Quality of life is significantly impaired in long-term survivors of acute liver failure and particularly in acetaminophen-overdose patients.
Functional outcomes for long-term survivors of acute liver failure (ALF) are not well characterized. The aim of this prospective study was to determine health-related quality of life in long-term adult ALF survivors. Acute Liver Failure Study Group registry participants completed the Centers for Disease Control and Prevention Health-Related Quality of Life 14 and Short Form 36 (SF-36) questionnaires at 1- and/or 2-year follow-up study visits. Responses were compared among ALF subgroups and to those for available general US population controls. Among the 282 adult ALF patients, 125 had undergone liver transplantation (LT), whereas 157, including 95 acetaminophen overdose (APAP) patients and 62 non-APAP patients, were spontaneous survivors (SSs). APAP SS patients reported significantly lower general health scores and more days of impaired mental and physical health, activity limitations due to poor health, pain, depression, and anxiety in comparison with the other groups (P ≤ 0.001). There were no significant differences in coma grade or in the use of mechanical ventilation or intracranial pressure monitoring among the patient groups during their ALF hospitalization, but APAP SSs had significantly higher rates of psychiatric disease and substance abuse (P < 0.001). In comparison with the general US population, a greater proportion of the combined SS patients reported fair or poor health and ≥14 days of impaired physical/mental health and activity limitations due to poor health. In addition, a greater proportion of LT recipients reported ≥14 days of impaired physical/mental health. Similar results were observed with the SF-36 across the 3 ALF subgroups and in comparison with population controls. In conclusion, long-term adult survivors of ALF reported significantly lower quality of life scores than US population controls. Furthermore, APAP SS patients reported the lowest quality of life scores, possibly because of higher rates of premorbid psychiatric and substance abuse disorders.


Characterization of high-grade pineal region lesions: the usefulness of apparent diffusion coefficient volumetric values.
High-grade pineal region tumors are rare and heterogeneous types of primary central nervous system neoplasms; radiological differential diagnosis is challenging but it is important because it has a therapeutic relevance. To discriminate among high-grade pineal region tumors by combining apparent diffusion coefficient (ADC) volumetric values and qualitative features in order to predict their histology. Twenty-two patients with high-grade pineal region tumors were assessed by qualitative and quantitative analysis. Margins, T2-weighted signal intensity, contrast enhancement, hemorrhage, calcifications, different volumetric ADC fractions (ADCmean, ADCmax, ADCmin) were evaluated and were compared to the histopathologic findings (cell count and proliferation index). Our qualitative imaging data showed that only margins were different among different tumors and each tumor type showed peculiar age onset. ADCmean was found the best quantitative value to discriminate high-grade tumors of the pineal region. ADCmean correlated with proliferation index but not with cell count. ADCmean values were lower in tumors with higher proliferation rate and a significant difference in ADCmean values were found between germinomas and pineoblastomas, between germinomas and papillary tumors and between papillary tumors and pineoblastomas. Moreover, the cut-off value of 0.865 × 10-3 mm2/s for ADCmean (ADC mean threshold value) could differentiate germinoma from pineoblastomas with the best combination of sensitivity and specificity. The ADCmean value measured on the whole tumor, reflecting tumor proliferative activity, may be a practical and non-invasive marker for predicting tumor histology in high-grade pineal region lesions and might be useful in preoperative assessment.


Topical cyclosporine in thyroid orbitopathy-related dry eye: clinical findings, conjunctival epithelial apoptosis, and MMP-9 expression.
To evaluate the effects of topical cyclosporine A (CsA) 0.05% (Restasis) on the signs and symptoms of dry eye, on apoptosis, and on MMP-9 expression in conjunctiva epithelial cells in thyroid orbitopathy (TO)-related dry eye patients. Prospective, clinical study. Twenty-four eyes of 12 consecutive TO patients with dry eye findings instilled CsA twice daily for 2 months. Ocular surface disease index, Schirmer tear test, tear breakup time (TBUT), conjunctival apoptosis index, and conjunctival MMP-9 expression were evaluated before and after 2 months treatment. Conjunctival biopsies were harvested from all eyes at baseline and after 2 months treatment. Apoptosis was detected by the terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL) assay. MMP-9 expression was determined by immunohistochemistry. After 2 months of topical CsA treatment, the mean OSDI score was significantly decreased from 58.08 +/- 6.28 to 36.41 +/- 11.75 (P = 0.001). At baseline, the mean Schirmer tear test score was 8.92 +/- 5.52 mm. It was increased to 11.25 +/- 4.71 mm after treatment (P > 0.05). The mean TBUT increased significantly from 3.92 +/- 2.18 sec to 9.16 +/- 3.34 sec (P = 0.001). The mean percentage of apoptosis index at baseline was 72.10 +/- 35.82%. This was significantly decreased to 53.29 +/- 34.46% after treatment (P = 0.008). The mean percentage of MMP-9 expression of the conjunctival epithelial cells was significantly decreased from 48.12 +/- 28.58% to 26.66 +/- 25.13% following treatment (P = 0.005). Topical CsA treatment appears to improve the signs and symptoms of dry eye and inhibits apoptosis and MMP-9 expression in conjunctival epithelial cells in TO-related dry eye patients after 2 months of treatment.


Proton transport and cell function.
The past five years have witnessed an explosion of information on the many and varied roles of H+ transport in cell function. H+ transport is involved in three broad areas of cell function: (a) maintenance and alteration of intracellular pH for initiation of specific cellular events, (b) generation of pH gradients in localized regions of the cell, including gradients involved in energy transduction, and (c) transepithelial ion transport. These processes each involve one or more of several H+ translocating mechanisms. The first section of this review will discuss these H+ translocating mechanisms and the second part will deal with the cellular functions controlled by H+ transport.


Measured and modelled effect of land-use change from temperate grassland to Miscanthus on soil carbon stocks after 12 years.
Soil organic carbon (SOC) is an important carbon pool susceptible to land-use change (LUC). There are concerns that converting grasslands into the C4 bioenergy crop Miscanthus (to meet demands for renewable energy) could negatively impact SOC, resulting in reductions of greenhouse gas mitigation benefits gained from using Miscanthus as a fuel. This work addresses these concerns by sampling soils (0-30 cm) from a site 12 years (T12) after conversion from marginal agricultural grassland into Miscanthus x giganteus and four other novel Miscanthus hybrids. Soil samples were analysed for changes in below-ground biomass, SOC and Miscanthus contribution to SOC (using a 13C natural abundance approach). Findings are compared to ECOSSE soil carbon model results (run for a LUC from grassland to Miscanthus scenario and continued grassland counterfactual), and wider implications are considered in the context of life cycle assessments based on the heating value of the dry matter (DM) feedstock. The mean T12 SOC stock at the site was 8 (±1 standard error) Mg C/ha lower than baseline time zero stocks (T0), with assessment of the five individual hybrids showing that while all had lower SOC stock than at T0 the difference was only significant for a single hybrid. Over the longer term, new Miscanthus C4 carbon replaces pre-existing C3 carbon, though not at a high enough rate to completely offset losses by the end of year 12. At the end of simulated crop lifetime (15 years), the difference in SOC stocks between the two scenarios was 4 Mg C/ha (5 g CO2-eq/MJ). Including modelled LUC-induced SOC loss, along with carbon costs relating to soil nitrous oxide emissions, doubled the greenhouse gas intensity of Miscanthus to give a total global warming potential of 10 g CO2-eq/MJ (180 kg CO2-eq/Mg DM).


Temperate radiations and dying embers of a tropical past: the diversification of Viburnum.
We used a near-complete phylogeny for the angiosperm clade Viburnum to assess lineage diversification rates, and to examine possible morphological and ecological factors driving radiations. Maximum-likelihood and Bayesian approaches identified shifts in diversification rate and possible links to character evolution. We inferred the ancestral environment for Viburnum and changes in diversification dynamics associated with subsequent biome shifts. Viburnum probably diversified in tropical forests of Southeast Asia in the Eocene, with three subsequent radiations in temperate clades during the Miocene. Four traits (purple fruits, extrafloral nectaries, bud scales and toothed leaves) were statistically associated with higher rates of diversification. However, we argue that these traits are unlikely to be driving diversification directly. Instead, two radiations were associated with the occupation of mountainous regions and a third with repeated shifts between colder and warmer temperate forests. Early-branching depauperate lineages imply that the rare lowland tropical species are 'dying embers' of once more diverse lineages; net diversification rates in Viburnum likely decreased in these tropical environments after the Oligocene. We suggest that 'taxon pulse' dynamics might characterize other temperate plant lineages.


Management of heart failure with reduced ejection fraction: challenges in patients with atrial fibrillation, renal disease and in the elderly.
Heart failure with reduced ejection fraction (HFrEF) is an increasing global pandemic affecting more than 30 million individuals worldwide. Importantly, HFrEF is frequently accompanied by the presence of cardiac and non-cardiac comorbidities that may greatly influence the management and prognosis of the disease. In this review article, we will focus on three important comorbidities in HFrEF; atrial fibrillation (AF), advanced renal disease, and elderly, which all have a paramount impact on progression of the disease, management strategies, and response to therapy. AF is very common in HFrEF and shares many risk factors. AF aggravates heart failure and contributes to HF-related adverse clinical outcomes; hence it requires special consideration in HFrEF management. The kidney function is largely affected by the reduced cardiac output developed in the setting of HFrEF, and the neurohormonal feedback effects create a complex interplay that pose challenges in the management of HFrEF when renal function is significantly impaired. Cardiorenal syndrome is a challenging sequela with increased morbidity and mortality thereby reflecting the delicate and complex balance between the heart and the kidney in HFrEF and renal failure conditions. Furthermore, patients with advanced renal failure have poor prognosis in the presence of HFrEF with limited treatment options. Finally, aging and frailty are important factors that influence treatment strategies in HFrEF with greater emphasis on tolerability and safety of the various HFrEF therapies in elderly individuals.


