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

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]

Painful diabetic neuropathy is a common and troubling complication of diabetes. Many current treatments are based on anecdotal reports or relatively small clinical trials in which the efficacy of the agents is questionable, reflecting the fact that none is specifically licensed for the management of painful diabetic neuropathy. Despite these limitations the authors provide a practical algorithm based on a number needed to treat analysis together with an assessment of drug safety. We advocate an improvement in overall glycaemic control together with a reduction in glucose flux, coupled with a stepwise approach starting with a tricyclic, followed by gabapentin, tramadol and carbamazepine. We do not recommend combination treatment. Copyright ©2004 John Wiley & Sons, Ltd. [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.

Noonan's syndrome is a relatively common, multiple congenital anomaly syndrome, genetically inherited as an autosomal dominant disorder with variable penetrance. It is defined by a characteristic phenotype, congenital heart disease, ocular defects and mild mental retardation. Molecular studies have confirmed that it is a heterogeneous disorder and there may be evidence for an autosomal recessive mode of inheritance.1 The gene responsible for Noonan' syndrome has been mapped to the long arm of chromosome 12.2,3 The human deltex gene (DLT x 1), mapping to chromosomal region 12q24 in the vicinity of the Noonan's syndrome critical region is being evaluated as a candidate gene for this disorder.4 Various types of musculoskeletal abnormalities have been reported, including short stature, craniofacial dysmorphism, short or webbed neck and fetal pads in fingers and toes.5 We report five cases with the unusual physical features of overriding toes and simian creases. Such abnormalities can be considered among the minor manifestations of the syndrome. [ABSTRACT FROM AUTHOR]

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.

An abstract of the article "Corneal Confocal Microscopy to Diagnose Idiopathic Small Fibre Neuropathy," is presented.

Early detection of cardiac autonomic neuropathy (CAN) is imperative for successful therapeutic intervention. The streptozotocin-diabetic minipig is a suitable model to study cardiac function and determine the earliest markers of the condition. Blood Pressure (BP) and Heart Rate (HR) variability, analysed with spectral analysis and performed in control animals exhibited a mostly unique peak synchronized with respiration. The Respiratory Peak (RP) of HR was dramatically reduced by atropine, suggesting a vagal control of this oscillation. A pharmacological baroreflex curve was also constructed, and the gain of this curve was found significantly related (r = 0.70, p < 0.05) with the gain of the cross-spectral analysis between SBP and HR. Diabetes significantly decreased BP at 3 and 6 months and increased HR at 6 months (77.4 ± 3.8 vs 66.6 ± 2.7 bpm). The RP of HR was significantly lowered at 3 months (3.2 ± 0.4 vs 5.6 ± 0.7 bpm) and was still decreased at 6 months (3.7 ± 0.5 vs 4.9 ± 0.7 bpm). The gain of the cross spectral analysis was also reduced at the early stage of the disease (1.1 ± 0.2 vs 1.6 ± 0.4 bpm/mmHg, p < 0.05). Morphometric analysis revealed abnormalities only in the proximal vagus nerve with a significant difference in the axon and fibre size frequency distribution between controls and diabetic animals (p = 0.05), due to a greater proportion of fibers with smaller axon sizes (<3 μm2) in diabetic minipigs. In conclusion this model exhibited CAN at an early stage of diabetes with an impairment of the baroreflex sensitivity associated with structural changes of proximal vagus nerve. [ABSTRACT FROM AUTHOR]

