Search

Aakash Ganju,1 Alessandra C Goulart,2 Amrit Ray,3 Anurita Majumdar,4 Barrett W Jeffers,3 Gloria Llamosa,5 Henry Cañizares,6 Ianne Jireh Ramos-Cañizares,6 Ibtihal Fadhil,7 Kannan Subramaniam,8 Lee-Ling Lim,9 Luna El Bizri,10 M Ramesh,11 Mathew Guilford,12 Raghib Ali,13 Ratna Duddi Devi,14,15 Rayaz A Malik,16 Shekhar Potkar,17 Yuan-Pang Wang18 1Executive Office, Saathealth, Mumbai, India; 2Center for Clinical and Epidemiological Research, University Hospital, University of São Paulo, São Paulo, Brazil; 3Research, Development and Medical, Upjohn – a Pfizer Division, New York, NY, USA; 4Research, Development and Medical, Emerging Markets, Upjohn – a Pfizer Division, Singapore; 5Mexican Neurology and Psychiatry Society, Mexico City, Mexico; 6Vicente Sotto Memorial Medical Center, Cebu City, Philippines; 7Eastern Mediterranean NCD Alliance, Kuwait City, Kuwait; 8Research, Development and Medical, Upjohn – a Pfizer Division, Sydney, Australia; 9Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 10School of Pharmacy, Lebanese University, Hadath, Lebanon; 11Lee Kuan Yew School of Public Policy, National University of Singapore, Singapore; 12Executive Office, Common Health, Kuala Lumpur, Malaysia; 13Public Health Research Center, New York University, Abu Dhabi, United Arab Emirates; 14Executive Office, DakshamA Health and Education, Gurgaon, India; 15Board of Directors, International Alliance of Patient Organizations, London, England; 16Weill Cornell Medicine, Doha, Qatar; 17Research, Development and Medical, Upjohn – a Pfizer Division, Dubai, United Arab Emirates; 18Instituto de Psiquiatria (LIM-23), Hospital das Clinicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, BrazilCorrespondence: Kannan SubramaniamResearch, Development and Medical, Upjohn – a Pfizer Division, Sydney, NSW 2000, AustraliaTel +61 413 569 077Email Kannan.Subramaniam@pfizer.comAbstract: Non-communicable diseases (NCDs) have been on the rise in low- and middle-income countries (LMICs) over the last few decades and represent a significant healthcare concern. Over 85% of “premature” deaths worldwide due to NCDs occur in the LMICs. NCDs are an economic burden on these countries, increasing their healthcare expenditure. However, targeting NCDs in LMICs is challenging due to evolving health systems and an emphasis on acute illness. The major issues include limitations with universal health coverage, regulations, funding, distribution and availability of the healthcare workforce, and availability of health data. Experts from across the health sector in LMICs formed a Think Tank to understand and examine the issues, and to offer potential opportunities that may address the rising burden of NCDs in these countries. This review presents the evidence and posits pragmatic solutions to combat NCDs.Keywords: low- and middle-income countries, multisectoral, non-communicable diseases, public–private partnership, universal health coverage

Mohamud A Verjee,1 Nael Amin Abdelsamad,2 Salman Qureshi,3,4 Rayaz A Malik1,5 1Department of Medicine, Weill Cornell Medicine – Qatar, Qatar Foundation, Education City, Doha, Qatar; 2Department of Paediatrics, University of Utah, Salt Lake City, UT 84112, USA; 3Department of Radiology, University of Manchester, Manchester M13 9PL, UK; 4Department of Radiology, Hamad Medical Corporation, Doha, Qatar; 5Institute of Cardiovascular Medicine, University of Manchester, Manchester, M13 9PL, UK Abstract: A patient with type 2 diabetes, retinopathy, neuropathy, and nephropathy presented with severe right distal thigh pain, which awoke him from sleep. He was diagnosed with musculoskeletal pain and discharged home. Two days later, the severity of pain increased in his right thigh and, subsequently, he developed pain in the proximal lateral aspect of his left thigh, for which he returned to hospital. He had elevated creatine kinase and myoglobin levels. An ultrasound of the right thigh identified a loss of definition of the normal muscular striations and subcutaneous edema. On MRI, the axial STIR image demonstrated extensive T2 hyperintensity in the right vastus medialis and left vastus lateralis, consistent with the diagnosis of diabetic muscle infarction (DMI). This presentation emphasizes the need for a thorough patient history and physical examination, and the importance of directed imaging for the prompt diagnosis of DMI. Keywords: muscle infarction, edema, microvascular, nephropathy, neuropathy, retinopathy, striations