Evidence for altered thiamine metabolism in diabetes: Is there a potential to oppose gluco- and lipotoxicity by rational supplementation?
Growing prevalence of diabetes (type 2 as well as type 1) and its related morbidity due to vascular complications creates a large burden on medical care worldwide. Understanding the molecular pathogenesis of chronic micro-, macro- and avascular complications mediated by hyperglycemia is of crucial importance since novel therapeutic targets can be identified and tested. Thiamine (vitamin B1) is an essential cofactor of several enzymes involved in carbohydrate metabolism and published data suggest that thiamine metabolism in diabetes is deficient. This review aims to point out the physiological role of thiamine in metabolism of glucose and amino acids, to present overview of thiamine metabolism and to describe the consequences of thiamine deficiency (either clinically manifest or latent). Furthermore, we want to explain why thiamine demands are increased in diabetes and to summarise data indicating thiamine mishandling in diabetics (by review of the studies mapping the prevalence and the degree of thiamine deficiency in diabetics). Finally, we would like to summarise the evidence for the beneficial effect of thiamine supplementation in progression of hyperglycemia-related pathology and, therefore, to justify its importance in determining the harmful impact of hyperglycemia in diabetes. Based on the data presented it could be concluded that although experimental studies mostly resulted in beneficial effects, clinical studies of appropriate size and duration focusing on the effect of thiamine supplementation/therapy on hard endpoints are missing at present. Moreover, it is not currently clear which mechanisms contribute to the deficient action of thiamine in diabetes most. Experimental studies on the molecular mechanisms of thiamine deficiency in diabetes are critically needed before clear answer to diabetes community could be given.


Magnetic Silicium Hydroxyapatite Nanorods for Enhancing Osteoblast Response in Vitro and Biointegration in Vivo.
Osteoblast behavior playing an important role in the biointegration of the Ti implant with host bone in vivo can be regulated by surface properties and magnetic field. In order to endow the Ti surface with good osteogenesis activity, Si monosubstituted and Fe and Si cosubstituted hydroxyapatite (HAp) nanorods were fabricated on microporous TiO2 by microarc oxidation (MAO) followed with hydrothermal treatment (HT). The surface properties including microstructure, microroughness, hydrophilicity, ion release, magnetic property, cytocompatibility, and biointegration of substituted HAp nanorods were observed and evaluated, together with pure HAp nanorods and microarc oxidated (MAOed) TiO2 as controls. After being doped with Fe, MAOed TiO2 has no changes in phase composition and microroughness, whereas it displays weakly ferromagnetic behavior and can enhance osteoblast differentiation in vitro and formation of new bone in vivo, compared with the undoped one. The substituted HAp nanorods adhere firmly to TiO2 and have almost the same wettability and microroughness but additional Si, Fe, and/or Ca released into the medium, compared with pure HAp nanorods. Moreover, the cosubstituted HAp has a small ferromagnetic signal, while its saturation magnetization value is less than that of the MAOed doped with Fe. Compared to pure HA nanorods, the substituted HAp nanorods not only improve cell proliferation and differentiation in vitro, but also enhance the ability of bone integration in vivo, especially for the cosubstituted one, which should be ascribed to the combined effect of microstructure, magnetic property, and released ions.


Validation of the International Physical Activity Questionnaire-Short among Blacks.
The International Physical Activity Questionnaire-Short Form (IPAQ-S) has been evaluated against accelerometer-determined physical activity measures in small homogenous samples of adults in the United States. There is limited information about the validity of the IPAQ-S in diverse US samples. 142 Blacks residing in low-income housing completed the IPAQ-S and wore an accelerometer for up to 6 days. Both 1- and 10-minute accelerometer bouts were used to define time spent in light, moderate, and vigorous physical activity. We found fair agreement between the IPAQ-S and accelerometer-determined physical activity (r=.26 for 10-minute bout, r=.36 for 1-minute bout). Correlations were higher among men than women. When we classified participants as meeting physical activity recommendations, agreement was low (kappa=.04, 10-minute; kappa=.21, 1-minute); only 25% of individuals were classified the same by both instruments (10-minute bout). In one of the few studies to assess the validity of a self-reported physical activity measure among Blacks, we found moderate correlations with accelerometer data, though correlations were weaker for women. Correlations were smaller when IPAQ-S data were compared using a 10- versus a 1-minute bout definition. There was limited evidence for agreement between the instruments when classifying participants as meeting physical activity recommendations.


Demographic and microbial characteristics of extrapulmonary tuberculosis cases diagnosed in Malatya, Turkey, 2001-2007.
Extrapulmonary tuberculosis (EPTB) has an increasing rate in Turkey. The reason remains largely unknown. A better understanding of the demographic and microbial characteristics of EPTB in the Turkish population would extend the knowledgebase of EPTB and allow us to develop better strategies to control tuberculosis (TB). We retrospectively evaluated clinical and laboratory data of 397 bacteriologically-confirmed TB cases diagnosed during an eight year-period using by chi-square analysis and multivariate logistic regression model. Of the 397 study patients, 103 (25.9%) had EPTB and 294 (74.1%) had pulmonary tuberculosis (PTB). The most commonly seen two types of EPTB were genitourinary TB (27.2%) and meningeal TB (19.4%). TB in bone/joints, pleural cavity, lymph nodes, skin, and peritoneal cavity occurred at a frequency ranging from 9.7% to 10.7%. The age distribution was significantly different (P<0.01) between PTB and EPTB, with patients older than 45 years tending to have an increased risk of EPTB. Furthermore, the distribution of different types of EPTB differed significantly among age groups (P=0.03). Meningeal and bone and/or joint TB were more commonly observed among the male patients, while lymphatic, genitourinary, and peritoneal TB cases were more frequently seen among females. Unique strain infection was statistically significantly associated with EPTB (OR: 2.82, 95% CI [1.59, 5.00]) EPTB accounted for a significant proportion of TB cases in Malatya, Turkey between 2001 and 2007. The current study has provided an insight into the dynamics of EPTB in Malatya, Turkey. However, the risk factors for having EPTB in Malatya, Turkey remain to be assessed in future studies using population-based or randomly selected sample.


Cloned alpha and beta C-protein antigens of group B streptococci elicit protective immunity.
Streptococcus agalactiae (group B streptococci [GBS]) is the leading cause of neonatal sepsis and meningitis in the United States. The surface-associated C proteins of GBS play a role in immunity, but their number, size, structure, function, and virulence properties have not been well characterized. A recombinant library of DNA fragments from GBS strain A909 (type Ia/C) was prepared in the plasmid pUX12, a specially constructed Escherichia coli expression vector. The library was screened with a rabbit antiserum shown to be protective for passive immunity to GBS infection in a mouse lethality model. Clones were divided into two distinct groups on the basis of DNA-DNA cross-hybridization, restriction enzyme analysis, and the expression of antigenic proteins in E. coli. A characteristic clone from each group was chosen for further study. Clone pJMS23 expresses gene products that biochemically and immunologically correspond to the trypsin-resistant, C-protein alpha antigen. Clone pJMS1 expresses a gene product that binds to immunoglobulin A and is similar to the trypsin-sensitive, C-protein beta antigen. Antisera raised in rabbits against E. coli containing each of the plasmid clones were able to elicit protective immunity in mice challenged by GBS strains carrying the C proteins but not by non-C-protein-bearing strains. Southern blot analysis shows no DNA homology between the clones, and there is no immunological cross-reactivity between the antigens they express. Therefore, pJMS23 and pJMS1 encode two different C proteins that define unique protective epitopes.


Experimental Study of L-shaped Silastic Stents for Microvascular Anastomosis.
Background: The stent technique of microvascular anastomosis, in which a stent is placed in the vessel before creating the anastomosis, is useful for accurate anastomosis formation, but the manipulation involved in stent insertion into the vessel and withdrawal from the anastomosis still poses problems. In this study, a silastic stent containing a copper wire-bent in an L-shape was designed and its utility in microvascular anastomosis was investigated in rats. Methods: Eighty end-to-end anastomosis procedures of the right femoral artery and vein were performed in rats. Anastomoses were conducted either by the conventional method (Method C) or using L-shaped silastic stents (Method L), with anastomosis condition assessed after one side had been sutured, at the completion of vascular anastomosis and on postoperative day 7. Results: After one side had been sutured, suture errors were observed in three veins with Method C. At the completion of vascular anastomosis, impaired blood flow was observed in two arteries and two veins with Method C, and in one artery with Method L. On postoperative day 7, impaired blood flow was observed in one artery and one vein with Method C and in one vein with Method L. Conclusions: The use of L-shaped silastic stents preserved the advantages of the stent technique while simplifying stent manipulation. This technique may help reduce the risk of intimal trauma.


[Prevention of cardiovascular disease in type 2 diabetes].
It is estimated that 80% of individuals with type 2 diabetes die of cardiovascular diseases. Several factors account for the accelerated atherosclerosis present in diabetic patients. These include hyperglycaemia, dyslipidaemia, hypertension and prothrombotic state. Hypoglycaemic agents, statin or fibrates that improve dyslipidaemia, anti-hypertensive agents, aspirin and healthy lifestyle can modify these factors and have been shown to reduce morbidity and mortality caused by coronary heart disease in diabetic patients. It was recently demonstrated that a multifactorial intervention on modifiable risk factors of cardiovascular disease in type 2 diabetic patients dramatically reduces the incidence of cardiovascular events. Thus, an intensified intervention aimed at multiple risk factors should be recommended in patients with type 2 diabetes.


Glucose repression in the yeast Saccharomyces cerevisiae.
Understanding the mechanism of glucose repression in yeast has proved to be a difficult and challenging problem. A multitude of genes in different pathways are repressed by glucose at the level of transcription. The SUC2 gene, which encodes invertase, is an excellent reporter gene for glucose repression, since its expression is controlled exclusively by this pathway. Genetic analysis has identified numerous regulatory mutations which can either prevent derepression of SUC2 or render its expression insensitive to glucose repression. These mutations allow us to sketch the outlines of a pathway for general glucose repression, which has several key elements: hexokinase PII, encoded by HXK2, which seems to play a role in the sensing of glucose levels; the protein kinase encoded by SNF1, whose activity is required for derepression of many glucose-repressible genes; and the MIG1 repressor protein, which binds to the upstream regions of SUC2 and other glucose-repressible genes. Repression by MIG1 requires the activity of the CYC8 and TUP1 proteins. Glucose repression of other sets of genes seems to be controlled by the general glucose repression pathway acting in concert with other mechanisms. In the cases of the GAL genes and possibly CYC1, regulation is mediated by a cascade in which the general pathway represses expression of a positive transcriptional activator.


Islet survival and function following intramuscular autotransplantation in the minipig.
The liver may not be an optimal site for islet transplantation due to obstacles by an instant blood-mediated inflammatory response (IBMIR), and low revascularization of transplanted islets. Therefore, intramuscular islet transplantation (IMIT) offers an attractive alternative, based on its simplicity, enabling easier access for noninvasive graft imaging and cell explantation. In this study, we explored the outcome of autologous IMIT in the minipig (n = 30). Using the intramuscular injection technique, we demonstrated by direct histological evidence the rapid revascularization of islets autotransplanted into the gracilius muscle. Islet survival assessment was performed using immunohistochemistry staining for insulin and glucagon up to a period of 6 months. Furthermore, we showed the crucial role of minimizing mechanical trauma to the myofibers and limiting exocrine contamination. Intramuscular islet graft function after transplantation was confirmed by documenting the acute insulin response to intravenous glucose in 5/11 pancreatectomized animals. Graft function after IMIT remained however significantly lower than the function measured in 12 out of 18 minipigs who received a similar islet volume in the liver through intraportal infusion. Collectively, these results demonstrated in a clinically relevant preclinical model, suggest IMIT as a promising alternative to intraportal infusion for the transplantation of β cells in certain medical situations.


