Basal Cell Carcinoma Formation Within A Spinal Cord Stimulator Surgical Scar: A Case Report.

Implanting neuromodulation devices requires that pain medicine physicians be well-versed in proper surgical technique and postoperative wound management. To be able to identify abnormal wound healing, a basic understanding of normal wound healing is required. When postoperative wounds deviate from expected healing, it is important that pain medicine physicians entertain a broad differential diagnosis, including nonsurgical dermatologic pathology.

How appropriate are referral letters written by school principals to a learning disability clinic? A retrospective audit.

This retrospective study analyzed the quality of 1069 referral letters written by school principals to our learning disability clinic. Utilizing a self-devised checklist having four domains (with 26 items), the audit revealed that in only nine (34.6%) items, the necessary information was available in >90% of referral letters.

Fluoride content in various types of tea used by tea stalls in Salem district - An in vitro cross sectional study.

Background: Tea leaves are natural rich source of fluoride and are known as fluorine absorbants. It is consumed on large scale in India and thus needs to be monitored for its daily fluoride consumption by customers. Tea manufacturers should mention fluoride concentrations on the packages to avoid overdose through unknown consumption by consumers. Objectives: To detect the levels of fluoride in tea at different periods of boiling and to compare the fluoride levels in various brands of tea at different periods of boiling. Methodology: A survey was conducted in 25 tea stalls of Salem on the type of tea and time of boiling black tea. The five most common brands of tea will bought for the study. The stainless-steel vessel will be used in the methodology for boiling tea. Mettur water will be used for the preparation of black tea and 1 g of tea leaves to 100 ml of hot (~95°C) deionized water (1% w/v tea infusion) and allowed the mixture to stand for 5 min in a glass beaker. After 5 min, the infusions were filtered and again left standing until they are cooled to room temperature. All fluoride measurements will be completed within 4 h of the preparation of the infusion. About 2 min and 4 min boiling will be followed. The fluoride present in each brand of tea will be calculated from black tea prepared using 2-(parasulfophenylazo)-1,8-dihydroxy-3,6-naphthalene-disulfonate (SPADNS) calorimetric method. Results: The distribution of mean score of fluoride level in tea powders available in tea shops of Salem when boiled in distilled water was (559.00 ± 112.12). The mean score of fluoride level in tea powders available in tea shops of Salem boiled in Mettur water was (689.05 ± 116.34). To test the significance of difference between the average fluoride in tea powders available in tea shops of Salem when boiled in distilled water and Mettur water, the independent t-test was used. the P value is <0.05, and hence, it is found that there is significant difference between the average fluoride in tea powders available in tea shops of Salem boiled in distilled water and Mettur water. Conclusion: Thus, the study showed tea consists of significant amount of fluoride concentration that is consumed on daily basis. The study also evaluated fluoride concentration in tea preparations using different water. The study shows necessity for regulations of mentioning fluoride concentration on tea packs.

Defining the clinical validity of genes reported to cause pulmonary arterial hypertension.

PURPOSE: Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. Genetic testing is currently recommended for adults diagnosed with heritable, idiopathic, anorexigen-, hereditary hemorrhagic telangiectasia-, and congenital heart disease-associated PAH, PAH with overt features of venous/capillary involvement, and all children diagnosed with PAH. Variants in at least 27 genes have putative evidence for PAH causality. Rigorous assessment of the evidence is needed to inform genetic testing. METHODS: An international panel of experts in PAH applied a semi-quantitative scoring system developed by the NIH Clinical Genome Resource to classify the relative strength of evidence supporting PAH gene-disease relationships based on genetic and experimental evidence. RESULTS: Twelve genes (BMPR2, ACVRL1, ATP13A3, CAV1, EIF2AK4, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17, and TBX4) were classified as having definitive evidence and 3 genes (ABCC8, GGCX, and TET2) with moderate evidence. Six genes (AQP1, BMP10, FBLN2, KLF2, KLK1, and PDGFD) were classified as having limited evidence for causal effects of variants. TOPBP1 was classified as having no known PAH relationship. Five genes (BMPR1A, BMPR1B, NOTCH3, SMAD1, and SMAD4) were disputed because of a paucity of genetic evidence over time. CONCLUSION: We recommend that genetic testing includes all genes with definitive evidence and that caution be taken in the interpretation of variants identified in genes with moderate or limited evidence. Genes with no known evidence for PAH or disputed genes should not be included in genetic testing.

Antidiabetic Potential of Selected Ethnomedicines Utilized for the Management of Diabetes Mellitus in Trinidad and Tobago: A Review.

