Opportunities and challenges for biomarker discovery using electronic health record data.

Electronic health records (EHRs) have become increasingly relied upon as a source for biomedical research. One important research application of EHRs is the identification of biomarkers associated with specific patient states, especially within complex conditions. However, using EHRs for biomarker identification can be challenging because the EHR was not designed with research as the primary focus. Despite this challenge, the EHR offers huge potential for biomarker discovery research to transform our understanding of disease etiology and treatment and generate biological insights informing precision medicine initiatives. This review paper provides an in-depth analysis of how EHR data is currently used for phenotyping and identifying molecular biomarkers, current challenges and limitations, and strategies we can take to mitigate challenges going forward.

Characteristics of Electrical Synapses, C-terminals and Small-conductance Ca2+ activated Potassium Channels in the Sexually Dimorphic Cremaster Motor Nucleus in Spinal Cord of Mouse and Rat.

Sexually dimorphic motoneurons (MNs) located in lower lumbar spinal cord are involved in mating and reproductive behaviours and are known to be coupled by electrical synapses. The cremaster motor nucleus in upper lumbar spinal cord has also been suggested to support physiological processes associated with sexual behaviours in addition to its thermoregulatory and protective role in maintaining testes integrity. Using immunofluorescence approaches, we investigated whether cremaster MNs also exhibit features reflecting their potential for electrical synaptic communication and examined some of their other synaptic characteristics. Both mice and rats displayed punctate immunolabelling of Cx36 associated with cremaster MNs, indicative of gap junction formation. Transgenic mice with enhanced green fluorescent protein (eGFP) reporter for connexin36 expression showed that subpopulations of cremaster MNs in both male and female mice express eGFP, with greater proportions of those in male mice. The eGFP+ MNs within the cremaster nucleus vs. eGFP- MNs inside and outside this nucleus displayed a 5-fold greater density of serotonergic innervation and exhibited a paucity of innervation by C-terminals arising from cholinergic V0c interneurons. All MNs within the cremaster motor nucleus displayed prominent patches of immunolabelling for SK3 (K+) channels around their periphery, suggestive of their identity as slow MNs, many though not all of which were in apposition to C-terminals. The results provide evidence for electrical coupling of a large proportion of cremaster MNs and suggest the existence of two populations of these MNs with possibly differential innervation of their peripheral target muscles serving different functions.

Expression of the gap junction protein connexin36 in small intensely fluorescent (SIF) cells in cardiac parasympathetic ganglia of rodents.

In mammals, several endocrine cell types are electrically coupled by connexin36 (Cx36)-containing gap junctions, which mediate intercellular communication and allow regulated and synchronized cellular activity through exchange of ions and small metabolites via formation of intercellular channels that link plasma membranes of apposing cells. One cell type thought to be endocrine-like in nature are small intensely fluorescent (SIF) cells that store catecholamines in their dense-core vesicles and reside in autonomic ganglia. Here, using immunofluorescence approaches, we examined whether SIF cells located specifically in cardiac parasympathetic ganglia of adult and neonatal mice and adult rats follow patterns of Cx36 expression seen in other endocrine cells. In these ganglia, SIF cells were identified by their distinct small soma size, autofluorescence at 475 nm, and immunolabelling for their markers tyrosine hydroxylase and vesicular monoamine transporter-1. SIF cells were often found in pairs or clusters among principal cholinergic neurons. Immunofluorescence labelling of Cx36 occurred exclusively as fine puncta that appeared at contacts between SIF cell processes and somata or at somato-somatic appositions of SIF cells. These puncta were absent in cardiac parasympathetic ganglia of Cx36 null mice. Transgenic mice expressing enhanced green fluorescent protein reporter for Cx36 expression displayed labelling for the reporter in SIF cells. The results suggest that Cx36-containing gap junctions electrically couple SIF cells, which is consistent with previous suggestions that these may be classified as endocrine-type cells that secrete catecholamines into the bloodstream in a regulated manner.

Total annulus excision tympanoplasty - a solution to recurrent myringitis: double blind randomised trial.