Transcriptional profiling of isogenic Friedreich ataxia neurons and effect of an HDAC inhibitor on disease signatures.
Friedreich ataxia (FRDA) is a neurodegenerative disorder caused by transcriptional silencing of the frataxin (FXN) gene, resulting in loss of the essential mitochondrial protein frataxin. Based on the knowledge that a GAA·TTC repeat expansion in the first intron of FXN induces heterochromatin, we previously showed that 2-aminobenzamide-type histone deacetylase inhibitors (HDACi) increase FXN mRNA levels in induced pluripotent stem cell (iPSC)-derived FRDA neurons and in circulating lymphocytes from patients after HDACi oral administration. How the reduced expression of frataxin leads to neurological and other systemic symptoms in FRDA patients remains unclear. Similar to other triplet-repeat disorders, it is unknown why FRDA affects only specific cell types, primarily the large sensory neurons of the dorsal root ganglia and cardiomyocytes. The combination of iPSC technology and genome-editing techniques offers the unique possibility to address these questions in a relevant cell model of FRDA, obviating confounding effects of variable genetic backgrounds. Here, using "scarless" gene-editing methods, we created isogenic iPSC lines that differ only in the length of the GAA·TTC repeats. To uncover the gene expression signatures due to the GAA·TTC repeat expansion in FRDA neuronal cells and the effect of HDACi on these changes, we performed RNA-seq-based transcriptomic analysis of iPSC-derived central nervous system (CNS) and isogenic sensory neurons. We found that cellular pathways related to neuronal function, regulation of transcription, extracellular matrix organization, and apoptosis are affected by frataxin loss in neurons of the CNS and peripheral nervous system and that these changes are partially restored by HDACi treatment.


Benzocyclotrimers: from the Mills-Nixon effect to gas hosting.
The formal annulation of three bicylic olefins yields a class of molecules termed benzocyclotrimers (BCTs), which have unusual electronic properties. The bonds in the central aromatic ring, for example, alternate in length: rather than resembling a substituted benzene, a BCT instead evokes comparison to a cyclohexatriene. Forty years have passed since the synthesis of heptiptycene, the first BCT, was reported. In the interim, many methods have been developed for preparing tris-bicycloannulated benzenes. More than thirty different BCTs have so far been reported, with a variety of morphological features and properties. Over the same period, yields have increased from just a few percent to almost quantitative conversion. This improvement in synthetic access has expanded interest beyond the original theoretical considerations (bond-length fixation in aromatics) to functional applications (supramolecular scaffolds). In this Account, we describe the evolution of synthetic approaches to BCTs and their derivatives, as well as the applications that are now being explored for these compounds. Early syntheses of BCTs involved chloroolefins treated with butyl lithium. A strained alkyne intermediate was postulated early on, and was indeed trapped in 1981. Subsequent efforts have focused on improving chemoselectivity by mitigating the drastic conditions required for the generation of the alkyne intermediate. Our introduction of Cu(I) to induce lithium-copper exchange was successful in this regard. Further improvement resulted from the use of bicylic bromo(trimethylstannyl)olefins. In an effort to avoid the toxicity of the tin reagents, the Heck reaction and Pd catalysis have been pursued for cyclotrimerizing bicylic bromo- and iodoolefins. Depending on the symmetry of the starting bicylic olefin, two diastereomers can be obtained in the preparation of a BCT: a syn compound with C(3) symmetry and an anti compound with C(s) symmetry. Studying the diastereomeric outcome in a variety of synthetic approaches has yielded valuable insight into the cyclotrimerization reaction. Moreover, highly symmetric compounds, such as a D(3)-symmetric trindane and C(3v)-symmetric sumanene, have been prepared as BCT derivatives. The structure of BCTs offers a versatile three-dimensional scaffold for studying molecular recognition. Like calixarenes, BCTs form complexes with a variety of guest molecules. Recent developments include the trapping of gases in a hydrogen-bonded dimer and the encapsulation of larger molecules within a covalently linked condensation derivative. Future innovations in this fertile research area will likely include highly functionalized curved aromatics, receptors, and sensors.


Calcium and vitamin D supplementation during androgen deprivation therapy for prostate cancer: a critical review.
Loss of bone mineral density is an unintended consequence of androgen deprivation therapy in men with prostate cancer. Supplementation with calcium and/or vitamin D in these men seems logical and is advocated by many lay and professional groups. We reviewed guidelines for calcium and vitamin D supplementation and the results of clinical trials of calcium and vitamin D supplementation on bone mineral density in men with prostate cancer undergoing androgen deprivation therapy. Whether supplementation of men undergoing androgen deprivation therapy with calcium and/or vitamin D results in higher bone mineral density than no supplementation has not been tested. The results of 12 clinical trials show that, at the doses commonly recommended, 500-1,000 mg calcium and 200-500 IU vitamin D per day, men undergoing androgen deprivation lose bone mineral density. The doses of calcium and vitamin D that have been tested are inadequate to prevent loss of bone mineral density in men undergoing androgen deprivation therapy. In light of evidence that high levels of dietary calcium and calcium supplement use are associated with higher risks for cardiovascular disease and advanced prostate cancer, intervention studies should evaluate the safety as well as the efficacy of calcium and vitamin D supplementation in these men.


Detailed dosimetric evaluation of inter-fraction and respiratory motion in lung stereotactic body radiation therapy based on daily 4D cone beam CT images.
Objective. Periodic respiratory motion and inter-fraction variations are sources of geometric uncertainty in stereotactic body radiation therapy (SBRT) of pulmonary lesions. This study extensively evaluates and validates the separate and combined dosimetric effect of both factors using 4D-CT and daily 4D-cone beam CT (CBCT) dose accumulation scenarios.Approach. A first cohort of twenty early stage or metastatic disease lung cancer patients were retrospectively selected to evaluate each scenario. The planned-dose (3DRef) was optimized on a 3D mid-position CT. To estimate the dosimetric impact of respiratory motion (4DRef), inter-fractional variations (3DAcc) and the combined effect of both factors (4DAcc), three dose accumulation scenarios based on 4D-CT, daily mid-cone beam CT (CBCT) position and 4D-CBCT were implemented via CT-CT/CT-CBCT deformable image registration (DIR) techniques. Each scenario was compared to 3DRef.A separate cohort of ten lung SBRT patients was selected to validate DIR techniques. The distance discordance metric (DDM) was implemented per voxel and per patient for tumor and organs at risk (OARs), and the dosimetric impact for CT-CBCT DIR geometric errors was calculated.Main results.Median and interquartile range (IQR) of the dose difference per voxel were 0.05/2.69 Gy and -0.12/2.68 Gy for3DAcc-3DRefand4DAcc-3DRef.For4DRef-3DRefthe IQR was considerably smaller -0.15/0.78 Gy. These findings were confirmed by dose volume histogram parameters calculated in tumor and OARs. For CT-CT/CT-CBCT DIR validation, DDM (95th percentile) was highest for heart (6.26 mm)/spinal cord (8.00 mm), and below 3 mm for tumor and the rest of OARs. The dosimetric impact of CT-CBCT DIR errors was below 2 Gy for tumor and OARs.Significance. The dosimetric impact of inter-fraction variations were shown to dominate those of periodic respiration in SBRT for pulmonary lesions. Therefore, treatment evaluation and dose-effect studies would benefit more from dose accumulation focusing on day-to-day changes then those that focus on respiratory motion.


3D printed gelatin-genipin scaffolds for temporomandibular joint cartilage regeneration.
Gelatin has emerged as a biocompatible polymer with high printability in scaffold-based tissue engineering. The aim of the current study was to investigate the potential of genipin-crosslinked 3D printed gelatin scaffolds for temporomandibular joint (TMJ) cartilage regeneration. Crosslinking with genipin increased the stability and mechanical properties, without any cytotoxic effects. Chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSC) on the scaffolds were compared to cell pellets and spheres. Although hBMSC seeded scaffolds showed a lower expression of chondrogenesis-related genes compared to cell pellets and spheres, they demonstrated a significantly reduced expression of collagen (COL) 10, suggesting a decreased hypertrophic tendency. After 21 days, staining with Alcian blue and immunofluorescence for SOX9 and COL1 confirmed the chondrogenic differentiation of hBMSC on genipin-crosslinked gelatin scaffolds. In summary, 3D printed gelatin-genipin scaffolds supported the viability, attachment and chondrogenic differentiation of hBMSC, thus, demonstrating potential for TMJ cartilage regeneration applications.


Preparation Ferrule Design Effect on Endocrown Failure Resistance.
To evaluate the effect of preparation ferrule inclusion with fracture resistance of mandibular molar endocrowns. Recently extracted mandibular third molars were randomly divided into 3 groups (n = 12) with the coronal tooth structure removed perpendicular to the root long axis approximately 2 mm above the cemento-enamel junction with a slow-speed diamond saw. The pulp chamber was exposed using a diamond bur in a high-speed handpiece with pulpal remnants removed and canals instrumented using endodontic hand instruments. The chamber floor was restored using a resin core material with a two-step, self-etch adhesive and photopolymerized with a visible light-curing unit to create a 2 mm endocrown preparation pulp chamber extension. One and two millimeter ferrule height groups were prepared using a diamond bur in a high-speed handpiece following CAD/CAM guidelines. Completed preparation surface area was determined using a digital measuring microscope. Scanned preparations were restored with lithium disilicate restorations with a self-adhesive resin luting agent. All manufacturer recommendations were followed. Specimens were stored at 37°C/98% humidity and tested to failure after 24 hours at a 45° angle to the tooth long axis using a universal testing machine. Failure load was converted to MPa using the available bonding surface area with mean data analyzed using Kruskal-Wallis/Dunn (p = 0.05). Calculated failure stress found no difference in failure resistance among the three groups; however, failure load results identified that the endocrown preparations without ferrule had significantly lower fracture load resistance. Failure mode analysis identified that all preparations demonstrated a high number of catastrophic failures. Under the conditions of this study, ferrule-containing endocrown preparations demonstrated significantly greater failure loads than standard endocrown restorations; however, calculated failure stress based on available surface area for adhesive bonding found no difference between the groups. Lower instances of catastrophic failure were observed with the endocrown preparations containing 1 mm of preparation ferrule design; however, regardless of the presence of ferrule, this study found that all endocrown restorations suffered a high proportion of catastrophic failures but at loads greater than reported under normal masticatory function.