12 diabetic patients aged 47.5 ± 9.4 yr., duration of diabetes (14.6 ± 10.3 yr.) and 15 control subjects were studied. In diabetic patients neuropathy symptom score =0, neuropathy deficit score = 4.5 + 0.7/30, vibration = 12.0 + 1.8 V, thermal perception (2.0 + 0.8°C), heart rate variation during deep breathing (17.8 + 2.3), 30:15 ratio (1.31 + 0.07) was normal. Baseline (n=12) and repeat neurophysiology (n=10) performed 8.7 + 0.6 years after sural nerve biopsy demonstrated normal values at baseline, with progression of neuropathy (peroneal motor nerve conduction velocity (ms−1) (42.3 + 2.9 v 39.4 +2.0), sural nerve conduction velocity (45.4 + 3.7 v 43.6 + 1.7). Myelinated fibre density, fibre and axonal area and g-ratio were not significantly reduced. Teased fibre studies showed paranodal abnormalities (p < 0.001), segmental demyelination (P < 0.01) with remyelination (P < 0.01) without axonal degeneration. Unassociated Schwann cell profile density (p < 0.04) and axon density (P < 0.001) were increased and axon diameter was decreased (P < 0.007) with a shift of the size frequency distribution to the left (skewness- 0.89 v 0.64, P < 0.03) suggestive of unmyelinated axonal atrophy/regeneration. Endoneurial capillary basement membrane thickening (P < 0.006), endothelial cell hyperplasia (P < 0.004) and luminal narrowing (P < 0.007) occurred. Current measures of neuropathy are too insensitive to detect significant nerve fibre pathology. The presence of microangiopathy provides support for a microvascular basis of diabetic neuropathy. [ABSTRACT FROM AUTHOR]

Aim: Obesity is a major risk factor for diabetic peripheral neuropathy (DPN) in type 2 diabetes (T2D). This study investigated the effect of glucose lowering medication associated with weight change on DPN., Methods: Participants with T2D were grouped based on whether their glucose lowering medications were associated with weight gain (WG) or weight loss (WL). They underwent clinical, metabolic testing and assessment of neuropathic symptoms, vibration perception threshold (VPT), sudomotor function and corneal confocal microscopy (CCM) at baseline and follow-up between 4 and 7 years., Results: Of 76 participants, 69.7% were on glucose lowering medication associated with WG, and 30.3% were on glucose lowering medication associated with WL. At baseline, participants in the WG group had a significantly longer duration of diabetes (p < .01), higher douleur neuropathique en 4 (DN4) score (p < .0001) and VPT (p = .01) compared with those in the WL group. Over a 56-month period, participants in the WG group showed no significant change in body weight (p = .11), HbA1c (p = .18), triglycerides (p = .42), DN4 (p = .11), VPT (p = .15) or Sudoscan (p = .43), but showed a decline in corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD) and corneal nerve fiber length (CNFL) (p < .0001). Participants in the WL group showed a reduction in weight (p = .01) and triglycerides (p < .05), no change in DN4 (p = .30), VPT (p = .31) or Sudoscan (p = .17) and a decline in the corneal nerve branch density (p < .01)., Conclusions: Participants treated with glucose lowering medication associated with weight gain had worse neuropathy and greater loss of corneal nerves during follow-up, compared to patients treated with medication associated with weight loss., (© 2024 The Author(s). Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.)