OBJECTIVE: In spite of continuous refinements in tympanoplasty techniques, results are variable, and it is not uncommon to see a discharging eardrum even after a good graft uptake. This study aimed to evaluate the efficacy of total annulus excision tympanoplasty in comparison with conventional underlay tympanoplasty. METHOD: This was a double blinded, randomised, controlled trial performed at a tertiary care centre. After inclusion and exclusion criteria were met, 56 patients were enrolled and randomised, and 28 patients were allocated to each group (group A (conventional tympanoplasty) and group B (total annulus excision)). Patients and evaluators were blind to the procedure performed. RESULTS: Patients in group B (total annulus excision) showed better graft uptake and no discharge with better gains in air conduction thresholds (p < 0.05) when compared with group A (conventional tympanoplasty). CONCLUSION: In view of the advantages it offers, total annulus excision tympanoplasty may be preferred over the conventional techniques in patients with central perforations.

Aging phenotype(s) in kidneys of diabetic mice are p66ShcA dependent.

The p66ShcA protein controls cellular responses to oxidative stress, senescence, and apoptosis. Here, we test the hypothesis that aging phenotype(s) commonly associated with the broad category of chronic kidney disease are accelerated in diabetic kidneys and linked to the p66ShcA locus. At the organ level, tissue stem cells antagonize senescent phenotypes by replacing old dysfunctional cells. Using established methods, we isolated a highly purified population of stem cell antigen-1-positive mesenchymal stem cells (Sca-1+ MSCs) from kidneys of wild-type (WT) and p66 knockout (p66 KO) mice. Cells were plated in culture medium containing normal glucose (NG) or high glucose (HG). Reactive oxygen species (ROS) metabolism was substantially increased in WT MSCs in HG medium in association with increased cell death by apoptosis and acquisition of the senescent phenotype. DNA microarray analysis detected striking differences in the expression profiles of WT and p66 KO-MSCs in HG medium. Unexpectedly, the analysis for p66 KO-MSCs revealed upregulation of Wnt genes implicated in self-renewal and differentiation. To test the in vivo consequences of constitutive p66 expression in diabetic kidneys, we crossed the Akita diabetic mouse with the p66KO mouse. Homozygous mutation at the p66 locus delays or prevents aging phenotype(s) in the kidney that may be precursors to diabetic nephropathy.

Tiered approaches to chromatographic bioanalytical method performance evaluation: recommendation for best practices and harmonization from the Global Bioanalysis Consortium harmonization team.

The A2 harmonization team, a part of the Global Bioanalysis Consortium (GBC), focused on defining possible tiers of chromatographic-based bioanalytical method performance. The need for developing bioanalytical methods suitable for the intended use is not a new proposal and is already referenced in regulatory guidance language. However, the practical implementation of approaches that differ from the well-established full validation requirements has proven challenging. Advances in technologies, the need to progress drug development more efficiently, and emerging new drug compound classes support the use of categorized tiers of bioanalytical methods. This paper incorporated the input from an international team of experienced bioanalysts to surmise the advantages and the challenges of tiered approaches and to provide recommendations on paths forward.

A rare case of subglottic embryonal rhabdomyosarcoma: managed with the aim of organ preservation.

BACKGROUND: Rhabdomyosarcoma is a malignant mesenchymal neoplasm rarely diagnosed in the larynx. Traditionally, it has been treated by radical surgery (i.e. total laryngectomy), followed by radiation and/or chemotherapy. Recent advances suggest that it may be treated with combination therapy comprising high-dose radiation and pulse chemotherapy, with a high success rate. CASE REPORT: We report the first documented case of subglottic embryonal rhabdomyosarcoma in an adolescent female treated with chemoradiation alone, and review the literature reflecting a move towards organ preservation. CONCLUSION: While surgery has been successfully used to treat this neoplasm, combination therapy, as described in our study, also seems effective and has the added advantage of preserving laryngeal function.

Systematic literature review of the risk factors, comorbidities, and consequences of hypogonadism in men.