The fence technique: Autogenous bone graft versus 50% deproteinized bovine bone matrix / 50% autogenous bone graft-A clinical double-blind randomized controlled trial.
The aim of this short-term double-blind, parallel, randomized clinical trial was to compare bone augmentation grafting with 100% autogenous bone (AB) or 50% deproteinized bovine bone matrix (DBBM)/ 50% autogenous bone (BOAB) using a guided bone regeneration procedure, the fence technique, in a two-stage implant placement. Partially edentulous patients with extensive three-dimensional osseous defects were included in this study. The main outcome measure was the differences in bone volume from pre-surgery (T1) to 6 months post-surgery (T2). Bone height, chair-time, pain, functional limitation, and complications were also assessed. Fifteen patients were allocated to the AB group and 15 patients to the BOAB group. The difference in bone volume from T1 to T2 was 648 mm3 for the AB group and 869mm3 for the BOAB group (difference between groups 221 mm3 , 95% CI from -363 to 804, p = .442). The surgery pain VAS was 1.6 for the AB group and 2.3 for the BOAB group (difference between groups 0.8, 95% CI from 0.0 to 1.5, p = .045 favoring the AB group). The height difference in bone from T1 to T2 was 2.2 mm for the AB group and 3.7 mm for the BOAB group (difference between groups 1.5mm, 95% CI from 0.1 to 2.9, p = .038 favoring the BOAB group). For complications, chair-time, post-surgery pain, and functional limitation, there were no differences between AB and BOAB. No significant differences, except for surgery pain VAS and difference in bone height, were observed in this trial comparing grafting with AB or BOAB.


A novel mouse model of Warburg Micro syndrome reveals roles for RAB18 in eye development and organisation of the neuronal cytoskeleton.
Mutations in RAB18 have been shown to cause the heterogeneous autosomal recessive disorder Warburg Micro syndrome (WARBM). Individuals with WARBM present with a range of clinical symptoms, including ocular and neurological abnormalities. However, the underlying cellular and molecular pathogenesis of the disorder remains unclear, largely owing to the lack of any robust animal models that phenocopy both the ocular and neurological features of the disease. We report here the generation and characterisation of a novel Rab18-mutant mouse model of WARBM. Rab18-mutant mice are viable and fertile. They present with congenital nuclear cataracts and atonic pupils, recapitulating the characteristic ocular features that are associated with WARBM. Additionally, Rab18-mutant cells exhibit an increase in lipid droplet size following treatment with oleic acid. Lipid droplet abnormalities are a characteristic feature of cells taken from WARBM individuals, as well as cells taken from individuals with other neurodegenerative conditions. Neurological dysfunction is also apparent in Rab18-mutant mice, including progressive weakness of the hind limbs. We show that the neurological defects are, most likely, not caused by gross perturbations in synaptic vesicle recycling in the central or peripheral nervous system. Rather, loss of Rab18 is associated with widespread disruption of the neuronal cytoskeleton, including abnormal accumulations of neurofilament and microtubule proteins in synaptic terminals, and gross disorganisation of the cytoskeleton in peripheral nerves. Global proteomic profiling of peripheral nerves in Rab18-mutant mice reveals significant alterations in several core molecular pathways that regulate cytoskeletal dynamics in neurons. The apparent similarities between the WARBM phenotype and the phenotype that we describe here indicate that the Rab18-mutant mouse provides an important platform for investigation of the disease pathogenesis and therapeutic interventions.


Incidence of haemagglutinating antibodies to meningococci in north-west England.
USING AN INDIRECT HAEMAGGLUTINATION TECHNIQUE THE INCIDENCE OF MENINGOCOCCAL ANTIBODIES IN ADULTS WAS FOUND TO BE: group A 21%, group B 3%, and group C 20%. The reasons for some differences between these results and those obtained in America are discussed. A low incidence of antibody was detected in preschool children but the incidence in school children was found to approach that of adults. Comparison of the antibody incidence in the adult population of an area where clinical infections were occurring with that in a similar population elsewhere failed to detect any significant difference.


Hydrogen breath testing in adults: what is it and why is it performed?
A hydrogen breath test is a safe, easy-to-perform, 2-to 3-hour outpatient procedure used to identify the presence of small intestine bacterial overgrowth, evaluate carbohydrate maldigestion or malabsorption, and measure intestinal transit time. Breath sample analysis can reveal bacterial overgrowth in the small intestine by the characteristic early rise in breath hydrogen concentration (i.e., an earlier-than-expected rise at approximately 90 minutes when the substrate reaches the colon). Patients with irritable bowel syndrome are often referred for a hydrogen breath test because of symptoms of abdominal bloating, cramping, and diarrhea that are also characteristic of bacterial overgrowth. The elderly are at greater risk for nutritional compromise from untreated small intestine bacterial overgrowth than are younger patients. Treatment often consists of one or more courses of antibiotics. Most patients experience a reduction in symptoms with treatment.


"Does the voice in your head get kinder as you get older?" Women's perceptions of body image in midlife.
This study aimed to identify attitudes and reactions toward physical changes in midlife women. A Facebook thread, presenting a series of comments related to an initial statement, instigated by a radio program was analyzed. The thread contained 87 responses to the question "Does the voice in your head get kinder as you get older?" Content analysis revealed positive (56%) and negative (40%) comments and four themes: physical changes with aging, the decreased importance of physical appearance, the importance of sociocultural influences, and the invisibility of women in midlife. Findings revealed both positive and negative body image experiences in women related to midlife and have implications for prevention.


Dual Inhibition of Angiopoietin-TIE2 and MET Alters the Tumor Microenvironment and Prolongs Survival in a Metastatic Model of Renal Cell Carcinoma.
Receptor tyrosine kinase inhibitors have shown clinical benefit in clear cell renal cell carcinoma (ccRCC), but novel therapeutic strategies are needed. The angiopoietin/Tie2 and MET pathways have been implicated in tumor angiogenesis, metastases, and macrophage infiltration. In our study, we used trebananib, an angiopoietin 1/2 inhibitor, and a novel small-molecule MET kinase inhibitor in patient-derived xenograft (PDX) models of ccRCC. Our goal was to assess the ability of these compounds to alter the status of tumor-infiltrating macrophages, inhibit tumor growth and metastases, and prolong survival. Seven-week-old SCID mice were implanted subcutaneously or orthotopically with human ccRCC models. One month postimplantation, mice were treated with angiopoietin 1/2 inhibitor trebananib (AMG 386), MET kinase inhibitor, or combination. In our metastatic ccRCC PDX model, RP-R-02LM, trebananib alone, and in combination with a MET kinase inhibitor, significantly reduced lung metastases and M2 macrophage infiltration (P = 0.0075 and P = 0.0205, respectively). Survival studies revealed that treatment of the orthotopically implanted RP-R-02LM tumors yielded a significant increase in survival in both trebananib and combination groups. In addition, resection of the subcutaneously implanted primary tumor allowed for a significant survival advantage to the combination group compared with vehicle and both single-agent groups. Our results show that the combination of trebananib with a MET kinase inhibitor significantly inhibits the spread of metastases, reduces infiltrating M2-type macrophages, and prolongs survival in our highly metastatic ccRCC PDX model, suggesting a potential use for this combination therapy in treating patients with ccRCC.


Diagnostic Comparison of CT Scans and Colonoscopy for Immune-Related Colitis in Ipilimumab-Treated Advanced Melanoma Patients.
Colitis can be a life-threatening toxicity for patients treated with immune checkpoint blockade antibodies. With the anticipated widespread use of these reagents, the timely and accurate diagnosis of immune-related colitis becomes increasingly important. To better understand the clinical presentation of colitis from ipilimumab and to assess the use of CT scans of the abdomen/pelvis as a diagnostic tool, we retrospectively analyzed patients with advanced melanoma who received ipilimumab at our institution. Ninety nine (33%) of 303 patients developed diarrhea during therapy, and 46 patients (15%) received corticosteroids for colitis. Of the patients with diarrhea, 48 (48%) underwent colonoscopy and 46 (46%) underwent both CT and colonoscopy. In the 34 patients (34%) with a CT and biopsy, CT was highly predictive of colitis on biopsy (positive predictive value 96%), and the absence of CT findings was predictive of a negative biopsy (negative likelihood ratio 0.2). In patients who had symptoms and CT evaluation, CT was highly predictive of the need for steroids to reach resolution of symptoms (positive predictive value 92%, positive likelihood ratio 7.3). We conclude that CT is a fast, reliable, and noninvasive mode of diagnosing colitis, whereas colonoscopy and biopsy may not be needed to establish that diagnosis. Cancer Immunol Res; 5(4); 286-91. ©2017 AACR.


Intestinal microbiome and its potential functions in bighead carp (Aristichthys nobilis) under different feeding strategies.
Bighead carps (Aristichthys nobilis) were divided into four groups with different feeding strategies: group A, nature live food only (fertiliser only, 200 g urea + 160 g ethylamine phosphate + 250 g Huangjintai bio-fertiliser); group B, nature live food + 1/2 formulated feed; group C, nature live food + formulated feed; and group D, formulated feed only. The intestinal microbiomes of the different groups were compared through the Illumina MiSeq sequencing of the bacterial 16S rRNA gene. The specific growth rate (SGR), survival and blood biochemical factors of the fish were also investigated. Results showed that feeding treatment influenced the intestinal communities in the fish. In specific, more bacterial phyla dominated in groups A and B (phyla Bacteroidetes, Fusobacteria, Firmicutes and Proteobacteria in group A, phyla Proteobacteria and Fusobacteria in group B) than in groups C and D (phylum Proteobacteria). The diversity was also lower in groups C and D than in groups A and B. Unweighted pair-group method analysis revealed a clear difference in intestinal microbiota among the different feeding treatments. No difference in survival rate was found among the treatment groups, but the SGR was significantly higher (P < 0.01) in groups B, C and D than in group A. Functional analysis showed that the intestinal bacteria correlated with fish glucose metabolism in group A but with lipid metabolic activity in groups B, C and D. In summary, the intestinal microbiomes and their potential functions vary in bighead carp under different feeding treatments. This study provides new insights into the gut microbiomes of filter-feeding and formulated diet-fed fish.