Saad Javed,1,2 Uazman Alam,3–5 Rayaz A Malik1,2,6 1Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK; 2Manchester University Hospital, Manchester, UK; 3Diabetes and Endocrinology Research, Department of Eye and Vision Sciences and Pain Research Institute, Institute of Ageing and Chronic Disease, University of Liverpool and Aintree University Hospital NHS Foundation Trust, Liverpool, UK; 4Department of Diabetes and Endocrinology, Royal Liverpool and Broadgreen University NHS Hospital Trust, Liverpool, UK; 5Division of Endocrinology, Diabetes and Gastroenterology, University of Manchester, Manchester, UK; 6Department of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar Abstract: There are currently no approved disease-modifying therapies for diabetic neuropathy, and there are only 3 US Food and Drug Administration-approved therapies (pregabalin, duloxetine, and tapentadol) for painful diabetic neuropathy. They each have moderate efficacy with adverse effects limiting optimal dose titration. There is a considerable need for new therapies for the management of painful diabetic neuropathy. We reviewed the potential role of mirogabalin, which like gabapentin and pregabalin modulates the alpha-2/delta-1 subunit of the voltage-gated calcium channel, allowing the influx of calcium and release of neurotransmitters at the synaptic cleft in the central nervous system and spinal cord. It has shown efficacy and good tolerability in a Phase II study in diabetic painful neuropathy and based on the results of two Phase III clinical trials in diabetic painful neuropathy and post-herpetic neuralgia, Daiichi Sankyo submitted a marketing application for neuropathic pain in Japan in February 2018. We have also reviewed potential new therapies, currently in Phase II clinical trials that may modify disease and/or relieve neuropathic pain through novel modes of action. Keywords: diabetic neuropathy, painful diabetic neuropathy, treatment, mirogabalin

Reza Hajhosseiny,1 Kaivan Khavandi,1 Soudeh Mashayekhi,2 Adam S Greenstein,3 Rayaz A Malik31British Heart Foundation Centre of Cardiovascular Excellence, St Thomas' Hospital, London, UK; 2Department of Primary Care and Public Health, Imperial College London, London, UK; 3Institute of Human Development, University of Manchester, Manchester, UKAbstract: Individuals with type 2 diabetes mellitus are at very substantial risk of cardiovascular disease, and most will succumb to complications from premature coronary artery events. At the same time, the diabetic myocardium undergoes unique phenotypic alterations as a consequence of multiple structural and cellular injuries, which together form "diabetic cardiomyopathy." Attempts to curb risk through intensive modulation of glycemia and blood pressure have proven disappointing in preventing cardiovascular events, and potentially even dangerous. Conversely, prior to development of disease, there appears to be a linear relationship between risk parameters and events. These observations are likely the consequence of widespread vascular damage, which is present at the point that glycemic thresholds meet diagnostic criteria for diabetes. This is particularly true of the microcirculation. Interventions at the prediabetic stage have been consistent with this, where early intensive risk-factor modulation has been successful in preventing events and even regressing existing risk. Upstream, the force driving these pathologies is being overweight and obesity. High-risk individuals can be identified through simple body mass parameters, with confirmation of prediabetes/metabolic syndrome with further assessment of other metabolic parameters such as glucose and lipids. A number of novel pharmacotherapies may prove beneficial at this stage, and incretin-based therapies appear particularly promising in this respect. Similarly, bariatric procedures have shown remarkable improvements in metabolic and cardiovascular outcomes, but are clearly unsuitable as a population-wide strategy. Therapeutic lifestyle change and diet have consistently shown efficacy in reversing dysglycemia, lowering blood pressure, and optimizing cholesterol profiles. However, the longevity of these improvements is often limited, and alternative approaches therefore need to be considered. With an evolving and increasingly sophisticated evidence base for nutritional interventions, there is a clear window of opportunity to rescue these individuals from the clinical sequelae of diabetes and consequent cardiovascular complications.Keywords: hypertension, diabetes, cardiovascular risk