BACKGROUND: Diabetes is a chronic metabolic disorder with a high global prevalence and one of the highest morbidity and mortality rates. Despite developments in synthetic medicine, the associated serious side effects with current antidiabetic drugs indicate an urgent need for novel effective treatments. Traditional medicinal plants offer great potential in the treatment of many diseases due to their bioactive phytochemicals and are a useful resource for developing safe and effective hypoglycemic agents. METHODS: The present review collates the most frequently used ethnomedicines for the management of diabetes mellitus in Trinidad and Tobago. Further, it provides scientific validation of the claimed antidiabetic effects of four selected ethnomedicines: Antigonon leptopus, Gomphrena globosa, Laportea aestuans and Stachytarpheta jamaicensis. A comprehensive literature search was conducted using various electronic scientific databases and search engines. Information was collected on the phytochemical and pharmacological aspects of these selected species to illustrate the antidiabetic activity and potential applications of these plants. CONCLUSION: The findings of the numerous in vitro and in vivo experiments from previously published literature indicate the four candidate plants as promising sources of antidiabetic lead compounds and provide useful information to stimulate extensive studies. Further investigations on the isolation, identification and clinical evaluation of the pharmacologically active constituents from these plants can lead to the discovery of new and effective antidiabetic agents.

Efficacy of Preoperative Piroxicam, Diclofenac, Paracetamol With Tramadol and Placebo Tablets for Relief of Postoperative Pain After the Removal of Impacted Mandibular Third Molars: A Randomised Controlled Trial.

Aim We aimed to analyze the influence of preoperative piroxicam, diclofenac, paracetamol, tramadol, and placebo tablets as measured in the time required for rescue analgesia for postoperative pain relief after the extraction of impacted mandibular third molar. Materials & methods Forty-four patients who needed extraction of impacted mandibular third molar were arbitrarily categorized into four groups namely, piroxicam, diclofenac, paracetamol with tramadol, and placebo. The test medicine was given one hour preoperatively before the surgical removal. The pain was assessed using visual analog scale (VAS) and verbal rating scale (VRS) scores preoperatively and at the third and 24th hours. The time required for escape analgesia was measured.  Results The mean VAS and VRS scores showed significant differences across the groups after 24 hours. The mean score was lowest for the patients taking piroxicam (1.30+1.95) and highest for patients taking tramadol + paracetamol (4.50+2.59). As far as escape analgesia is concerned piroxicam group was by far superior. Conclusion The pain scores and the rescue analgesic requirement suggested that piroxicam analgesic significantly reduced pain; moreover, it is a safe as well as an efficacious substitute to the conventional non-steroidal anti-inflammatory drugs (NSAIDs) for mandibular third molar impactions.

Biallelic variants of ATP13A3 cause dose-dependent childhood-onset pulmonary arterial hypertension characterised by extreme morbidity and mortality.

BACKGROUND: The molecular genetic basis of pulmonary arterial hypertension (PAH) is heterogeneous, with at least 26 genes displaying putative evidence for disease causality. Heterozygous variants in the ATP13A3 gene were recently identified as a new cause of adult-onset PAH. However, the contribution of ATP13A3 risk alleles to child-onset PAH remains largely unexplored. METHODS AND RESULTS: We report three families with a novel, autosomal recessive form of childhood-onset PAH due to biallelic ATP13A3 variants. Disease onset ranged from birth to 2.5 years and was characterised by high mortality. Using genome sequencing of parent-offspring trios, we identified a homozygous missense variant in one case, which was subsequently confirmed to cosegregate with disease in an affected sibling. Independently, compound heterozygous variants in ATP13A3 were identified in two affected siblings and in an unrelated third family. The variants included three loss of function variants (two frameshift, one nonsense) and two highly conserved missense substitutions located in the catalytic phosphorylation domain. The children were largely refractory to treatment and four died in early childhood. All parents were heterozygous for the variants and asymptomatic. CONCLUSION: Our findings support biallelic predicted deleterious ATP13A3 variants in autosomal recessive, childhood-onset PAH, indicating likely semidominant dose-dependent inheritance for this gene.

Pulmonary Arterial Hypertension: A Deeper Evaluation of Genetic Risk in the -Omics Era.

Pulmonary arterial hypertension (PAH) is a highly heterogeneous disorder with a complex, multifactorial aetiology [...].

Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension.

Background - Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods - We analyzed 13,037 participants enrolled in the NIHR BioResource - Rare Diseases (NBR) study, of which 1,148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension (PH), we used the Bayesian rare-variant association method BeviMed. Results - Heterozygous, high impact, likely loss-of-function variants in the Kinase Insert Domain Receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (KCO, posterior probability (PP)=0.989) and older age at diagnosis (PP=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the five patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions - The Bayesian inference approach allowed us to independently validate KDR, which encodes for the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.