[Exposure to nitrogen dioxide and respiratory health at 2 years in the INMA-Valencia cohort].
To analyze the association between exposure to nitrogen dioxide (NO2) during pregnancy and the postnatal period up to the age of 2 years old and the incidence of respiratory problems in children from the INMA-Valencia cohort. The study population included 624 children from the INMA-Valencia cohort. Individual exposure to NO2 was estimated in different environments outside the home during pregnancy and up to the age of 2 using empirical measurement and data from geo-statistical methods. Respiratory symptoms were obtained from a questionnaire applied at the age of two. The association between NO2 exposure and respiratory symptoms was performed using multivariate logistic regression. The cumulative incidence was 16.3% for persistent cough, 34.9% for wheezing and 27.6% for lower respiratory tract infections. No association was found between respiratory symptoms and exposure to NO2 in any of the children. However an association between NO2 exposure and persistent cough was found at two years of life in the children with a parental history of allergy. NO2 exposure would lead to persistent cough in children with a parental history of allergies.


NEIL3 promotes cell proliferation of ccRCC via the cyclin D1-Rb-E2F1 feedback loop regulation.
Nei endonuclease VIII-like 3 (NEIL3), a novel tumor-related gene, is differentially expressed and involved in pathophysiological processes in multiple tumors. However, the potential biological functions and molecular mechanisms of NEIL3 in human clear cell renal cell carcinoma (ccRCC) have not been identified. In this research, we demonstrated that NEIL3, transcriptionally activated by E2F1, served as an oncogene to facilitate cell proliferation and cell cycle progression and contribute to tumorigenesis via the cyclin D1-Rb-E2F1 feedback loop in ccRCC. First, we found that NEIL3 expression was upregulated in ccRCC tissues and cell lines compared with matched adjacent nontumor tissues and renal tubular epithelial cells and was also positively correlated with adverse clinicopathological characteristics, such as advanced cancer stages and higher tumor grades, and acted as an independent prognostic marker in ccRCC. Mechanistically, we demonstrated that NEIL3 promoted cell proliferation, DNA replication and cell cycle progression in vitro and tumor growth in vivo. Furthermore, we found that NEIL3 overexpression activated the cyclin D1-Rb-E2F1 pathway, and the E2F1 upregulation transcriptionally activated NEIL3 expression, thus forming a feedback loop. In addition, there was a positive correlation between NEIL3 and E2F1 expression in clinical specimens of ccRCC. Taken together, our results suggest that NEIL3 serves as a proto-oncogene in ccRCC and presents as a novel candidate for ccRCC diagnosis and treatment.


Alveolar bone regeneration using poly-(lactic acid-co-glycolic acid-co-ε-caprolactone) porous membrane with collagen sponge containing basic fibroblast growth factor: an experimental study in the dog.
The aim of this study was to evaluate the effects of combining porous poly-lactic acid-co-glycolic acid-co-ε-caprolactone (PLGC) as a barrier membrane and collagen sponge containing basic fibroblast growth factor (bFGF) to promote bone regeneration in the canine mandible. In six beagle dogs, two lateral bone defects per side were created in the mandible. The lateral bone defects on the left side were treated with a PLGC membrane plus a collagen sponge containing bFGF. In half of these, the collagen sponge contained 50 µg of bFGF. In the other half, it contained 250 µg of bFGF. As a control, we treated the right-side bone defects in each animal with the same PLGC membrane but with a collagen sponge containing phosphate buffered saline. Computed tomography (CT) images were recorded at 3 and 6 months post-op to evaluate regeneration of the bone defects. After a healing period of 6 months, whole mandibles were removed for micro-CT and histological analyses. The post-op CT images showed that more bone had formed at all experimental sites than at control sites. At 3 months post-op, the volume of bone at defect sites covered with PLGC membrane plus 250 µg of bFGF was significantly greater than it was at defect sites covered with PLGC membrane plus 50 µg of bFGF. At 6 months post-op, however, this difference was smaller and not statistically significant. Micro-CT measurement showed that the volume of new bone regenerated at bone-defect sites, covered with PLGC membrane plus bFGF, was significantly greater than that of control sites. However, the presence or absence of bFGF in the collagen sponge did not significantly affect the bone density of new bone. These results suggest that the macroporous bioresorbable PLGC membrane plus collagen sponge containing bFGF effectively facilitates healing in GBR procedures.


Prenyl Ammonium Salts--New Carriers for Gene Delivery: A B16-F10 Mouse Melanoma Model.
Prenyl ammonium iodides (Amino-Prenols, APs), semi-synthetic polyprenol derivatives were studied as prospective novel gene transfer agents. AP-7, -8, -11 and -15 (aminoprenols composed of 7, 8, 11 or 15 isoprene units, respectively) were examined for their capacity to form complexes with pDNA, for cytotoxicity and ability to transfect genes to cells. All the carriers were able to complex DNA. The highest, comparable to commercial reagents, transfection efficiency was observed for AP-15. Simultaneously, AP-15 exhibited the lowest negative impact on cell viability and proliferation--considerably lower than that of commercial agents. AP-15/DOPE complexes were also efficient to introduce pDNA to cells, without much effect on cell viability. Transfection with AP-15/DOPE complexes influenced the expression of a very few among 44 tested genes involved in cellular lipid metabolism. Furthermore, complexes containing AP-15 and therapeutic plasmid, encoding the TIMP metallopeptidase inhibitor 2 (TIMP2), introduced the TIMP2 gene with high efficiency to B16-F10 melanoma cells but not to B16-F10 melanoma tumors in C57BL/6 mice, as confirmed by TIMP2 protein level determination. Obtained results indicate that APs have a potential as non-viral vectors for cell transfection.


Designed guanidinium-rich amphipathic oligocarbonate molecular transporters complex, deliver and release siRNA in cells.
The polyanionic nature of oligonucleotides and their enzymatic degradation present challenges for the use of siRNA in research and therapy; among the most notable of these is clinically relevant delivery into cells. To address this problem, we designed and synthesized the first members of a new class of guanidinium-rich amphipathic oligocarbonates that noncovalently complex, deliver, and release siRNA in cells, resulting in robust knockdown of target protein synthesis in vitro as determined using a dual-reporter system. The organocatalytic oligomerization used to synthesize these co-oligomers is step-economical and broadly tunable, affording an exceptionally quick strategy to explore chemical space for optimal siRNA delivery in varied applications. The speed and versatility of this approach and the biodegradability of the designed agents make this an attractive strategy for biological tool development, imaging, diagnostics, and therapeutic applications.


Defining targets for investigating the pharmacogenomics of adverse drug reactions to antifungal agents.
Adverse drug reactions (ADRs) associated with antifungal therapy are major problems in patients with invasive fungal infections. Whether by clinical history or patterns of genetic variation, the identification of patients at risk for ADRs should result in improved outcomes while minimizing deleterious side effects. A major contributing factor to ADRs with antifungal agents relates to drug distribution, metabolism and excretion. Genetic variation in key genes can alter the structure and expression of genes and gene products (e.g., proteins). Thus far, the effort has focused on identifying polymorphisms with either empirical or predicted in silico functional consequences; the best candidate genes encode phase I and II drug-metabolizing enzymes (e.g., CYP2C19 and N-acetyltransferase), plasma proteins (albumin and lipoproteins) and drug transporters (P-glycoprotein and multidrug resistance proteins), which can affect the disposition of antifungal agents, eventually leading to dose-dependent (type A) toxicity. Less is known regarding the key genes that interact with antifungal agents, resulting in idiosyncratic (type B) ADRs. The possible role of certain gene products and genetic polymorphisms in the toxicities of antifungal agents are discussed in this review. The preliminary data address the following: low-density lipoproteins and cholesteryl ester transfer protein in amphotericin B renal toxicity; toll-like receptor 1 and 2 in amphotericin B infusion-related ADRs; phosphodiesterase 6 in voriconazole visual adverse events; flavin-containing monooxygenase, glutathione transferases and multidrug resistance proteins 1 and 2 in ketoconazole and terbinafine hepatotoxicity; CYP enzymes and P-glycoprotein in drug interactions between azoles and coadministered medications; multidrug resistance proteins 8 and 9 on 5-flucytosine bone marrow toxicity; and mast cell activation in caspofungin histamine release. This will focus on high-priority candidate genes, which could provide a starting point for molecular studies to elucidate the potential mechanisms for understanding toxicity associated with antifungal drugs as well as identifying candidate genes for large population prospective genetic association studies.


Clinical usefulness of MR imaging of the breast in the evaluation of the problematic mammogram.
This study was undertaken to determine the usefulness of MR imaging of the breast as an adjunct to mammography in problematic cases in which the significance, presence, or location of an abnormality could not be determined. From January 1993 through February 1998, 86 lesions for which histologic or mammographic follow-up was available were evaluated by breast MR imaging because of equivocal findings on mammography. MR studies were performed with a dedicated breast multicoil on a 1.5-T scanner. Early studies were done using a T1-weighted two-dimensional spin-echo sequence before and after the administration of contrast material. Later studies were performed using a three-dimensional fast spoiled gradient sequence with fat suppression. Studies were considered to be positive for an abnormality if a focal area of enhancement was seen after contrast administration. MR imaging had positive findings in 38 sites. Twenty-six of these sites corresponded in location to the mammographic abnormality that had prompted the recommendation for MR imaging. The remaining 12 sites occurred in areas not suspected mammographically. At biopsy, 10 (26%) of the 38 positive sites were malignant. MR imaging had negative findings at 60 other sites that had been suspected mammographically. Of these 60 sites, six were treated with excision, all with benign results; the remaining 54 sites showed mammographic stability on follow-up that ranged from 5 to 66 months (mean, 19 months). MR imaging of the breast can be a valuable adjunct to mammography for selected problematic cases.


Protein Digestion and Quality of Goat and Cow Milk Infant Formula and Human Milk Under Simulated Infant Conditions.
The aim of this study was to determine the kinetics of true ileal protein digestion and digestible indispensable amino acid score (DIAAS) of a goat milk-based infant formula (GIF), a cow milk-based infant formula (CIF), and human milk (HM). The GIF, CIF, and HM were investigated in an in vitro gastrointestinal model simulating infant conditions. Digested compounds were dialyzed from the intestinal compartment as bioaccessible fraction. Dialysate was collected in 15 to 60-minute periods for 4 hours. True ileal protein digestibility and DIAAS were determined as bioaccessible nitrogen (N) and amino acids. N bioaccessibility from the GIF showed similar kinetics to that of HM. The CIF showed a delay in N bioaccessibility versus the GIF and HM. In the 1st hour of digestion, N bioaccessibility was 19.9% ± 3.5% and 23.3% ± 1.3% for the GIF and HM, respectively, and 11.2% ± 0.6% for CIF (P < 0.05 vs HM). In the 3rd hour of digestion, the N bioaccessibility was higher (P < 0.05) for the CIF (28.9% ± 1.2%) than for the GIF (22.5% ± 1.6%) and HM (20.6% ± 1.0%). After 4 hours, the true ileal protein digestibility of the GIF, CIF, and HM was 78.3% ± 3.7%, 73.4% ± 2.7%, and 77.9% ± 4.1%, respectively. The DIAAS for the GIF, CIF, and HM for 0- to 6-month-old infants was 83%, 75%, and 77% for aromatic AA. The protein quality is not different between the GIF, CIF, and HM, but the kinetics of protein digestion of the GIF is more comparable to that of HM than that of the CIF.