The objective of this review was to summarize the literature on the risk factors, comorbidities, and consequences of male hypogonadism, which is defined as a syndrome complex that includes biochemical confirmation of low testosterone (T) and the consistent symptoms and signs associated with low T. A systematic literature search was performed in PubMed/MEDLINE, EMBASE, Cochrane Library for articles published in the last 10 years on risk factors, comorbidities, and consequences of male hypogonadism. Of the 53 relevant studies identified, nine examined potential risk factors, 14 examined potential comorbidities, and 30 examined potential consequences of male hypogonadism. Based on studies conducted in Asia, Australia, Europe, and North & South America, the important factors that predicted and correlated with hypogonadism were advanced age, obesity, a diagnosis of metabolic syndrome (MetS), and a poor general health status. Diabetes mellitus was correlated with hypogonadism in most studies, but was not established as a risk factor. Although diseases, such as coronary heart disease, hypertension, stroke, and peripheral arterial disease did not predict hypogonadism, they did correlate with incident low T. The data reviewed on potential consequences suggest that low T levels may be linked to earlier all-cause and cardiovascular related mortality among men. This literature review suggests that men with certain factors, such as advanced age, obesity, MetS, and poor general health, are more likely to have and develop hypogonadism. Low levels of T may have important long-term negative health consequences.

Primary intimal (spindle cell) sarcoma of the heart: a case report and review of the literature.

Intimal (spindle cell) sarcomas of the left atrium are extremely rare primary cardiac tumours with three cases reported (Li et al. (2013), Cho et al. (2006), and Modi et al. (2009)). We present a 69-year-old man who first came to medical attention after experiencing abdominal discomfort. He had a 30 lb weight loss apparently due to dieting. He denied any other constitutional symptoms. His symptoms persisted despite a course of antibiotics for presumed diverticulitis. Laboratory values were within normal limits, though the haemoglobin was 131 g/L (normal: 140-180). Subsequent abdominal computed tomography (CT) scan revealed an abdominal wall mass and intracardiac lesion; the cardiac mass was further characterized by transesophageal echo (TEE), magnetic resonance imaging (MRI), and dedicated cardiac CT. TEE revealed a mass attached to the posterolateral wall of the left atrium above the mitral annulus, and the cardiac CT and MRI confirmed the TEE findings. The patient underwent extensive surgical resection and repair of the left side of the heart. Postoperatively, he developed acute renal failure requiring dialysis and reintubation for volume overload. He became acutely hypotensive, developed multiorgan failure, and succumbed to his illness. Histopathologic examination of the left atrial mass showed an intimal sarcoma.

An analysis of the impact of previous laparoscopic hysterectomy experience on the learning curve for robotic hysterectomy.

