ApoA-I mimetics favorably impact cyclooxygenase 2 and bioactive lipids that may contribute to cardiometabolic syndrome in chronic treated HIV.

OBJECTIVE: We investigated whether apolipoprotein A-I (apoA-I) mimetic peptides 4F and 6F can be a novel therapeutic strategy to reduce blood and gut bioactive lipids, proinflammatory effects of endotoxin (LPS) and aberrant activation of cyclooxygenase 2 (COX-2) as instigators of increased risk for cardiometabolic disease in chronic treated HIV. METHODS: We used two humanized murine models of chronic treated HIV infection (n = 109 mice) and gut explants from HIV infected (n = 10) persons to determine whether Tg6F and 4F attenuate in vivo and ex vivo increased blood and gut bioactive lipids (measured by mass spectrometry) and intestinal protein levels of COX-2 (measured by immunoassays) in chronic treated HIV. RESULTS: In these models of HIV, when compared to HIV-1 infected mice on antiretroviral therapy (ART) alone, oral Tg6F in combination with ART attenuated increases in plasma and gut bioactive lipids (and particularly COX lipids) and intestinal COX-2. 4F and Tg6F also reduced ex vivo production of COX-2 protein and associated secretion of bioactive lipids in gut explants from HIV-1 infected persons treated with LPS. CONCLUSION: ApoA-I mimetics favorably impact the proinflammatory effects of LPS, COX-2 and production of bioactive lipids that collectively drive gut and systemic inflammation in chronic treated HIV. Given prior experimental evidence that the proinflammatory effects of LPS, COX-2 and gut dysfunction contribute to cardiometabolic syndrome in chronic HIV, apoA-I mimetic peptides may be a novel therapy to treat cardiometabolic syndrome in chronic HIV.

Physics-informed machine learning: case studies for weather and climate modelling.

Machine learning (ML) provides novel and powerful ways of accurately and efficiently recognizing complex patterns, emulating nonlinear dynamics, and predicting the spatio-temporal evolution of weather and climate processes. Off-the-shelf ML models, however, do not necessarily obey the fundamental governing laws of physical systems, nor do they generalize well to scenarios on which they have not been trained. We survey systematic approaches to incorporating physics and domain knowledge into ML models and distill these approaches into broad categories. Through 10 case studies, we show how these approaches have been used successfully for emulating, downscaling, and forecasting weather and climate processes. The accomplishments of these studies include greater physical consistency, reduced training time, improved data efficiency, and better generalization. Finally, we synthesize the lessons learned and identify scientific, diagnostic, computational, and resource challenges for developing truly robust and reliable physics-informed ML models for weather and climate processes. This article is part of the theme issue 'Machine learning for weather and climate modelling'.

The quality of life index: a pilot study integrating treatment efficacy and quality of life in oncology.

The majority of women diagnosed with breast cancer will experience some form of drug-related toxicity and subsequent impairments in Health-related Quality of Life (HRQoL). Despite this, HRQoL is assessed inconsistently and there is no validated method to integrate HRQoL data into the assessment of therapeutic agents. This proof of concept study utilizes data from the neoadjuvant I-SPY 2 clinical trial to describe the development of the Quality of Life Index (QoLI) measure. The QoLI represents a single composite score that incorporates validated longitudinal measures of clinical efficacy and QoL and one that permits a more comprehensive, direct comparison of individual therapeutic agents. Preliminary data suggest the QoLI is able to distinguish between agents based on their efficacy and toxicity; with further validation, the QoLI has the potential to provide more patient-centered evaluations in clinical trials and help guide treatment decision making in breast cancer and other oncologic diseases.

Synthesis and characterization of monodispersed water dispersible Fe3O4 nanoparticles and in vitro studies on human breast carcinoma cell line under hyperthermia condition.

Monodispersed Fe3O4 magnetic nanoparticles (MNPs) having size of 7 nm have been prepared from iron oleate and made water dispersible by functionalization for biomedical applications. Three different reactions employing thioglycolic acid, aspartic acid and aminophosphonate were performed on oleic acid coated Fe3O4. In order to achieve a control on particle size, the pristine nanoparticles were heated in presence of ferric oleate which led to increase in size from 7 to 11 nm. Reaction parameters such as rate of heating, reaction temperature and duration of heating have been studied. Shape of particles was found to change from spherical to cuboid. The cuboid shape in turn enhances magneto-crystalline anisotropy (Ku). Heating efficacy of these nanoparticles for hyperthermia was also evaluated for different shapes and sizes. We demonstrate heat generation from these MNPs for hyperthermia application under alternating current (AC) magnetic field and optimized heating efficiency by controlling morphology of particles. We have also studied intra-cellular uptake and localization of nanoparticles and cytotoxicity under AC magnetic field in human breast carcinoma cell line.