NIDDK, JDRF, and the Diabetic Neuropathy Study Group of EASD sponsored a meeting to explore the current status of animal models of diabetic peripheral neuropathy. The goal of the workshop was to develop a set of consensus criteria for the phenotyping of rodent models of diabetic neuropathy. The discussion was divided into five areas: (1) status of commonly used rodent models of diabetes, (2) nerve structure, (3) electrophysiological assessments of nerve function, (4) behavioral assessments of nerve function, and (5) the role of biomarkers in disease phenotyping. Participants discussed the current understanding of each area, gold standards (if applicable) for assessments of function, improvements of existing techniques, and utility of known and exploratory biomarkers. The research opportunities in each area were outlined, providing a possible roadmap for future studies. The meeting concluded with a discussion on the merits and limitations of a unified approach to phenotyping rodent models of diabetic neuropathy and a consensus formed on the definition of the minimum criteria required for establishing the presence of the disease. A neuropathy phenotype in rodents was defined as the presence of statistically different values between diabetic and control animals in 2 of 3 assessments (nocifensive behavior, nerve conduction velocities, or nerve structure). The participants propose that this framework would allow different research groups to compare and share data, with an emphasis on data targeted toward the therapeutic efficacy of drug interventions.

Abstract Background Non-reducing polyketide synthases (NR-PKSs) account for a major share of natural product diversity produced by both Asco- and Basidiomycota. The present evolutionary diversification into eleven clades further underscores the relevance of these multi-domain enzymes. Following current knowledge, NR-PKSs initiate polyketide assembly by an N-terminal starter unit:acyl transferase (SAT) domain that catalyzes the transfer of an acetyl starter from the acetyl-CoA thioester onto the acyl carrier protein (ACP). Results A comprehensive phylogenetic analysis of NR-PKSs established a twelfth clade from which three representatives, enzymes CrPKS1-3 of the webcap mushroom Cortinarius rufoolivaceus, were biochemically characterized. These basidiomycete synthases lack a SAT domain yet are fully functional hepta- and octaketide synthases in vivo. Three members of the other clade of basidiomycete NR-PKSs (clade VIII) were produced as SAT-domainless versions and analyzed in vivo and in vitro. They retained full activity, thus corroborating the notion that the SAT domain is dispensable for many basidiomycete NR-PKSs. For comparison, the ascomycete octaketide synthase atrochrysone carboxylic acid synthase (ACAS) was produced as a SAT-domainless enzyme as well, but turned out completely inactive. However, a literature survey revealed that some NR-PKSs of ascomycetes carry mutations within the catalytic motif of the SAT domain. In these cases, the role of the domain and the origin of the formal acetate unit remains open. Conclusions The role of SAT domains differs between asco- and basidiomycete NR-PKSs. For the latter, it is not part of the minimal set of NR-PKS domains and not required for function. This knowledge may help engineer compact NR-PKSs for more resource-efficient routes. From the genomic standpoint, seemingly incomplete or corrupted genes encoding SAT-domainless NR-PKSs should not automatically be dismissed as non-functional pseudogenes, but considered during genome analysis to decipher the potential arsenal of natural products of a given fungus.