Background/aim: Obesity and related metabolic abnormalities in adults are associated with peripheral neuropathy. Acanthosis nigricans (AN) is associated with insulin resistance, fatty liver, hyperlipidemia and glucose intolerance, all of which are risk factors for neuropathy. The aim of this study was to investigate if obese adolescents with AN have evidence of small nerve fiber damage., Material and Methods: Adolescents with obesity with and without AN underwent body composition analysis, assessment of vibration perception threshold (VPT), monofilament sensitivity and corneal confocal microscopy (CCM) to quantify corneal nerve fiber density (CNFD), branch density (CNBD), length (CNFL) and inferior whorl length (IWL)., Results: Forty-six participants with obesity with (n = 31) and without (n = 15) AN aged 15(14-17) years were compared to 20 healthy controls aged 13(12-14) years. There was no difference in VPT, monofilament sensitivity and CCM measures between adolescents with obesity and controls. However, adolescents with AN had a significantly higher weight (P = 0.022), fat% (P = 0.029) and fat-muscle ratio (P = 0.012) with a lower CNFD (P = 0.045) compared to those with obesity without AN., Conclusion: Adolescents with obesity and acanthosis nigricans have a higher fat mass and small nerve fibre loss, indicative of a sub-clinical neuropathy., Competing Interests: NO authors have competing interests., (Copyright: © 2024 Gad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Epidemiological and toxicological studies indicate that increased exposure to air pollutants can lead to neurodegenerative diseases. To further confirm this relationship, we evaluated the association between exposure to ambient air pollutants and corneal nerve measures as a surrogate for neurodegeneration, using corneal confocal microscopy., Methods: We used population-based observational cross-sectional data from The Maastricht Study including N = 3635 participants (mean age 59.3 years, 51.6% were women, and 19.9% had type 2 diabetes) living in the Maastricht area. Using the Geoscience and hEalth Cohort COnsortium (GECCO) data we linked the yearly average exposure levels of ambient air pollutants at home address-level [particulate matter with diameters of ≤ 2.5 µm (PM2.5), and ≤ 10.0 µm (PM10), nitrogen dioxide (NO2), and elemental carbon (EC)]. We used linear regression analysis to study the associations between Z-score for ambient air pollutants concentrations (PM 2.5 , PM 10 , NO 2 , and EC) and Z-score for individual corneal nerve measures (corneal nerve bifurcation density, corneal nerve density, corneal nerve length, and fractal dimension)., Results: After adjustment for potential confounders (age, sex, level of education, glucose metabolism status, corneal confocal microscopy lag time, inclusion year of participants, smoking status, and alcohol consumption), higher Z-scores for PM 2.5 and PM 10 were associated with lower Z-scores for corneal nerve bifurcation density, nerve density, nerve length, and nerve fractal dimension [stβ (95% CI): PM 2.5 -0.10 (-0.14; -0.05), -0.04 (-0.09; 0.01), -0.11 (-0.16; -0.06), -0.20 (-0.24; -0.15); and PM 10 -0.08 (-0.13; -0.03), -0.04 (-0.09; 0.01), -0.08 (-0.13; -0.04), -0.17 (-0.21; -0.12)], respectively. No associations were found between NO 2 and EC and corneal nerve measures., Conclusions: Our population-based study demonstrated that exposure to higher levels of PM 2.5 and PM 10 are associated with higher levels of corneal neurodegeneration, estimated from lower corneal nerve measures. Our results suggest that air pollution may be a determinant for neurodegeneration assessed in the cornea and may impact the ocular surface health as well., (© 2024. The Author(s).)

Aims: Steroid injections are used for subacromial pain syndrome and can be administered via the anterolateral or posterior approach to the subacromial space. It is not currently known which approach is superior in terms of improving clinical symptoms and function. This is the protocol for a randomized controlled trial (RCT) to compare the clinical effectiveness of a steroid injection given via the anterolateral or the posterior approach to the subacromial space., Methods: The Subacromial Approach Injection Trial (SAInT) study is a single-centre, parallel, two-arm RCT. Participants will be allocated on a 1:1 basis to a subacromial steroid injection via either the anterolateral or the posterior approach to the subacromial space. Participants in both trial arms will then receive physiotherapy as standard of care for subacromial pain syndrome. The primary analysis will compare the change in Oxford Shoulder Score (OSS) at three months after injection. Secondary outcomes include the change in OSS at six and 12 months, as well as the Pain Numeric Rating Scale (0 = no pain, 10 = worst pain), Disabilities of Arm, Shoulder and Hand questionnaire (DASH), and 36-Item Short-Form Health Survey (SF-36) (RAND) at three months, six months, and one year after injection. Assessment of pain experienced during the injection will also be determined. A minimum of 86 patients will be recruited to obtain an 80% power to detect a minimally important difference of six points on the OSS change between the groups at three months after injection., Conclusion: The results of this trial will demonstrate if there is a difference in shoulder pain and function after a subacromial space steroid injection between the anterolateral versus posterior approach in patients with subacromial pain syndrome. This will help to guide treatment for patients with subacromial pain syndrome., Competing Interests: R. A. Malik declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novo Nordisk, Eli Lilly and Sanofi; and participation on a data safety monitoring board or advisory board Novo Nordisk for the PACT-MEA study, all of which are unrelated to this work. F. L. Martin discloses financial or non-financial interests from NIHR Manchester Biomedical Research Centre (NIHR203308), which is also unrelated., (© 2024 Charalambous et al.)