To analyze and compare the safety and perioperative outcomes of newly trained robotic surgeons with previous laparoscopic hysterectomy experience (TLH Exp) and those without previous laparoscopic hysterectomy experience (Non-TLH Exp). The purpose is to determine the effect of previous advanced laparoscopic skills on the performance in robotic assisted laparoscopic surgery. We will also compare the perioperative outcomes between the total laparoscopic hysterectomies (TLH), and robotic assisted laparoscopic hysterectomies (RALH) of a single experienced (TLH Exp) robotic surgeon. The purpose is to determine benefits and/or risks, if any, of one approach over the other in the hands of an experienced laparoscopic surgeon. Prospective data were collected on the first consecutive series of RALH performed by (TLH Exp) and (Non-TLH Exp) surgeons, with perioperative outcomes and morbidity being evaluated. In addition, retrsopective data were collected on a consecutive series of patients in a TLH group and compared with the outcomes in the robotic group for benign hysterectomies by the same surgeon. The parameters that were analyzed for associations with these two groups were estimated blood loss (EBL), Hb drop, length of hospital stay (LOS), procedure time, pain medication use, and complications. The (TLH Exp) group had 64 patients, and the (Non-TLH Exp) group had 72 patients. When comparing patients in the (TLH Exp) group with patients in (Non-TLH Exp) group, the mean age was 44 and 45 (P = 0.8), mean BMI was 27.7 and 29.5 kg/m(2) (P = 0.2), mean procedure time was 121 and 174 min (P < 0.05), mean console time was 70 and 119 min (P < 0.05), mean EBL was 64 and 84 ml (P = 0.3), with a Hb drop 1.7 and 1.33 (P = 0.2), uterine weight was 192 and 205 gms (P = 0.7), and length of stay was 1.07 and 1.33 days (P = 0.2), respectively. The (TLH Exp) surgeons had a lower OR, procedure and console time, but a higher hemoglobin drop, with no difference in EBL. There were no operative deaths, or conversions in either group. Morbidity occurred in two patients (3 %) in each group, with no statistically significant difference between the groups. In the (TLH Exp) group it included a blood transfusion and a readmission for a postoperative ileus. In the (Non-TLH Exp), the complications included a blood transfusion and a return to the OR for a vaginal cuff dehiscence. When comparing a single (TLH Exp) surgeon's own TLH versus RALH, there were 64 RALH and 49 TLH cases. There was a statistically significant difference in the mean procedure time 121.1 versus 88.8 min (P < 0.05), mean Hb drop 1.7 versus 2.3 (P < 0.05), and mean EBL 64.2 versus 158 ml (P < 0.05), respectively. The RALH group had a longer procedure time, but lower Hb drop, and less estimated blood loss. There were no operative deaths, or conversions in either group. Morbidity occurred in 2 patients in the robotic group, and included one blood transfusion, and one postoperative ileus. There were no complications noted in the laparoscopic hysterectomy group. Previous advanced laparoscopic skills appear to only significantly impact the length of the procedure, but not other variables. Robotic surgery may level the playing field between the basic and advanced laparoscopic surgeon for robotic assisted laparoscopic hysterectomy. In comparing the outcomes of RALH versus TLH by a single surgeon, the robotic assistance appeared to lengthen the procedure time, but reduce the amount of blood loss. Robotic surgery may offer a benefit of reduced blood loss at the expense of longer operating time. Similar studies including different surgeons are needed to validate these points, and thereby determine the risk-benefit balance between the two approaches for benign simple hysterectomies.

A rare case report of orofacial granulomatosis in a pediatric patient.

Orofacial granulomatosis comprises a group of diseases characterized by noncaseating granulomatous inflammation affecting the soft tissues of the oral and maxillofacial region. The most common clinical presentation is persistent swelling of one or both lips. It is important to establish the diagnosis accurately because this condition is sometimes a manifestation of Crohn's disease or sarcoidosis. This article describes a case of orofacial granulomatosis.

Population dynamics of a parasite Pallisentis in two species of fish Channa punctatus and Channa striatus.

In an aquatic environment, there is a profound and inverse relationship between environment quality and disease status of fish. Parasites are one of the most serious limiting factors in aquaculture. Therefore, the present investigation has been undertaken to sort out the population dynamics of Pallisentis (Acanthocephala), in relation to host sex from freshwater fishes, Channa of Rohilkhand region. A total of 517 fishes (Channa punctatus, n = 198 and C. striatus, n = 319) were examined regularly from August 2006 to February 2010. Overall prevalence of Pallisentis in C. striatus was higher in females (67.78%) as compared to males (63.52%). In case of C. punctatus, overall prevalence of Pallisentis was higher in males (53.77%) as compared to females (52.17%) whereas, relative density was higher in females (61.41%) than in males (52.72%). Intensity (2-3 parasite/host, in both sexes), density (1.36 in males and 1.69 in females) and infection index (0.73 in males and 0.88 in females) were recorded.

Peripheral osteoma in a young patient: a marker for precancerous condition?

Osteoma is a benign osteogenic tumor arising from the proliferation of cancellous or compact bone. The osteoma can be central, peripheral, or of an extraskeletal type. Peripheral type of osteoma is most common in the lower jaws, which occurs at the surface of the cortical bone and is sessile or pedicled. The overall incidence of osteoma is low, affecting 0.01-0.04% of the population; osteomas comprise 12.1% of benign bone tumors and 2.9% of all bone tumors. Most of the osteomas occurring in the mandible are dense osteomas, and the cancellous osteoma is comparatively rare. Maxillofacial osteoma associated with cutaneous sebaceous cysts, multiple supernumerary teeth, and colorectal polyposis is known as Gardener's syndrome. However, in some cases, maxillofacial osteomas with multiple impacted and supernumerary teeth are not accompanied by a fixed complex of symptoms. We report one such case in a 15-year-old female patient.