Abstract Background Secondary metabolites (SMs) from mushroom-forming fungi (Basidiomycota) and early diverging fungi (EDF) such as Mucoromycota are scarcely investigated. In many cases, production of SMs is induced by unknown stress factors or is accompanied by seasonable developmental changes on fungal morphology. Moreover, many of these fungi are considered as non-culturable under laboratory conditions which impedes investigation into SM. In the post-genomic era, numerous novel SM genes have been identified especially from EDF. As most of them encode multi-module enzymes, these genes are usually long which limits cloning and heterologous expression in traditional hosts. Results An expression system in Aspergillus niger is presented that is suitable for the production of SMs from both Basidiomycota and EDF. The akuB gene was deleted in the expression host A. niger ATNT∆pyrG, resulting in a deficient nonhomologous end-joining repair mechanism which in turn facilitates the targeted gene deletion via homologous recombination. The ∆akuB mutant tLK01 served as a platform to integrate overlapping DNA fragments of long SM genes into the fwnA locus required for the black pigmentation of conidia. This enables an easy discrimination of correct transformants by screening the transformation plates for fawn-colored colonies. Expression of the gene of interest (GOI) is induced dose-dependently by addition of doxycycline and is enhanced by the dual TetON/terrein synthase promoter system (ATNT) from Aspergillus terreus. We show that the 8 kb polyketide synthase gene lpaA from the basidiomycete Laetiporus sulphureus is correctly assembled from five overlapping DNA fragments and laetiporic acids are produced. In a second approach, we expressed the yet uncharacterized > 20 kb nonribosomal peptide synthetase gene calA from the EDF Mortierella alpina. Gene expression and subsequent LC–MS/MS analysis of mycelial extracts revealed the production of the antimycobacterial compound calpinactam. This is the first report on the heterologous production of a full-length SM multidomain enzyme from EDF. Conclusions The system allows the assembly, targeted integration and expression of genes of > 20 kb size in A. niger in one single step. The system is suitable for evolutionary distantly related SM genes from both Basidiomycota and EDF. This uncovers new SM resources including genetically intractable or non-culturable fungi.

Advanced LIGO and Advanced Virgo are monitoring the sky and collecting gravitational-wave strain data with sufficient sensitivity to detect signals routinely. In this paper we describe the data recorded by these instruments during their first and second observing runs. The main data products are gravitational-wave strain time series sampled at 16384 Hz. The datasets that include this strain measurement can be freely accessed through the Gravitational Wave Open Science Center at http://gw-openscience.org, together with data-quality information essential for the analysis of LIGO and Virgo data, documentation, tutorials, and supporting software.

Preceding the joint meeting of the 19th annual Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes (NEURODIAB) and the 8th International Symposium on Diabetic Neuropathy in Toronto, Canada, 13-18 October 2009, expert panels were convened to provide updates on classification, definitions, diagnostic criteria, and treatments of diabetic peripheral neuropathies (DPNs), autonomic neuropathy, painful DPNs, and structural alterations in DPNs. [ABSTRACT FROM AUTHOR]

Objective: The accurate quantification of human diabetic neuropathy is important to define at-risk patients, anticipate deterioration, and assess new therapies.Research Design and Methods: A total of 101 diabetic patients and 17 age-matched control subjects underwent neurological evaluation, neurophysiology tests, quantitative sensory testing, and evaluation of corneal sensation and corneal nerve morphology using corneal confocal microscopy (CCM).Results: Corneal sensation decreased significantly (P = 0.0001) with increasing neuropathic severity and correlated with the neuropathy disability score (NDS) (r = 0.441, P < 0.0001). Corneal nerve fiber density (NFD) (P < 0.0001), nerve fiber length (NFL), (P < 0.0001), and nerve branch density (NBD) (P < 0.0001) decreased significantly with increasing neuropathic severity and correlated with NDS (NFD r = -0.475, P < 0.0001; NBD r = -0.511, P < 0.0001; and NFL r = -0.581, P < 0.0001). NBD and NFL demonstrated a significant and progressive reduction with worsening heat pain thresholds (P = 0.01). Receiver operating characteristic curve analysis for the diagnosis of neuropathy (NDS >3) defined an NFD of <27.8/mm(2) with a sensitivity of 0.82 (95% CI 0.68-0.92) and specificity of 0.52 (0.40-0.64) and for detecting patients at risk of foot ulceration (NDS >6) defined a NFD cutoff of <20.8/mm(2) with a sensitivity of 0.71 (0.42-0.92) and specificity of 0.64 (0.54-0.74).Conclusions: CCM is a noninvasive clinical technique that may be used to detect early nerve damage and stratify diabetic patients with increasing neuropathic severity. [ABSTRACT FROM AUTHOR]