[Change in prostanoid metabolism in cystic kidney lesion].
A wide range of renal prostaglandins in cysts has been studied as compared with their content in the daily urine, activity of plasma renin, level of adrenocorticotropic hormone (ACTH) in the tissues, methionine enkephalin and aldosterone. High activity of renin, met-enkephalin and ACTH was observed in the patients with one cyst. Under renal polycystosis the activity of plasma renin is higher and the amount of ACTH positively decreases. The comparison of prostanoids content in the cystic fluid of a single cyst and polycystic one demonstrates that the polycystic level of all prostanoids in the punctate increase 2-3 times.


Overcoming of multidrug resistance by introducing the apoptosis gene, bcl-Xs, into MRP-overexpressing drug resistant cells.
Multidrug resistance associated protein (MRP) is one of drug transport membranes that confer multidrug resistance in cancer cells. Multidrug resistance has been known to be associated with resistance to apoptosis. In this study, using MRP overexpressing multidrug resistant nasopharyngeal cancer cells, we examined the expression of apoptosis related genes including p53, p21WAF1, bax and bcl-Xs between drug sensitive KB and its resistant KB/7D cells. We also examined whether the introduction of apoptosis related gene could increase the sensitivity to anticancer drugs in association with apoptotic cell death. The relative resistances to anticancer drugs in KB/7D cells evaluated by IC50 values were 3.6, 61.3, 10.4 and 10.5 to adriamycin (ADM), etoposide (VP-16), vincristine (VCR) and vindesine (VDS), respectively. The resistance to anticancer drugs in KB/7D cells was associated with the attenuation of internucleosomal DNA ladder formation in apoptosis. Of important, the mRNA expression of bcl-Xs gene in KB/7D cells was decreased in one-fourth as compared to that of KB cells among the apoptosis genes. The mRNA expression of bcl-Xs gene in a bcl-Xs transfected clone (KB/7Dbcl-Xs) was increased about 2-fold compared to that of KB/7Dneo cells, while the mRNA expression of MRP gene was not significantly different in KB/7bcl-Xs and KB/7Dneo cells. The sensitivities to anticancer drugs including ADM, VCR and VDS except VP-16 were increased in KB/7Dbcl-Xs cells, in turn, the relative resistance in KB/7Dbcl-Xs cells was decreased to 1.4, 4.0, and 3.0 in ADM, VCR and VDS, respectively, as compared to those of KB/7Dneo cells. Of interest, the studies on the accumulation of [3H]VCR showed that the decrease of [3H]VCR accumulation in KB/7Dbcl-Xs was not significantly different from that of KB/7Dneo cells. Collectively, these results indicated that the mechanism(s) of drug resistance in KB/7D cells could be explained at least by two factors: a) reduced drug accumulation mediated by MRP; b) resistance to apoptosis due to the decreased expression of the bcl-Xs gene. These results also indicated that the multidrug resistance mediated by MRP might be partially overcome by introducing apoptosis gene into drug resistant cells without modulation of MRP function in drug accumulation.


Monochloramine induces contraction of guinea pig gallbladder via two different pathways.
The purpose of the present investigation was to examine the effect and mechanism of action of the reactive oxygen metabolites monochloramine (NH2Cl), hypochlorous acid (HOCl), and hydrogen peroxide (H2O2) on gallbladder smooth muscle contractility. All oxidants caused concentration-dependent increases in resting tension of gallbladder muscle; the rank order of potencies (half-maximal concentration) was NH2Cl (30 microM) greater than HOCl (70 microM) greater than H2O2 (100 microM). The oxidant concentrations employed are those found to exist in inflamed tissue. Tetrodotoxin (0.5 microM) had no effect on gallbladder muscle contraction caused by the oxidants, suggesting a direct, nonneural action. The maximal response induced by NH2Cl, HOCl, or H2O2 was significantly (P less than 0.05) inhibited by 5 microM indomethacin and 5 microM piroxicam. The calcium channel blocker verapamil partially inhibited the contractile effect of NH2Cl but had no effect on the contraction induced by exogenous cyclooxygenase products. Monochloramine induced significant prostaglandin E2 release from the gallbladder, which was blocked by indomethacin. Furthermore, the effect of NH2Cl on the smooth muscle was blocked by 5-aminosalicylic acid (1 mM). We conclude that reactive oxygen metabolites induce contraction of gallbladder smooth muscle by a direct action. The effect is mediated via cyclooxygenase metabolites and activation of calcium influx.


Transcriptome profiling of individual rhesus macaque oocytes and preimplantation embryos.
Early mammalian embryonic transcriptomes are dynamic throughout the process of preimplantation development. Cataloging of primate transcriptomics during early development has been accomplished in humans, but global characterization of transcripts is lacking in the rhesus macaque: a key model for human reproductive processes. We report here the systematic classification of individual macaque transcriptomes using RNA-Seq technology from the germinal vesicle stage oocyte through the blastocyst stage embryo. Major differences in gene expression were found between sequential stages, with the 4- to 8-cell stages showing the highest level of differential gene expression. Analysis of putative transcription factor binding sites also revealed a striking increase in key regulatory factors in 8-cell embryos, indicating a strong likelihood of embryonic genome activation occurring at this stage. Furthermore, clustering analyses of gene co-expression throughout this period resulted in distinct groups of transcripts significantly associated to the different embryo stages assayed. The sequence data provided here along with characterizations of major regulatory transcript groups present a comprehensive atlas of polyadenylated transcripts that serves as a useful resource for comparative studies of preimplantation development in humans and other species.


Energy and nutrient intakes of Okinawan centenarians.
Energy and nutrient requirements of younger people have been well studied, unlike that of centenarians. The average life span of the Japanese is the longest in the world, and the population of the very aged is rapidly growing. In addition, the average life span of Okinawan people is the longest in all of Japan. Their food habits also differ from other parts of Japan. To obtain basic dietary information, we surveyed 21 centenarians in Okinawa (17 women and 4 men). The dietary survey was done by one 24 h recall method, as was done for centenarians living throughout Japan (3). The energy intake of the Okinawan centenarians living at home was about 1,100 kcal/day for both sexes, which was similar to that of centenarians throughout Japan. Energy, some nutrient intakes and food consumption pattern (in terms of food groups) were different from those of the centenarians throughout Japan. We also measured their heights, weights, hematological values and activities of daily living (ADL). Comparison between the nutrient intakes and the recommended dietary allowances (RDAs) estimated for the centenarians showed that the estimated RDA of energy for the Okinawan centenarians might be less than their actual intakes.


Isolation of an arsenate-respiring bacterium from a redox front in an arsenic-polluted aquifer in West Bengal, Bengal Basin.
Natural pollution of groundwater by arsenic adversely affects the health of tens of millions of people worldwide, with the deltaic aquifers of SE Asia being particularly polluted. The pollution is caused primarily by, or as a side reaction of, the microbial reduction of sedimentary Fe(III)-oxyhydroxides, but the organism(s) responsible for As release have not been isolated. Here we report the first isolation of a dissimilatory arsenate reducer from sediments of the Bengal Basin in West Bengal. The bacterium, here designated WB3, respires soluble arsenate and couples its reduction to the oxidation of acetate; WB3 is therefore implicated in the process of arsenic pollution of groundwater, which is largely by arsenite. The bacterium WB3 is also capable of reducing dissolved Fe(III) citrate, solid Fe(III)-oxyhydroxide, and elemental sulfur, using acetate as the electron donor. It is a member of the Desulfuromonas genus and possesses a dissimilatory arsenate reductase that was identified using degenerate polymerase chain reaction primers. The sediment from which WB3 was isolated was brown, Pleistocene sand at a depth of 35.2 m below ground level (mbgl). This level was some 3 cm below the boundary between the brown sands and overlying reduced, gray, Holocene aquifer sands. The color boundary is interpreted to be a reduction front that releases As for resorption downflow, yielding a high load of labile As sorbed to the sediment at a depth of 35.8 mbgl and concentrations of As in groundwater that reach >1000 μg/L.


Improved heart preservation with University of Wisconsin solution: experimental and preliminary human experience.
We tested the ability of University of Wisconsin solution (UWS) to extend hypothermic nonperfused heart preservation in baboons and then proceeded to human transplantation. Orthotopic transplantation was performed in five baboons (UWS cardioplegia and storage [4 degrees C]; preservation time 10.3 +/- 0.6 hours). Four survivors were immunosuppressed for 45 days and killed. One animal died from disruption of the aortic anastomosis due to technical error. Preservation did not alter histology under light and electron microscopy or heart weight (at harvest, 51.4 +/- 11.6 g; before implant, 52.5 +/- 11.1 g). Animals were weaned from bypass (mean, 23 +/- 12 minutes) and returned to their cages without intravenous support within 3.6 +/- 0.6 hours. Weekly biopsy, electrocardiogram, enzyme analysis, echocardiogram, and right heart catheterization demonstrated excellent cardiac function. Following success in baboons, UWS was applied to human transplantation (n = 2, UWS cardioplegia and storage [4 degrees C]; preservation time 4.2 and 2.1 hours). The hearts returned to sinus rhythm within 4 minutes of reperfusion without defibrillation, and enzymatic and hemodynamic data reveal excellent heart preservation. Preliminary data suggest the ability of UWS to prolong heart preservation in baboons and be used safely in humans. Further studies are required to compare UWS with crystalloid cardioplegia and saline storage and to prolong donor heart preservation in humans.