Fabricating feeding plate in CLP infants with two different material: a series of case report.

Feeding is a family's biggest concerns when a child is born with cleft lip and/or palate. The goal for that child is to have as near normal feeding as possible. This report presents fabrication of feeding plates in two infants born with cleft lip and palate using two different materials.

Cemento-ossifying fibroma of maxillary antrum in a young female patient.

The cemento-ossifying fibroma is classified as a fibro-osseous lesion of the jaws. It commonly presents as a progressively growing lesion that can attain an enormous size with resultant deformity if left untreated. The cemento-ossifying fibroma is a central neoplasm of bone as well as periodontium which has caused considerable controversy because of controversy regarding terminology and the criteria for its diagnosis. This case report describes a female patient with cemento-ossifying fibroma involving maxillary antrum. The clinical, radiographic and histological features as well as the surgical findings are presented.

Lingual thyroid in children.

Lingual thyroid is a rare embryological anomaly and originates from failure of the thyroid gland to descend from the foramen caecum to its normal eutopic pre-laryngeal site. The ectopic gland located at the base of the tongue is often asymptomatic but may cause local symptoms such as dysphagia, dysphonia with stomatolalia, upper airway obstruction and haemorrhage, often with hypothyroidism. One case is presented, in a 5 year-old girl patient, who complained of sensation of a foreign body and progressive dysphagia and dyspnoea caused by ectopic lingual thyroid. The diagnosis of lingual thyroid is usually made clinically and radionuclide scanning is used to confirm the diagnosis. In this case report, presentation, diagnosis and management of this condition is highlighted.

Safe and rapid resolution of severe hypertriglyceridaemia in two patients with intravenous insulin.

AIM: To rapidly reduce serum triglyceride to a safe serum level. Severe hypertriglyceridaemia is associated with uncontrolled diabetes, obesity and poor physical activity. Even moderate increases in triglyceride levels (> 5mmol/L) confer an increased risk of pancreatitis and coronary artery disease. We present two patients with diabetes and serum triglyceride levels of greater than 85mmol/L despite polypharmacy intervention. METHOD: 72-hour intravenous insulin infusion was administered. RESULTS: Serum triglyceride levels fell to 9.4 and 4.6 mmol/L respectively, without adverse events and sustained effect over several months. CONCLUSION: We suggest the use of intravenous insulin infusion where lifestyle and oral drug therapies have failed can impact on severe hypertriglyceridaemia.

DC-specific ICAM-3-grabbing nonintegrin mediates internalization of HIV-1 into human podocytes.

Human immunodeficiency virus (HIV)-1 has been demonstrated to contribute to the pathogenesis of HIV-associated nephropathy. In renal biopsy studies, podocytes have been reported to be infected by HIV-1. However, the mechanism involved in HIV-1 internalization into podocytes is not clear. In the present study, we evaluated the occurrence of HIV-1 internalization into conditionally immortalized human podocytes and the mechanism involved. Human podocytes rapidly internalized R5 and X4 HIV-1 primary strains via an endocytosis-dependent pathway, without establishing a productive infection. The HIV-1 internalization was dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) receptor mediated. The role of DC-SIGN was confirmed by using specific blocking antibodies and transfection with small interfering (si) RNA/DC-SIGN. Since podocyte HIV-1 trafficking was not altered by pH-modulating agents, it appeared that HIV-1 routing occurred through nonacid vesicular compartments. Interestingly, transfection of podocytes with neither siRNA/caveolin-1 nor siRNA/clathrin heavy chain inhibited podocyte viral accumulation. Thus it appears that clathrin-coated vesicles and caveosomes may not be contributing to HIV-1-associated membrane traffic.