Objective: The objective of this analysis was to evaluate the cost-effectiveness of duloxetine when considered as an additional treatment option for UK-based patients suffering from diabetic peripheral neuropathic pain.Research Design and Methods: A decision-analytic model was used to represent the sequential management of patients with diabetic peripheral neuropathic pain. The standard UK treatment strategy was defined as first-line tricyclic antidepressants (amitriptyline), second-line anticonvulsants (gabapentin) and lastly an opioid-related treatment. The cost-effectiveness of duloxetine was evaluated as an additional first, second, third or fourth-line therapy over a 6-month treatment period for a cohort of 1000 patients. Treatment response was modelled based on changes from baseline pain severity using a standard 11-point pain scale (0-10); full response (>or= 50% change), partial response (30-49%) and no response (< 30%). The model was populated with efficacy and discontinuation data using indirect comparisons of treatment efficacy based on relative effects to a common placebo comparator.Results: The second-line use of duloxetine resulted in cost savings of pound 77,071 for every 1000 treated patients, with an additional 29 patients achieving a full pain response when compared to standard UK treatment. Additional quality-adjusted life years (QALYs) were achieved at 1.88 QALYs per 1000 patients.Conclusions: This UK-based economic model suggests that second-line use of duloxetine is a beneficial and cost-effective treatment strategy for diabetic peripheral neuropathic pain. [ABSTRACT FROM AUTHOR]

The long-term microvascular complications of diabetes pose a major health burden. Although, much of the focus has been on the macrovascular complications, it is clear that the microvascular complications have a significant impact on both morbidity and mortality amongst diabetic patients. Indeed retinopathy, nephropathy, and neuropathy compete as the leading causes of premature blindness, end-stage renal disease, and non-traumatic lower-limb amputation, respectively. Furthermore, complications develop and progress in unison and indeed share many common risk factors. Effective evaluation and monitoring of these complications in clinical practice is clearly important, however, it is also relevant to clinical intervention studies, and drug development programs addressing microvascular complications. Novel diagnostic and therapeutic strategies are continually evolving in this area and will be discussed in more detail in this review. [ABSTRACT FROM AUTHOR]

Background and Aims: Eclampsia is a common hypertensive disorder of pregnancy and treatment often includes termination of pregnancy with elective postoperative mechanical ventilation. The present study was aimed to compare midazolam, propofol, and dexmedetomidine for sedation and antihypertensive requirements of such patients admitted to Intensive Care Unit (ICU) after termination of pregnancy. Material and Methods: A total of ninety eclamptic patients administered general anesthesia for the termination of pregnancy through cesarean section and who also required postoperative ventilation were taken up for the study and were randomly allocated into three groups. All patients received MgSO4 (loading dose, 4 g intravenous) following first seizure episode followed by a continuous infusion for next 24 h. Midazolam group (GrM) received 0.05 mg/kg loading dose of midazolam, followed by infusion of 0.05–0.3 mg/kg/h, propofol group (GrP) received 1 mg/kg loading dose of propofol followed by infusion of 2–8 mg/kg/h, and dexmedetomidine group (GrD) received dexmedetomidine loading dose at 1 mcg/kg followed by infusion of 0.2–1.2 mcg/kg/h. Postoperatively, patients were assessed for hemodynamic stability, requirement of antihypertensive and analgesics, duration of sedation and stop sedation-discharge, and total time spent in the ICU. Results: Mean heart rate and mean arterial pressure recorded at different time intervals were lowest in GrD. Nearly 70% (n = 21) patients in the GrM required antihypertensive, 50% (n = 15) in GrP, and 36.6% (n = 11) in the GrD (P < 0.05). Duration of stop sedation-discharge from ICU was least in GrD. A number of patients demanding additional analgesics was also least in GrD. Conclusion: Sedation with dexmedetomidine produced better hemodynamic stability in eclamptic patients, and there was a significant reduction in requirement of additional analgesics (P = 0.035) and antihypertensive (P = 0.004). Total duration of ICU stay was also less in this group of patients.