Aims: To develop a standardised, automated protocol for detecting protein gene product 9.5 (PGP9.5) positive intra-epidermal nerve fibres (IENFs) in skin biopsies, transitioning from the established manual technique to an automated platform. This automated method, although currently intended for research applications, may improve the accessibility of this diagnostic test for small fibre neuropathy in clinical settings., Methods: Skin biopsies (n = 274) from 100 participants (fibromyalgia syndrome n = 62; idiopathic small fibre neuropathy: n = 16; healthy volunteers: n = 22) were processed using an automated immunohistochemistry platform. IENF quantification was performed by blinded examiners, with reliability assessed via a two-way mixed-effects model to evaluate inter- and intra-observer variability., Results: The automated staining system reproduced intra-epidermal nerve fibre density (IENFD) counts consistent with free-floating sections (mean ± standard deviation: free-floating: 5.6 ± 3.4 fibres/mm; automated: 5.9 ± 3.2 fibres/mm). A median difference of 0.3 with a lower bound 95% Confidence Interval (CI) at -0.00005 established non-inferiority against a margin of -0.4 (p = .08). Specifically, the inter-class correlation coefficient (class denotes consistency in measured observations) was 99% (95% CI: 0.9-1), indicating excellent agreement between free-floating and automated methods. The inter- and intra-class coefficient between examiners were both 99% (95% CI: 0.9-0.1) for IENFD, demonstrating high reliability using sections stained using the automated method., Interpretation: Automated immunohistochemistry provides high-throughput reliable and reproducible intra-epidermal nerve fibre quantification. This method, although currently proof-of-concept, for research use only, may be more widely deployed in histopathology laboratories to increase the adoption of IENFD assessment for the diagnosis of peripheral neuropathies., (© 2024 The Author(s). Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.)

Aim: An objective assessment of small nerve fibers is key to the early detection of diabetic peripheral neuropathy (DPN). This study investigates the diagnostic accuracy of a novel perception threshold tracking technique in detecting small nerve fiber damage., Methods: Participants with type 1 diabetes (T1DM) without DPN (n = 20), with DPN (n = 20), with painful DPN (n = 20) and 20 healthy controls (HCs) underwent perception threshold tracking on the foot and corneal confocal microscopy. Diagnostic accuracy of perception threshold tracking compared to corneal confocal microscopy was analyzed using logistic regression., Results: The rheobase, corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and corneal nerve fiber length (CNFL) (all P < .001) differed between groups. The diagnostic accuracy of perception threshold tracking (rheobase) was excellent for identifying small nerve fiber damage, especially for CNFL with a sensitivity of 94%, specificity 94%, positive predictive value 97%, and negative predictive value 89%. There was a significant correlation between rheobase with CNFD, CNBD, CNFL, and Michigan Neuropathy Screening Instrument (all P < .001)., Conclusion: Perception threshold tracking had a very high diagnostic agreement with corneal confocal microscopy for detecting small nerve fiber loss and may have clinical utility for assessing small nerve fiber damage and hence early DPN., Clinical Trials: NCT04078516., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Painful idiopathic distal sensory polyneuropathy (IDSP) and fibromyalgia syndrome (FMS) are cryptogenic chronic pain syndromes. The contribution of small fibre pathology (SFP) in FMS remains controversial. This study aims to quantify small nerve pathology in participants with IDSP and FMS and identify relationships of SFP with sensory phenotypes., Methods: In this study, 73 individuals (FMS: 25, IDSP: 23, healthy volunteers: 25) underwent comprehensive assessment, including neurological exams, questionnaires, sensory tests, and corneal confocal microscopy., Results: IDSP participants displayed lower wind-up ratio (WUR) relative to FMS (p < 0.001), loss of function to thermal and mechanical stimuli and elevated neuropathy disability scores compared to FMS and healthy volunteers (all p < 0.001). FMS participants demonstrated gain of function to heat and blunt pressure pain responses relative to IDSP, and healthy volunteers (heat: p = 0.002 and p = 0.003; pressure: both p < 0.001) and WUR (both p < 0.001). FMS participants exhibited reduced corneal nerve fibre density (p = 0.02), while IDSP participants had lower global corneal nerve measures (density, branch density, and length) relative to healthy volunteers (all p < 0.001). Utilising corneal nerve fibre length, SFP was demonstrated in 66.6% of participants (FMS: 13/25; IDSP: 22/23)., Conclusion: Participants with SFP, in both FMS and IDSP, reported symptoms indicative of small nerve fibre disease. Although distinctions in pain distributions are evident between individuals with FMS and IDSP, over 50% of participants between the two conditions displayed both a loss and gain of thermal and mechanical function suggestive of shared mechanisms. However, sensory phenotypes were associated with the presence of SFP in IDSP but not in FMS., (© 2024. The Author(s).)