Whole Exome Sequence Analysis Provides Novel Insights into the Genetic Framework of Childhood-Onset Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) describes a rare, progressive vascular disease caused by the obstruction of pulmonary arterioles, typically resulting in right heart failure. Whilst PAH most often manifests in adulthood, paediatric disease is considered to be a distinct entity with increased morbidity and often an unexplained resistance to current therapies. Recent genetic studies have substantially increased our understanding of PAH pathogenesis, providing opportunities for molecular diagnosis and presymptomatic genetic testing in families. However, the genetic architecture of childhood-onset PAH remains relatively poorly characterised. We sought to investigate a previously unsolved paediatric cohort (n = 18) using whole exome sequencing to improve the molecular diagnosis of childhood-onset PAH. Through a targeted investigation of 26 candidate genes, we applied a rigorous variant filtering methodology to enrich for rare, likely pathogenic variants. This analysis led to the detection of novel PAH risk alleles in five genes, including the first identification of a heterozygous ATP13A3 mutation in childhood-onset disease. In addition, we provide the first independent validation of BMP10 and PDGFD as genetic risk factors for PAH. These data provide a molecular diagnosis in 28% of paediatric cases, reflecting the increased genetic burden in childhood-onset disease and highlighting the importance of next-generation sequencing approaches to diagnostic surveillance.

Spinal cord stimulation in Parkinson's disease: a review of the preclinical and clinical data and future prospects.

Parkinson's disease (PD) is a progressive neurodegenerative disease with an incidence of 0.1 to 0.2% over the age of 40 and a prevalence of over 1 million people in North America. The most common symptoms include tremor, bradykinesia, rigidity, pain, and postural instability, with significant impact in quality of life and mortality. To date there is ongoing research to determine the optimum therapy for PD. In this review we analyze the current data in the use of spinal cord stimulation (SCS) therapy for treatment for Parkinsonian symptoms. We specifically address waveform pattern, anatomic location and the role of spinal cord stimulation (SCS) as a salvage therapy after deep brain stimulation (DBS) therapy. We also outline current experimental evidence from preclinical research highlighting possible mechanisms of beneficial effects of SCS in this context. Though the use of SCS therapy is in its infancy for treatment of PD, the data points to an exciting area for ongoing research and exploration with positive outcomes from both cervical and thoracic tonic and BURSTDR spinal cord stimulation.

Molecular genetic framework underlying pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare, progressive disorder typified by occlusion of the pulmonary arterioles owing to endothelial dysfunction and uncontrolled proliferation of pulmonary artery smooth muscle cells and fibroblasts. Vascular occlusion can lead to increased pressure in the pulmonary arteries, often resulting in right ventricular failure with shortness of breath and syncope. Since the identification of BMPR2, which encodes a receptor in the transforming growth factor-ß superfamily, the development of high-throughput sequencing approaches to identify novel causal genes has substantially advanced our understanding of the molecular genetics of PAH. In the past 6 years, additional pathways involved in PAH susceptibility have been described through the identification of deleterious genetic variants in potassium channels (KCNK3 and ABCC8) and transcription factors (TBX4 and SOX17), among others. Although familial PAH most often has an autosomal-dominant pattern of inheritance, cases of incomplete penetrance and evidence of genetic heterogeneity support a model of PAH as a Mendelian disorder with complex disease features. In this Review, we outline the latest advances in the detection of rare and common genetic variants underlying PAH susceptibility and disease progression. These findings have clinical implications for lung vascular function and can help to identify mechanistic pathways amenable to pharmacological intervention.

Characterization of GDF2 Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension.

Rationale: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor.Objectives: Here we determined the functional impact of GDF2 mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH.Methods: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signaling, and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in patients with PAH with GDF2 variants and in control subjects. Levels were also measured in a larger cohort of control subjects (n = 120) and patients with idiopathic PAH (n = 260).Measurements and Main Results: We identified a novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. Patients with PAH who carried these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between patients with PAH and control subjects, BMP10 levels were lower in PAH females. A subset of patients with PAH had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations.Conclusions: Our findings demonstrate that GDF2 mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.

A Review of Clinical Data on Salvage Therapy in Spinal Cord Stimulation.