Human papillomavirus and oral cancer: a primer for dental public health professionals.

UNLABELLED: There is strong evidence for causal association between human papillomavirus (HPV) and cervical cancer, evidence of association of HPV and oropharyngeal cancer is beginning to mount. OBJECTIVES: To review the HPV-oral cancer literature for a comprehensive assessment of the issues involved. METHODS: Literature search conducted using PubMed, Google Scholar and Google search engine. RESULTS: Both available HPV vaccines are efficacious and safe although expensive. Policy for mandatory HPV vaccination for cervical prevention is mired in political issues stemming from negative cost-effectiveness balance. Dental professionals are not ready to discuss the role of HPV vaccine in cancer prevention. This review discusses the impact of HPV on cervical cancer, transmission of HPV among humans, impact of HPV in oral health, and its plausible role in oral and oropharyngeal cancer, prevention of HPV transmission, available vaccines against HPV, testing, cost, policy and use of HPV vaccines internationally and dentists readiness related to HPV associated health communication. CONCLUSIONS: Given the mounting literature on the association between HPV and oropharyngeal cancer, the dental community must be prepared to answer patients' HPV-related questions and to educate patients about the role of HPV as a risk factor for oral and oropharyngeal cancers.

Determinants and trends in dental expenditures in the adult US population: Medical Expenditure Panel Survey 1996-2006.

OBJECTIVES: To estimate dental expenditures in 2006, to analyse dental expenditures by potential explanatory factors for 2006 and to explore trends in dental expenditures from 1996-2006. METHODS: Medical Expenditure Panel Survey (MEPS) data were used. T-tests and analysis of variance were used to test for significance. Multivariable linear regression analysis was conducted to identify independent predictors of dental expenditures. The trend analysis was conducted for the 11-year period, 1996-2006, on adults aged 25 years and older. Expenditures were inflation adjusted to 2006 dollars using the annual average Consumer Price Index. Data were analysed using the MEPS query tool and SASv9.2. RESULTS: In the 2006 MEPS sample, 8,001 adults had dental expenditures and when weighted represented about 93 million non-institutionalised adult US civilians. The mean dental expenditures for this weighted sample were $611 (sd 1,309), median $233 (inter-quartile range 466). As expected, in 2006, dental expenditures increased with age. Those adults who reported their self-perceived health status as 'excellent' were observed to have lowest dental expenditures in this category. After adjusting for other variables in the multivariable linear regression analysis of dental expenditures, age, race/ethnicity, income, geographic location, perceived health status and dental insurance coverage remained significant. CONCLUSION: Dental expenditures for 2006 were $611 (mean) and $233 (median). The time-trend showed substantial but non-uniform annual changes in real dental expenditures between 1996 and 2006.

Functional characterization of rare variants in human dopamine receptor D4 gene by genotype-phenotype correlations.

Next generation sequencing technologies have facilitated a notable shift from common disease common variant hypothesis to common disease rare variant, as also witnessed in recent literature on schizophrenia. Dopamine receptor D4 (DRD4), a G-protein-coupled receptor is associated with psychiatric disorders and has high affinity for atypical antipsychotic clozapine. We investigated the functional role of rare genetic variants in DRD4 which may have implications for translational medicine. CHO-K1 cells independently expressing four rare non-synonymous variants of DRD4 namely R237L, A281P, S284G located in the third cytosolic loop and V194G, located in the fifth transmembrane domain were generated. Their genotype-phenotype correlations were evaluated using [³H]spiperone binding, G-protein activation and molecular dynamics-simulation studies. A281P and S284G were functionally similar to wildtype (WT). With R237L, potency of dopamine and quinpirole reduced ∼sixfold and threefold respectively compared to WT; [³H]spiperone binding studies showed a reduction in total number of binding sites (∼40%) but not binding affinity, in silico docking studies revealed that binding of both dopamine and spiperone to R237L was structurally similar to WT. Of note, V194G variant failed to inhibit forskolin-stimulated adenylate cyclase activity and phosphorylate extracellular signal-regulated kinase; showed significant reduction in binding affinity (K(d)=2.16 nM) and total number of binding sites (∼66%) compared to WT in [³H]spiperone binding studies; and ligand docking studies showed that binding of dopamine and spiperone is superficial due to probable structural alteration. Transmembrane variant V194G in DRD4.4 results in functional alteration warranting continuing functional analysis of rare variants.

Oral health care services utilisation in the adult US population: Medical Expenditure Panel Survey 2006.