As major terrestrial carbon sinks, forests play an important role in mitigating climate change. The relationship between the seasonal uptake of carbon and its allocation to woody biomass remains poorly understood, leaving a significant gap in our capacity to predict carbon sequestration by forests. Here, we compare the intra-annual dynamics of carbon fluxes and wood formation across the Northern hemisphere, from carbon assimilation and the formation of non-structural carbon compounds to their incorporation in woody tissues. We show temporally coupled seasonal peaks of carbon assimilation (GPP) and wood cell differentiation, while the two processes are substantially decoupled during off-peak periods. Peaks of cambial activity occur substantially earlier compared to GPP, suggesting the buffer role of non-structural carbohydrates between the processes of carbon assimilation and allocation to wood. Our findings suggest that high-resolution seasonal data of ecosystem carbon fluxes, wood formation and the associated physiological processes may reduce uncertainties in carbon source-sink relationships at different spatial scales, from stand to ecosystem levels., (© 2024. The Author(s).)

Aims/introduction: Deficiency of neurotropic factors is implicated in diabetic neuropathy (DN). Netrin-1 is a neurotropic factor, but its association with DN has not been explored. We have assessed the association between serum netrin-1 levels and early diabetic neuropathy assessed by quantifying corneal nerve fiber loss using corneal confocal microscopy., Materials and Methods: A total of 72 participants with type 2 diabetes, without and with corneal nerve fiber loss (DN- n = 42, DN+ n = 30), and 45 healthy controls were studied. Serum netrin-1 levels were measured by enzyme-linked immunosorbent assay, and corneal nerve morphology was assessed using corneal confocal microscopy., Results: Corneal nerve fiber density, branch density, fiber length and serum netrin-1 levels were significantly lower in the DN- and DN+ groups compared with controls (P < 0.001). Netrin-1 levels correlated with corneal nerve fiber length in the DN+ group (r = 0.51; P < 0.01). A receiver operating characteristic curve analysis showed that a netrin-1 cut-off value of 599.6 (pg/mL) had an area under the curve of 0.85, with a sensitivity of 76% and specificity of 74% (P < 0.001; 95% confidence interval 0.76-0.94) for differentiating patients with and without corneal nerve loss., Conclusions: Serum netrin-1 levels show a progressive decline with increasing severity of small nerve fiber damage in patients with diabetes. Netrin-1 could act as a biomarker for small nerve fiber damage in DN., (© 2024 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)