent an extremely drifted ancient northern Eurasian population that also contributed to European and Near Eastern ancestry. Since the split from other South Asian populations, the Kalash have maintained a low long-term effective population size (2,319-2,603) and experienced no detectable gene flow from their geographic neighbors in Pakistan or from other extant Eurasian populations. The mean time of divergence between the Kalash and other populations currently residing in this region was estimated to be 11,800 (95% confidence interval = 10,600-12,600) years ago, and thus they represent present-day descendants of some of the earliest migrants into the Indian sub-continent from West Asia. © 2015 The Authors. Source

Abdullah M.A.,Health Services Academy | Abdullah M.A.,Shifa Tameer e Millat University | Shaikh B.T.,Health Services Academy
Global Health Action

Pakistan has moved from a 'low prevalence-high risk' to a 'concentrated epidemic' state, yet the forcefulness required for managing this silent escalation of HIV infected numbers is not being highlighted, as it should be. A more comprehensive review of the national strategy for HIV/AIDS would necessitate a system's thinking. For this purpose, the WHO's Health Systems Building Blocks have been discussed to analyse whether this framework can be employed to take some corrective measures. An extensive literature review in this regard helps to understand that the service delivery has to be responsive, but skilled human resources, a robust information system, an uninterrupted supplies and use of latest technology, adequate financing, and above all good governance at operational level are essential ingredients, which call for re-orienting the national programme today. Lack of coordination, capacity, and interventions with questionable sustainability pave a perilous path. Hitherto, the issue can be addressed by involving stakeholders from all levels of the society and managing the void between policy and implementation. Furthermore, interventions that focus on the long-term future are imperative to combat the menace threatening human lives. © 2015 Muhammad Ahmed Abdullah and Babar Tasneem Shaikh. Source

Omair A.,University of Oslo | Omair A.,Shifa Tameer e Millat University | Mannion A.F.,Spine Center Division | Holden M.,Norwegian Computing Center | And 5 more authors.
European Spine Journal

Purpose: Does lumbar fusion lead to accelerated adjacent segment disc degeneration (ASDD) or is it explained by genetics and aging? The influence of genetics on ASDD remains to be explored. This study assesses whether the disc space height adjacent to a fused segment is associated with candidate gene single nucleotide polymorphisms (SNPs). Methods: Patients with low back pain from four RCTs (N = 208 fusion; 77 non-operative treatment) underwent standing plain radiography and genetic analyses at 13 ± 4 years follow-up. Disc space height was measured using a validated computer-assisted distortion-compensated roentgen analysis technique and reported in standard deviations from normal values. Genetic association analyses included 34 SNPs in 25 structural, inflammatory, matrix degrading, apoptotic, vitamin D receptor and OA-related genes relevant to disc degeneration. These were analysed for their association with disc space height (after adjusting for age, gender, smoking, duration of follow-up and treatment group) first, separately, and then together in a stepwise multivariable model. Results: Two SNPs from the IL18RAP gene (rs1420106 and rs917997) were each associated with a lower disc space height at the adjacent level (B = −0.34, p = 0.04 and B = −0.35, p = 0.04, respectively) and the MMP-9 gene SNP rs20544 was associated with a greater disc space height (B = 0.35, p = 0.04). Age (p < 0.001) and fusion (p < 0.008) were also significant variables in each analysis. The total explained variance in disc space height was for each SNP model 13–14 %, with 11–12 % of this being accounted for by the given SNP, 64–67 % by age and 19–22 % by fusion. In the multivariable regression analysis (with nine SNPs selected for entry, along with the covariates) the total explained variance in disc space height was 23 %, with the nine SNPs, age and fusion accounting for 45, 45 and 7 % of this, respectively. Conclusions: Age was the most significant determinant of adjacent segment disc space height followed by genetic factors, specifically inflammatory genes. Fusion explained a statistically significant but small proportion of the total variance. Much of the variance remained to be explained. © 2015, Springer-Verlag Berlin Heidelberg. Source

Rashid M.,Shifa Tameer e Millat University | Tamimy M.S.,Royal Infirmary
Indian Journal of Plastic Surgery

Phalloplasty has come a long way as Plastic Surgery has evolved over the years. The complication ridden multistage tube pedicles popularized by Gillis were, with the advent of microsurgery, replaced by radial forearm flaps. The composite osteo.cutaneous version of this flap promised 'eAll for one and one for all'f assuring both a reliable urinary conduit and a phallus stiffener. Prelamination and prefabrication to make the neo.urethra came with the promise of reducing both fistula and strictures but that did not happen and flap failure rates increased. Penile stiffeners of various types have been introduced; the artificial ones were associated with high infection and failure rates and are best inserted after the neo.penis regains some sensitivity. With the introduction of perforator flaps the Anterolateral thigh flap in its sensate pedicled form has started replacing the Radial forearm free flap as the first choice flap because of a hidden donor area and lack of microsurgical expertise requirement. Being sensate it tolerates a stiffener better. It is now possible to reconstruct an aesthetically pleasing glans as well, thus meeting both the aesthetic and functional desires of the patient. Complications encountered in this reconstructive effort include flap failure, urethral fistula, urethral stricture and stiffener related problems. Source

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