OBJECTIVES: To estimate the proportion of dental visits and to explore determinants of oral health care service (OHCS) utilisation among US civilian non-institutionalised adults. METHODS: Cross-sectional data from the 2006 Medical Expenditure Panel Survey (MEPS) were used to analyse adults' self-reported dental visits across potential risk factors (n = 22,721). MEPS uses a complex sample design including stratification, clustering, multiple stages of selection, and disproportionate sampling. These survey design complexities were taken into account for analysis in this study. The analysis was performed in SAS 9.2 and used chi-square tests and binary logistic regression. RESULTS: MEPS (2006) represented approximately 222 million non-institutionalised US adults. 42% (weighted) of this population reported a dental visit in the past 12 months. Dental visit numbers were observed to increase with age, with the 55-64-year-olds approximately 44% more likely than the 18-24-year olds to have visited the dentist in the past year. Hispanics were 48% less likely to report a dental visit compared to Non-Hispanic Whites. Respondents with public- or no- dental insurance were less likely to report a dental visit than persons with private dental coverage. CONCLUSIONS: Under half the US adult civilian non-institutionalised population reported a dental visit during 2006. To help address utilisation disparities, creative initiatives and systemic approaches aimed at groups currently utilising OHCS less often could be an important step towards oral health equity.

Spherical mesh adaptive direct search for separating quasi-uncorrelated sources by range-based independent component analysis.

It is seemingly paradoxical to the classical definition of the independent component analysis (ICA), that in reality, the true sources are often not strictly uncorrelated. With this in mind, this letter concerns a framework to extract quasi-uncorrelated sources with finite supports by optimizing a range-based contrast function under unit-norm constraints (to handle the inherent scaling indeterminacy of ICA) but without orthogonality constraints. Albeit the appealing contrast properties of the range-based function (e.g., the absence of mixing local optima), the function is not differentiable everywhere. Unfortunately, there is a dearth of literature on derivative-free optimizers that effectively handle such a nonsmooth yet promising contrast function. This is the compelling reason for the design of a nonsmooth optimization algorithm on a manifold of matrices having unit-norm columns with the following objectives: to ascertain convergence to a Clarke stationary point of the contrast function and adhere to the necessary unit-norm constraints more naturally. The proposed nonsmooth optimization algorithm crucially relies on the design and analysis of an extension of the mesh adaptive direct search (MADS) method to handle locally Lipschitz objective functions defined on the sphere. The applicability of the algorithm in the ICA domain is demonstrated with simulations involving natural, face, aerial, and texture images.

Membrane lipids in the function of serotonin and adrenergic receptors.

G-protein coupled receptors (GPCRs) are the largest class of molecules involved in signal transduction across membranes, and represent major targets in the development of novel drug candidates in all clinical areas. Since GPCRs are integral membrane proteins, interaction of membrane lipids such as cholesterol and sphingolipids with GPCRs constitutes an emerging area of research in contemporary biology. Cholesterol and sphingolipids represent important lipid components of eukaryotic membranes and play a crucial role in a variety of cellular functions. In this review, we highlight the role of these vital lipids in the function of two representative GPCRs, the serotonin(1A) receptor and the adrenergic receptor. We believe that development in deciphering molecular details of the nature of GPCR-lipid interaction would lead to better insight into our overall understanding of GPCR function in health and disease.

Lipoprotein lipase is frequently overexpressed or translocated in cervical squamous cell carcinoma and promotes invasiveness through the non-catalytic C terminus.

BACKGROUND: We studied the biological significance of genes involved in a novel t(8;12)(p21.3;p13.31) reciprocal translocation identified in cervical squamous cell carcinoma (SCC) cells. METHODS: The rearranged genes were identified by breakpoint mapping, long-range PCR and sequencing. We investigated gene expression in vivo using reverse-transcription PCR and tissue microarrays, and studied the phenotypic consequences of forced gene overexpression. RESULTS: The rearrangement involved lipoprotein lipase (LPL) and peroxisome biogenesis factor-5 (PEX5). Whereas LPL-PEX5 was expressed at low levels and contained a premature stop codon, PEX5-LPL was highly expressed and encoded a full-length chimeric protein (including the majority of the LPL coding region). Consistent with these findings, PEX5 was constitutively expressed in normal cervical squamous cells, whereas LPL expression was negligible. The LPL gene was rearranged in 1 out of 151 cervical SCCs, whereas wild-type LPL overexpression was common, being detected in 10 out of 28 tissue samples and 4 out of 10 cell lines. Forced overexpression of wild-type LPL and PEX5-LPL fusion transcripts resulted in increased invasiveness in cervical SCC cells, attributable to the C-terminal non-catalytic domain of LPL, which was retained in the fusion transcripts. CONCLUSION: This is the first demonstration of an expressed fusion gene in cervical SCC. Overexpressed wild-type or translocated LPL is a candidate for targeted therapy.

Outcome of colostomy closure with different skin closure techniques in a developing country.