This paper presents a FACTS operation scheme to enhance the power system security. Three main generic types of FACTS devices are introduced. Line overloads are solved by controlling active power of series compensators and low voltages are solved by controlling reactive power of shunt compensators, respectively. Especially, the combined series-shunt compensators such as UPFC are applied to solve both line congestions and low voltages simultaneously. Two kinds of indices that indicate the security level related to line flow and bus voltage is utilized in this paper. They are iteratively minimized to determine operating points of the devices for security enhancement. The sensitivity vectors of the indices are derived to determine the direction of minimum. The proposed algorithm is verified on the IEEE 14-bus system with FACTS devices in a normal condition and in a line-faulted contingency.

Let $M$ be a prime $\Gamma$-ring and $U$ be a nonzero ideal of $M$. An additive mapping $d:M\longrightarrow M,$ where $M$ is a $\Gamma$-ring, is called a derivation if for any $a,b\in M$ and$\alpha \in \Gamma$, $d(a\alpha b)=d(a)\alpha b+a\alpha d(b)$. In this paper, we investigate the commutativity of prime $\Gamma$-ring satisfying certain differential identities.

Mechanical removal of the biofilm and adjunctive use of antibacterial disinfectants or various antibiotics have been conventional methods of the periodontitis therapy. There has been an upsurge of bacterial strains becoming resistant due to the injudicious use of antibiotics, recently. As a result there is pronounced interest and keenness in the development of alternate antimicrobial concepts. As the scientific community seeks alternatives to antibiotic treatment, periodontal researchers have found that photodynamic therapy (PDT) is advantageous to suppress anaerobic bacteria. Hence, PDT could be an alternative to conventional periodontal therapeutic methods. This review elucidates the evolution and use of photo dynamic therapy. The application of photosensitizing dyes and their excitation by visible light enables effective killing of periodontopathogens. Even though PDT is still in the experimental stages of development and testing, the method may be an adjunct to conventional antibacterial measures in periodontology. PDT application has an adjunctive benefit besides mechanical treatment at sites with difficult access. Necessity for flap operations may be reduced, patient comfort may increase and treatment time decrease. Clinical follow-up studies are needed to confirm the efficacy of the procedure.

Classification of skeletal angiomatosis into aggressive and nonaggressive types is on the basis of their clinical behavior and pattern of skeletal involvement (regional and disseminated). Gorham′s disease (massive osteolysis) is an aggressive form of skeletal angiomatosis that shows regional involvement, frequently involving the shoulder and hip areas. Cystic angiomatosis is a nonaggressive form of skeletal angiomatosis with multifocal involvement, predominantly affecting the trunk bones. The imaging modalities gave the diagnosis of cystic angiomatosis of humerus showing multicystic lytic areas. The histopathological differential diagnosis was cystic angiomatosis and Gorham′s disease, as microscopically both are indistinguishable from each other. Both represent a complex network of dilated thin-walled capillaries growing in the marrow space associated with the destruction of bone and infiltration into the adjacent soft tissues. The case is presented because of its extreme rarity and due to the diagnostic dilemma, whether to label it as Gorham′s disease or as cystic angiomatosis. Considering the site involved and its aggressiveness, the diagnosis is in favor of Gorham′s vanishing bone disease as cystic angiomatosis is multicentric and nonaggressive, involving mostly vertebrae and skull with multicystic lytic lesions.