Exploration of genetic architecture through sib-ship reconstruction in advanced breeding population of Eucalyptus nitens.
Accurate inference of relatedness between individuals in breeding population contributes to the precision of genetic parameter estimates, effectiveness of inbreeding management and the amount of genetic progress delivered from breeding programs. Pedigree reconstruction has been proven to be an efficient tool to correct pedigree errors and recover hidden relatedness in open pollinated progeny tests but the method can be limited by the lack of parental genotypes and the high proportion of alien pollen from outside the breeding population. Our study investigates the efficiency of sib-ship reconstruction in an advanced breeding population of Eucalyptus nitens with only partially tracked pedigree. The sib-ship reconstruction allowed the identification of selfs (4% of the sample) and the exploration of their potential effect on inbreeding depression in the traits studied. We detected signs of inbreeding depression in diameter at breast height and growth strain while no indications were observed in wood density, wood stiffness and tangential air-dry shrinkage. After the application of a corrected sib-ship relationship matrix, additive genetic variance and heritability were observed to increase where signs of inbreeding depression were initially detected. Conversely, the same genetic parameters for traits that appeared to be free of inbreeding depression decreased in size. It therefore appeared that greater genetic variance may be due, at least in part, to contributions from inbreeding in these studied populations rather than a removal of inbreeding as is traditionally thought.


Lack of humanlike active vasodilation in skin of heat-stressed baboons.
To discover whether humanlike active skin vasodilation occurs in a sweating, subhuman primate, four unanesthetized male baboons (Papio anubis) were heated (blood temp = 39-39.5 degrees C) before and after arterial administration of the alpha-adrenergic blocking agent phenoxybenzamine HCl. Hcat stress alone increased common iliac vascular conductance (CIVC) from 1.2 to 3.7 ml-min-1-mmHg-1 (averages). alpha-Blockade alone increased CIVC from 1.2 to 3.3 ml-min-1-mmHg-1. Heat stress subsequent to alpha-blockade further increased CIVC by only 0.4 ml-min-1-mmHg-1. Thus, most of the rise in CIVC caused by heat stress could be mimicked by alpha-blockade. If, as in man, the dominant means of raising skin blood flow were nonadrenergic active vasodilation, the response of CIVC to heating would far exceed that due to alpha-blockade. We conclude that, in baboons, humanlike active vasodilation of skin plays no significant role in CIVC response to heat stress. Thus, the baboon is not an appropriate model for investigation of control of human skin circulation during hyperthermia.


Suramin inhibits the early effects of PLA(2) neurotoxins at mouse neuromuscular junctions: A twitch tension study.
Several phospholipase A(2) (PLA(2)) neurotoxins from snake venoms can affect acetylcholine release at the neuromuscular junction. In isolated nerve-muscle preparations three distinct phases have been described for this phenomenon: An initial transient decrease in twitch tension; a second facilitatory phase during which twitch height is greater than control twitch height; and the last phase which causes a reduction in twitch height that finally results in paralysis. Suramin has been reported to inhibit the toxic effects of β-bungarotoxin and another PLA(2) neurotoxin, crotoxin in vitro and in vivo. We have further examined the effects of suramin on the three phases of the effects of the presynaptic PLA(2) neurotoxins β-bungarotoxin, taipoxin and ammodytoxin on mouse phrenic nerve-hemidiaphragm preparations. When preparations were pre-treated with suramin (0.3mM), the early biphasic effects (depression followed by facilitation) were abolished, and the time taken for final blockade induced by β-bungarotoxin, taipoxin and ammodytoxin A was significantly prolonged. In contrast, suramin did not significantly affect the facilitation induced by the potassium channel blocking toxin dendrotoxin I when applied under the same conditions. In addition, application of 0.3mM suramin did not prevent the facilitatory actions of 3,4-diaminopyridine (3,4-DAP) and tetraethylammonium chloride (TEA). Overall, the mechanism whereby suramin reduces the effects of PLA(2) neurotoxins remains elusive. Since suramin reduces both enzyme-dependent and enzyme-independent effects of the toxins, suramin is not acting as a simple enzyme inhibitor. Furthermore, the observation that suramin does not affect actions of standard K(+) channel blockers suggests that suramin does not stabilise nerve terminals.


Decreased glutamate/glutamine levels may mediate cytidine's efficacy in treating bipolar depression: a longitudinal proton magnetic resonance spectroscopy study.
Targeting the glutamatergic system has been suggested as a promising new option for developing treatment strategies for bipolar depression. Cytidine, a pyrimidine, may exert therapeutic effects through a pathway that leads to altered neuronal-glial glutamate cycling. Pyrimidines are also known to exert beneficial effects on cerebral phospholipid metabolism, catecholamine synthesis, and mitochondrial function, which have each been linked to the pathophysiology of bipolar depression. This study was aimed at determining cytidine's efficacy in bipolar depression and at assessing the longitudinal effects of cytidine on cerebral glutamate/glutamine levels. Thirty-five patients with bipolar depression were randomly assigned to receive the mood-stabilizing drug valproate plus either cytidine or placebo for 12 weeks. Midfrontal cerebral glutamate/glutamine levels were measured using proton magnetic resonance spectroscopy before and after 2, 4, and 12 weeks of oral cytidine administration. Cytidine supplementation was associated with an earlier improvement in depressive symptoms (weeks 1-4; p=0.02, 0.001, 0.002, and 0.004, respectively) and also produced a greater reduction in cerebral glutamate/glutamine levels in patients with bipolar depression (weeks 2, 4, and 12; p=0.004, 0.004, and 0.02, respectively). Cytidine-related glutamate/glutamine decrements correlated with a reduction in depressive symptoms (p=0.001). In contrast, these relationships were not observed in the placebo add-on group. The study results suggest that cytidine supplementation of valproate is associated with an earlier treatment response in bipolar depression. Furthermore, cytidine's efficacy in bipolar depression may be mediated by decreased levels of cerebral glutamate and/or glutamine, consistent with alterations in excitatory neurotransmission.


Ligilactobacillus acidipiscis YJ5 modulates the gut microbiota and produces beneficial metabolites to relieve constipation by enhancing the mucosal barrier.
Constipation is a prevalent gastrointestinal (GI) problem affecting a large number of individuals. This study aimed to investigate peristalsis-promoting potential characteristics of Ligilactobacillus acidipiscis YJ5 and the underlying molecular mechanism. The study demonstrated the relieving effect of L. acidipiscis YJ5 on constipation in both zebrafish and mouse models. L. acidipiscis YJ5 intervention significantly increased intestinal peristalsis by reducing the peak time and increasing the fluorescence disappearance rate in the zebrafish model. In the mouse model, the symptoms of constipation relief induced by L. acidipiscis YJ5 included a shortened first black stool time, an increased number of defecation particles, an accelerated propulsion rate of the small intestine, and an increase in fecal water content. L. acidipiscis YJ5 was found to reduce the expression of colonic aquaporins to normalize the colonic water transport system of constipated mice. Additionally, L. acidipiscis YJ5 reversed loperamide-induced morphological damage in the ileum and colon and increased the colonic mucosal barrier. The results of the 16S rRNA gene analysis indicated that L. acidipiscis YJ5 could reverse the structure of gut microbiota to a near-normal group, including levels of β-diversity, phylum, family, and genus. Furthermore, the fermentation supernatant of L. acidipiscis YJ5 was shown to relieve constipation, and metabolomics analysis revealed that these positive effects were related to its metabolites like malic acid and heliangin.


Exercise Rescues Gene Pathways Involved in Vascular Expansion and Promotes Functional Angiogenesis in Subcutaneous White Adipose Tissue.
Exercise mitigates chronic diseases such as diabetes, cardiovascular diseases, and obesity; however, the molecular mechanisms governing protection from these diseases are not completely understood. Here we demonstrate that exercise rescues metabolically compromised high fat diet (HFD) fed mice, and reprograms subcutaneous white adipose tissue (scWAT). Using transcriptomic profiling, scWAT was analyzed for HFD gene expression changes that were rescued by exercise. Gene networks involved in vascularization were identified as prominent targets of exercise, which led us to investigate the vasculature architecture and endothelial phenotype. Vascular density in scWAT was found to be compromised in HFD, and exercise rescued this defect. Similarly, angiogenic capacity as measured by ex vivo capillary sprouting was significantly promoted with exercise. Together, these data demonstrate that exercise enhances scWAT vascularization and functional capacity for angiogenesis, and can prevent the detrimental effects of HFD. The improvement in these indices correlates with improvement of whole-body metabolism, suggesting that scWAT vascularization may be a potential therapeutic target for metabolic disease.


Differences in the compressive stress-strain response of infiltrating ductal carcinomas with and without lobular features--implications for mammography and elastography.
In a previous study, it was noted that in some cases when compressive strains greater than about 5% were applied to tumors removed from the breast, there was an abrupt and irreversible change in the tissue stiffness. The data from that study were further analyzed and infiltrating ductal carcinomas with and without lobular features were selected for additional testing to explore their behavior under compressive strains from 0-10%. Fresh tumor samples were tested using a servo-hydraulic Instron testing machine to apply ramp type displacement loads to the samples. The results show that when strains greater than 5% are applied to the tumor tissue without lobular features, there is an irreversible decrease in the stiffness of the tissue while no such change is noted in the other tumor tissue. The implications for this behavior in making mammographic and elastographic images of the breast were then explored using finite element simulations to determine under what compression conditions could the critical strain threshold be reached in the tumor tissue.


Neural network in the clinical diagnosis of acute pulmonary embolism.
The purpose of this investigation was to test the hypothesis that computer-based pattern recognition can accurately assess the likelihood of acute pulmonary embolism (PE) based on readily obtainable clinical characteristics. Data were obtained from 1,213 patients who participated in the collaborative study of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). Characteristics of the history, physical examination, electrocardiograph, chest radiograph, and arterial blood gases of patients with suspected acute PE were presented to a back propagation neural network. The 1,213 patients were divided into training set A (n = 606) and test set B (n = 607). These groups were then reversed into training set B (n = 607) and test set A (n = 606). A receiver operating characteristic (ROC) curve was constructed from PIOPED clinical assessment, and from neural network clinical assessment in groups A and B. Areas under the respective ROC curves were 0.7450, 0.7477, and 0.7324. All differences were not significant. Areas under ROC curves for PIOPED clinical assessment combined with ventilation/perfusion (V/Q) scan results were compared with neural network clinical assessment combined with V/Q scan results in groups A and B. The respective ROC areas were 0.8324, 0.8203, 0.8496 (all differences not significant). These data show that neural networks were able to predict the clinical likelihood of PE with an accuracy comparable to experienced clinicians.