BACKGROUND: Colostomy site, which is a potentially contaminated wound, is traditionally closed with interrupted skin stitches and placement of intraperitoneal or parietal or both drains; often with poor cosmetic outcome in our country. This study aims at prospective evaluation of colostomy closure wounds by different techniques. PATIENTS AND METHODS: This study was carried out in all infants and children with colostomy (for different pathologies) admitted for colostomy closure in our institute from August 1, 2006 to February 29, 2008. Patients were divided into two groups: Group A with colostomy closure without any drain and subcuticular skin closure and Group B with colostomy closure with both intraperitoneal and parietal drain and interrupted skin closure. Patient's details, including age, sex, body weight, diagnosis, preoperative bowel preparation, peroperative antibiotics, postoperative wound infection, anastomotic leaks, duration of hospitalisation and postoperative follow-up for wound assessment, were recorded. By the end of February 2008, 151 cases of colostomy closure were recorded, 70 in Group A and 81 in Group B. RESULTS: Statistical analysis of the data showed no statistically significant difference in wound infection and anastomotic leak between the two groups. On postoperative follow-up, wound assessment showed significantly better cosmesis in the no drain subcuticular group. CONCLUSION: This study shows that closing colostomies without any drain and subcuticular skin closure does not result in any increased incidence of wound infection and has better cosmetic results.

Professional charges not reimbursed to dentists in the U.S.: evidence from Medical Expenditure Panel Survey, 1996.

OBJECTIVES: This cross-sectional study examined professional charges not paid to dentists. METHODS: This analysis used logistic regression in SUDAAN examining the 1996 MEPS data from 12,931 adults. RESULTS: Among people incurring dental care charges, 13.6% had more than $50 of unpaid charge (UC). The percapita UC was $53.30. Total UC was higher for highest income group [45.4% of total] compared to lowest income group [26.0%]. The percapita UC of $76.70 for low income group was significantly greater than for high income group ($47.80, P < 0.01). More Medicaid recipients (52% vs. non-recipients: 12%) incurred at least $50 in UC (P < 0.01). Adjusted odds of incurring UC were greater for those employed (OR = 1.3, 95% CI: 1.0-1.7), and for those with private insurance (OR: 1.5, CI: 1.3-1.9). Number of dental procedure types modified the association between Medicaid recipient and UC (OR = 13.6 for Medicaid recipients undergoing multiple procedure types; OR: 2.3 for Medicaid non-recipients with multiple procedure types; OR: 1.9 for Medicaid recipients receiving single dental procedure. CONCLUSIONS: Having private insurance, being unemployed and being Medicaid insured undergoing multiple procedure were strongest predictors of UC.

Erythropoietin-induced deep vein thrombosis in myelodysplastic syndrome.

We report a rare case of deep vein thrombosis (DVT) secondary to erythropoietin (EPO) in an 89-year-old patient with myelodysplastic syndrome (MDS). The incidence of EPO-induced thrombotic episode increases with an absolute increase of hemoglobin (Hb) beyond >12 gm/dL or rate of increase of Hb level >1 gm/dL every 2 weeks.

Albendazole therapy for single small enhancing CT lesions (SSECTL) in the brain in epilepsy.

BACKGROUND: Single small enhancing CT lesions (SSECTL) of the brain with or without perifocal oedema are common in patients with symptomatic epilepsy in India. Solitary cysticercus granuloma, a benign form of parenchymal neurocysticercosis, is considered to be the most common aetiology for SSECTL. Definite information is lacking regarding the effectiveness of antiparasitic treatment on resolution of these lesions and on long term seizure recurrence. OBJECTIVE: To evaluate the response to albendazole treatment in patients who had SSECTL and new onset seizures treated with antiepileptic drugs (AED) in a prospective clinical trial. METHODS: 43 patients who presented with new onset seizures and were documented to have SSECTL were alternatively allocated to receive albendazole 15 mg/kg/day for 2 weeks or no cysticidal therapy. All patients were treated with AED and followed for at least 6 months for seizure recurrence, and serial CT scans were obtained at 4 weeks, 3 months and at study completion. RESULTS: 28 (65%) patients were aged 5-25 years and 31 (72%) presented clinically with partial motor seizures with or without generalisation. Most of the SSECTL were ring lesions (75%) and located in and around the sensory-motor cortex at the gray-white junction (65%). In the albendazole group, 56% of patients compared with 35% in the control group showed resolution of SSECTL (p = 0.154) at 1 month. 22 of 23 patients (95.6%), who received albendazole, compared with 14 of 20 patients (70%) in the control group, demonstrated radiological resolution on study completion (p = 0.03). Punctate residual calcification and seizure recurrence were observed in four patients (9.3%) in the control group and in three (7%) patients in the albendazole group (p = 0.47). CONCLUSIONS: In patients presenting with seizures due to single viable parenchymal neurocysticercosis, albendazole hastens the resolution of SSECTL if treatment is given in the early phase of the illness.