The U.S. Environmental Protection Agency’s (EPA) Water Laboratory Alliance relies on the Centers for Disease Control and Prevention’s ultrafiltration-based Water Processing Procedure (WPP) for concentration of biosafety level 3 (BSL-3) agents from 10 L to 100 L of drinking water. The WPP requires comprehensive training and practice to maintain proficiency, resulting in a critical need for quality control (QC) criteria. The aim of this study was to develop criteria using male-specific (MS2) coliphage (BSL-2 agent) to minimize safety hazards associated with BSL-3 agents and to use the criteria to evaluate analytical proficiency during a demonstration exercise. EPA Method 1602 with EasyPhage was used during the study to develop QC criteria for 100-mL, and 40–100 L samples. The demonstration exercise indicated that the MS2 criteria would allow laboratories to demonstrate proficiency using the WPP with 40–100 L samples. In addition, the QC criteria developed for 100-mL samples has broad applicability at laboratories that are using MS2 for other types of analyses, such as assessment of water treatment devices. The development of MS2 QC criteria allows laboratories to develop and confirm ongoing proficiency using the WPP.

Abstract Papillary carcinoma of thyroid is the most common type of thyroid neoplasm which is usually confined to the thyroid and tends to metastasize to regional lymph nodes. Distant metastasis occur in up to 15% of cases. Thymic metastasis from any malignant carcinoma is extremely rare with only four cases reported in medical literature. We report a case of papillary carcinoma of thyroid metastasizing to ectopic cervical thymus which has not been previously reported.

Abstract Background Alstrom syndrome (AS) is a rare autosomal recessive disease characterized by multiorgan dysfunction. The key features are childhood obesity, blindness due to congenital retinal dystrophy, and sensorineural hearing loss. Associated endocrinologic features include hyperinsulinemia, early-onset type 2 diabetes, and hypertriglyceridemia. Thus, AS shares several features with the common metabolic syndrome, namely obesity, hyperinsulinemia, and hypertriglyceridemia. Mutations in the ALMS1 gene have been found to be causative for AS with a total of 79 disease-causing mutations having been described. Case presentation We describe the case of a 27-year old female from an English (Caucasian) kindred. She had been initially referred for hypertriglyceridemia, but demonstrated other features suggestive of AS, including blindness, obesity, type 2 diabetes, renal dysfunction, and hypertension. DNA analysis revealed that she is a compound heterozygote with two novel mutations in the ALMS1 gene – H3882Y and V424I. Examination of her family revealed that her phenotypically unaffected mother and younger sister also had heterozygous mutations in the ALMS1 gene. In addition to presenting these novel molecular findings for AS, we review the clinical and genetic features of AS in the context of our case. Conclusion Two novel mutations in the ALMS1 gene causative for AS have been reported here, thereby increasing the number of reported mutations to 81 and providing a wider basis for mutational screening among affected individuals.

Abstract Background Head and neck cancers are a major cancer burden in Pakistan. They share a common risk factor profile including regular consumption of products of betel, areca and tobacco. Use of paan, chaalia, gutka, niswar and tumbaku is acceptable in Pakistan and is considered a normal cultural practice. This cross-sectional study was carried out to understand the relation of socio-demographic factors for the consumption of paan, chaalia, gutka, niswar and tumbaku in Pakistani population. Through systematic sampling, 425 subjects from a squatter settlement in Karachi were interviewed using a structured questionnaire. High risk behavior was defined as Daily use of any of the above products. Results Daily use of all the substances except chaalia was higher among males compared to females. Chaalia use was higher among adolescents than adults while non-married consumed both chaalia and gutka more than married. Mohajir ethnicity had higher prevalence of paan, gutka and tumbaku use while Pathans had higher prevalence of niswar use. Conclusion Prevalence of use of chewable products is high in Pakistan with particularly high use of certain substances related with socio-demographic profiles. Industrially prepared products, chaalia and gutka, are gaining popularity among youth. Policies and focused interventions can be developed taking into consideration the preferred use of products among different socio-demographic groups.