BACKGROUND: Since its introduction in 1967, neuromodulation through spinal cord stimulation (SCS) or dorsal root ganglion stimulation (DRGs) has advanced significantly in both the technology and indications for use. There are now over 14,000 SCS implants performed worldwide every year. This review focuses on mechanisms behind the loss of efficacy in neuromodulation and current data on salvage therapy, defined as the conversion of a neuromodulation device to an alternative SCS or DRG stimulation, in the event of loss of efficacy or failure of a trial. STUDY DESIGN: A narrative review of clinical studies regarding habituation, explant data, and salvage therapy with SCS. METHODS: Available literature was reviewed on spinal cord stimulation technology and salvage therapy. Data sources included relevant literature identified through searches of PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles. OUTCOME MEASURES: The primary outcome measures were to understand the mechanisms of loss of efficacy, provide a review of explants due to failure in treatment, and summarize the data on current salvage therapy in SCS. RESULTS: A total of eight studies and four abstracts/poster presentations were identified and reviewed. Of the eight studies, only one was a randomized controlled trial. CONCLUSIONS: There is limited evidence for the appropriate treatment alternatives, but from data currently available the conversion from conventional tonic stimulation to burst, high frequency (10 kHz), multiple wave forms, and/or DRGs may be appropriate in select patients and will require further research to determine the most appropriate first line salvage in the context of the underlying pain pathology.

Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-ß pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.

Mass spectrometry based identification of galectin-3 interacting proteins potentially involved in lung melanoma metastasis.

Adhesive interactions between molecules on tumor cells and those on target organs play a key role in organ specific metastasis. Poly-N-acetyl-lactosamine (polyLacNAc) substituted N-oligosaccharides on melanoma cell surface glycoproteins promote lung specific metastasis via galectin-3 by facilitating their arrest and extravasation. This study reports the identification and characterization of galectin-3 interacting proteins using a combination of galectin-3 sepharose affinity and leucoagglutinating phytohemagglutinin (L-PHA) columns. A total of 83 proteins were identified as galectin-3 interacting glycoproteins, of which 35 were constituents of the L-PHA bound fraction, suggesting that these proteins carry polyLacNAc substituted ß1,6 branched N-glycans. The identities of some of these proteins, like LAMP-1, LAMP-3, basigin, embigin, and α5 and ß1 Integrin, have been confirmed by western blotting, and functional relevance with respect to metastatic properties has been established.

Pharmacokinetics, biodistribution and antitumour effects of Sclerotium rolfsii lectin in mice.

Sclerotium rolfsii lectin (SRL) is a lectin isolated from the fungus Sclerotium rolfsii and has exquisite binding specificity towards the oncofetal Thomsen-Friedenreich antigen (TF-Ag; Galß1-3GalNAcα-O-Ser/Thr) and its derivatives. Previous studies have shown that SRL inhibits the proliferation of human colon, breast and ovarian cancer cells in vitro and suppresses tumour growth in mice when introduced intratumourally. The present study assessed the effect of SRL on tumour growth when introduced intraperitoneally in BALB/c nude mice and investigated the pharmacokinetics and biodistribution of SRL in Swiss albino mice. When 9 doses of SRL (30 mg/kg body weight/mice) was administered to BALB/c nude mice bearing human colon cancer HT-29 xenografts, a substantial reduction in tumour size was observed. A 35.8% reduction in tumour size was noted in the treated animals after 17 days. SRL treatment also inhibited angiogenesis, and the tumours from the treated animals were observed to carry fewer blood vessels and express less angiogenesis marker protein CD31, than that from the control animals. Pharmacokinetics and biodistribution analysis revealed that SRL was detected in the serum after 1 h and its level peaked after 24 h. SRL was not detected in any of the organs apart from the kidney where a trace amount was detected after 24 h of SRL injection. No significant changes were observed in any of the biochemical parameters tested including SGOT, SGPT, LDH, CREAT and BUN in the SRL-treated mice compared to these levels in the controls. This suggests that SRL has good potential to be developed as a therapeutic agent for cancer treatment and warrant further investigations in vivo and subsequent clinical trials.

Galectin-3-induced cell spreading and motility relies on distinct signaling mechanisms compared to fibronectin.

Secreted galectin-3 often gets incorporated into extracellular matrix and is utilized by cancer cells for spreading, movement, and metastatic dissemination. Here we investigate molecular mechanisms by which galectin-3 brings about these effects and compare it with fibronectin. Imaging of cells spread on fibronectin showed stress fibers throughout cell body, however, galectin-3-induced formation of parallel actin bundles in the lamellipodial region resulting in unique morphological features. FRAP analysis showed that the actin turnover in the lamellipodial region was much higher in cells spread on galectin-3 as compared to that on fibronectin. Rac1 activation is correlated with lamellipodial organization on both the substrates. Activation of Akt and Rac1, the regulators of actin dynamics, show inverse correlation with each other on both galectin-3 and fibronectin. Activation of Erk however, remained similar. Further, inhibition of activation of Akt and Erk inhibited spreading and motility of cells on galectin-3 but not on fibronectin. The results very comprehensively demonstrate distinct signaling pathways that regulate microfilament organization, lamellipodial structures, spreading, and movement of cells plated on galectin-3 as opposed to fibronectin.