Five-year retention of volunteer community health workers in rural Uganda: a population-based retrospective cohort.
Community health workers (CHWs) effectively improve maternal, newborn and child health (MNCH) outcomes in low-to-middle-income countries. However, CHW retention remains a challenge. This retrospective registry analysis evaluated medium-term retention of volunteer CHWs in two rural Ugandan districts, trained during a district-wide MNCH initiative. From 2012 to 2014, the Healthy Child Uganda partnership facilitated district-led CHW programme scale-up. CHW retention was tracked prospectively from the start of the intervention up to 2 years. Additional follow-up occurred at 5 years to confirm retention status. Database analysis assessed CHW demographic characteristics, retention rates and exit reasons 5 years post-intervention. A multivariable logistic regression model examined 5-year retention-associated characteristics. Of the original cohort of 2317 CHWs, 70% were female. The mean age was 38.8 years (standard deviation, SD: 10.0). Sixty months (5 years) after the start of the intervention, 84% of CHWs remained active. Of those exiting (n = 377), 63% reported a 'logistical' reason, such as relocation (n = 96), new job (n = 51) or death (n = 30). Sex [male, female; odds ratio (OR) = 1.53; 95% confidence interval (CI): 1 · 20-1 · 96] and age group (<25 years, 30-59; OR = 0.40; 95% CI: 0.25-0.62) were significantly associated with 5-year retention in multivariable modelling. Education completion (secondary school, primary) was not significantly associated with retention in adjusted analyses. CHWs in this relatively large cohort, trained and supervised within a national CHW programme and district-wide MNCH initiative, were retained over the medium term. Importantly, high 5-year retention in this intervention counters findings from other studies suggesting low retention in government-led and volunteer CHW programmes. Encouragingly, findings from our study suggest that retention was high, not significantly associated with timing of external partner support and largely not attributed to the CHW role i.e. workload and programme factors. Our study showcases the potential for sustainable volunteer CHW programming at scale and can inform planners and policymakers considering programme design, including selection and replacement planning for CHW networks.


Bone marrow transplantation attenuates murine IgA nephropathy: role of a stem cell disorder.
The pathogenesis of IgA nephropathy is still obscure. The aim of this study was to investigate whether the fundamental pathogenesis of IgA nephropathy lies in bone marrow stem cells (BMCs). We used donors of two different strains for bone marrow transplantation (BMT) into mice with a high content of serum IgA (ddY strain, HIGA mice), a murine model of IgA nephropathy. One group (B6-->HIGA, N = 5) received BMCs of C57BL/6j (B6) mice, and the other (HIGA-->HIGA, N = 8) were reconstituted with BMCs of HIGA mice. Twenty-six weeks after BMT, in B6-->HIGA mice, mesangial deposits of IgA and C3 were statistically milder than those in HIGA-->HIGA mice. Light microscopic observations disclosed that glomerular sclerosis and mesangial matrix expansion in B6-->HIGA mice were decreased compared with those in HIGA-->HIGA mice. These B6-->HIGA mice also excreted less urinary albumin than HIGA-->HIGA mice. Furthermore, serum levels of IgA in B6-->HIGA mice were markedly lower than those in HIGA-->HIGA mice. Size analysis of serum IgA revealed that macromolecular IgA were notably lower in B6-->HIGA mice than in HIGA-->HIGA mice. Our results suggest that qualitative and quantitative changes of serum IgA are determined at the level of stem cells, and that BMT from normal donors can attenuate glomerular lesions in HIGA mice. This approach may offer a new avenue to study the pathogenesis of IgA nephropathy.


Effect of single and contiguous teeth extractions on alveolar bone remodeling: a study in dogs.
Tooth extraction is associated with dimensional changes in the alveolar ridge. The aim was to examine the effect of single versus contiguous teeth extractions on the alveolar ridge remodeling. Five female beagle dogs were randomly divided into three groups on the basis of location (anterior or posterior) and number of teeth extracted - exctraction socket classification: group 1 (one dog): single-tooth extraction; group 2 (two dogs): extraction of two teeth; and group 3 (two dogs): extraction of three teeth in four anterior sites and four posterior sites in both jaws. The dogs were sacrificed after 4 months. Sagittal sectioning of each extraction site was performed and evaluated using microcomputed tomography. Buccolingual or palatal bone loss was observed 4 months after extraction in all three groups. The mean of the alveolar ridge width loss in group 1 (single-tooth extraction) was significantly less than those in groups 2 and 3 (p < .001) (multiple teeth extraction). Three-teeth extraction (group 3) had significantly more alveolar bone loss than two-teeth extraction (group 2) (p < .001). The three-teeth extraction group in the upper and lower showed more obvious resorption on the palatal/lingual side especially in the lower group posterior locations. Contiguous teeth extraction caused significantly more alveolar ridge bone loss as compared with when a single tooth is extracted.


Prevalence of coronary heart disease and risk factors in an urban Indian population: Jaipur Heart Watch-2.
The prevalence of risk factors for coronary heart disease has been inadequately studied in India. A repeat cross-sectional survey was carried out to evaluate the changes in the major coronary risk factors in the urban population of Jaipur previously studied in the early 1990s. Randomly selected adults > or =20 years of age were studied using stratified sampling. The target study sample was 1800 with a population proportionate gender distribution (males 960, females 840). Coronary risk factors, anthropometric variables, blood pressure, ECG, fasting blood glucose and lipids were evaluated. A total of 1123 subjects (62.4%) (males 550, females 573) were examined. Fasting blood samples were available in 523 males and 559 females. Overall coronary heart diesase prevalence, diagnosed by history or ECG changes, was found in 34 males (6.18%) and 58 females (10.12%). Risk factor prevalence showed that smoking/tobacco use was present in 201 males (36.5%) and 67 females (11.7%). Physical inactivity, either work-related or leisure time, was seen in 157 males (28.5%) and 130 females (22.7%). Hypertension (> or =140 and/or 90 mmHg) was present in 200 males (36.4%) and 215 females (37.5%). Diabetes diagnosed by history or fasting glucose > or =126 mg/dl was found in 72 males (13.1%) and 65 females (11.3%). Obesity, body mass index > or =27 kg/m2 was present in 135 males (24.5%) and 173 females (30.2%), while truncal obesity (waist:hip >0.9 males, >0.8 females) was found in 316 males (57.4%) and 392 females (68.4%). The most common dyslipidemia in both males and females was low HDL-cholesterol (<40 mg/dl: males 54.9%, females 54.2%). High total cholesterol levels of > or =200 mg/dl (males 37.4%, females 4.1%), high LDL-cholesterol levels of > or =130 mg/dl (males 37.0%, females 45.8%) and high levels of triglycerides > or = 150 mg/dl (males 32.3%, females 28.6%) were also seen in a significant number. Hypertension, obesity, truncal obesity, diabetes and dyslipidemias increased significantly with age in both males and females (Mantel-Haenzel chi2 for trend, p<0.05). There is a high prevalence of standard coronary risk factors--smoking, physical inactivity, hypertension, hypercholesterolemia, diabetes and obesity--as well as factors peculiar to south Asians--truncal obesity, low HDL-cholesterol and high triglycerides--in this urban Indian population. As compared to a previous study in the early 1900s in a similar population, there is a significant increase in the number of people with obesity, diabetes and dyslipidemias.


Formation and Disproportionation of Xanthenols to Xanthenes and Xanthones and Their Use in Synthesis.
A facile and versatile strategy employing TiCl4-mediated cyclization followed by a Cannizzaro reaction has been developed for the synthesis of various xanthene derivatives. The reaction proceeded smoothly to afford both xanthenes/xanthones or their sulfur derivatives and tolerated a wide range of electronically diverse substrates. Using this methodology, pranoprofen was synthesized in three steps in 59% overall yield from commercially available starting materials.


Superficialization of deep arteriovenous access procedures in obese patients using suction-assisted lipectomy: A novel approach.
Successful dialysis access necessitates superficial arteriovenous fistula (AVF) placement to facilitate identification of anatomical landmarks for safe cannulation. Suction-assisted lipectomy (SAL) may be an alternative to traditional surgical AVF revision procedures for placing fistulas more superficially. Three patients with an average body mass index of 45.2 kg/m(2), with inaccessible AVFs due to obesity, underwent ultrasound-guided SAL of their upper extremities. Successful cannulation was achieved within two weeks. A clinically insignificant hematoma and arm swelling occurred in one patient. SAL provides a safe and effective alternative for salvaging deep AVFs for dialysis access in the upper extremities of obese patients.


Formulation optimization and in vivo proof-of-concept study of thermosensitive liposomes balanced by phospholipid, elastin-like polypeptide, and cholesterol.
One application of nanotechnology in medicine that is presently being developed involves a drug delivery system (DDS) employing nanoparticles to deliver drugs to diseased sites in the body avoiding damage of healthy tissue. Recently, the mild hyperthermia-triggered drug delivery combined with anticancer agent-loaded thermosensitive liposomes was widely investigated. In this study, thermosensitive liposomes (TSLs), composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-PEG), cholesterol, and a fatty acid conjugated elastin-like polypeptide (ELP), were developed and optimized for triggered drug release, controlled by external heat stimuli. We introduced modified ELP, tunable for various biomedical purposes, to our thermosensitive liposome (e-TSL) to convey a high thermoresponsive property. We modulated thermosensitivity and stability by varying the ratios of e-TSL components, such as phospholipid, ELP, and cholesterol. Experimental data obtained in this study corresponded to results from a simulation study that demonstrated, through the calculation of the lateral diffusion coefficient, increased permeation of the lipid bilayer with higher ELP concentrations, and decreased permeation in the presence of cholesterol. Finally, we identified effective drug accumulation in tumor tissues and antitumor efficacy with our optimized e-TSL, while adjusting lag-times for systemic accumulation.


Causes of community stillbirths and early neonatal deaths in low-income countries using verbal autopsy: an International, Multicenter Study.
Six million stillbirths (SB) and early neonatal deaths (END) occur annually worldwide, mostly in rural settings distant from health facilities. We used verbal autopsy (VA), to understand causes of non-hospital, community-based SB and END from four low-income countries. This prospective observational study utilized the train-the-trainer method. VA interviewers conducted standardized interviews; in each country data were reviewed by two local physicians who assigned an underlying causes of deaths (COD). There were 252 perinatal deaths (118 END; 134 SB) studied from pooled data. Almost half (45%) the END occurred on postnatal day 1, 19% on the second day and 16% the third day. Major early neonatal COD were infections (49%), birth asphyxia (26%), prematurity (17%) and congenital malformations (3%). Major causes of SB were infection (37%), prolonged labor (11%), antepartum hemorrhage (10%), preterm delivery (7%), cord complications (6%) and accidents (5%). Many of these SB and END were from easily preventable causes. Over 80% of END occurred during the first 3 days of postnatal life, and >90% were due to infection, birth asphyxia and prematurity. The causes of SB were more varied, and maternal infections were the most common cause. Increased attention should be targeting at interventions that reduce maternal and neonatal infections and prevent END, particularly during the first 3 days of life.