MRI features and texture analysis for the early prediction of therapeutic response to neoadjuvant chemoradiotherapy and tumor recurrence of locally advanced rectal cancer.
This study aimed to evaluate the efficiency of imaging features and texture analysis (TA) based on baseline rectal MRI for the early prediction of therapeutic response to neoadjuvant chemoradiotherapy (nCRT) and tumor recurrence in patients with locally advanced rectal cancer (LARC). Consecutive patients with LARC who underwent rectal MRI between January 2014 and December 2015 and surgical resection after completing nCRT were retrospectively enrolled. Imaging features were analyzed, and TA parameters were extracted from the tumor volume of interest (VOI) from baseline rectal MRI. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the optimal TA parameter cutoff values to stratify the patients. Logistic and Cox regression analyses were performed to assess the efficacy of each imaging feature and texture parameter in predicting tumor response and disease-free survival. In total, 78 consecutive patients were enrolled. In the logistic regression, good treatment response was associated with lower tumor location (OR = 13.284, p = 0.012), low Conv_Min (OR = 0.300, p = 0.013) and high Conv_Std (OR = 3.174, p = 0.016), Shape_Sphericity (OR = 3.170, p = 0.015), and Shape_Compacity (OR = 2.779, p = 0.032). In the Cox regression, a greater risk of tumor recurrence was related to higher cT stage (HR = 5.374, p = 0.044), pelvic side wall lymph node positivity (HR = 2.721, p = 0.013), and gray-level run length matrix_long-run low gray-level emphasis (HR = 2.268, p = 0.046). Imaging features and TA based on baseline rectal MRI could be valuable for predicting the treatment response to nCRT for rectal cancer and tumor recurrence. • Imaging features and texture parameters of T2-weighted MR images of rectal cancer can help to predict treatment response and the risk for tumor recurrence. • Tumor location as well as conventional and shape indices of texture features can help to predict treatment response for rectal cancer. • Clinical T stage, positive pelvic side wall lymph nodes, and the high-order texture parameter, GLRLM_LRLGE, can help to predict tumor recurrence for rectal cancer.


Frequency of major complications after EUS-guided FNA of solid pancreatic masses: a prospective evaluation.
EUS-guided FNA is effective for establishing tissue diagnosis in suspected pancreatic cancer. However, data on the frequency of major complications following EUS-FNA are limited. To evaluate the frequency of major complications after EUS-FNA of solid pancreatic masses. Prospective cohort study. Tertiary University based referral center for pancreatico-biliary disorder. Consecutive patients who underwent EUS-FNA of a solid pancreatic over a 42-month period. All immediate complications were recorded by the endosonographer. Late complications were assessed at 72 hours and at 30-days after the procedure. Major complications were defined as acute pancreatitis, bleeding, infection, perforation, use of reversal medication, hospitalization or death. A total of 355 consecutive patients with a solid pancreatic mass underwent EUS FNA. Major complications were encountered in 9 patients (2.54%, 95% CI 1.17-4.76). Acute pancreatitis occurred in 3 of 355 (0.85 %, 95% CI 0.17-2.45); 2 patients were hospitalized, and 1 patient recovered with outpatient analgesics. Three patients were admitted for severe pain after the procedure; all were treated with analgesics and subsequently discharged with no sequela. Two patients (0.56%, 95% CI 0.07-2.02) developed fever and were admitted for intravenous antibiotics; 1 patient recovered with intravenous antibiotics and the other required surgical debridement for necrosis. One patient required the use of reversal medication. Overall, 1.97% (95% CI 0.80-4.02) of the patients were hospitalized for complications (range 1-16 days). None of the patients experienced clinically significant hemorrhage, perforation, or death. No clear predisposing risk factors were identified. Lack of surgical gold standard and referral to a tertiary center. EUS-FNA of solid pancreatic masses infrequently leads to major complications. Our results can be used by endosonographers to counsel patients before EUS-FNA of solid pancreatic masses.


Diastolic relaxation and compliance reserve during dynamic exercise in heart failure with preserved ejection fraction.
Recent studies have examined haemodynamic changes with stressors such as isometric handgrip and rapid atrial pacing in heart failure with preserved ejection fraction (HFpEF), but little is known regarding left ventricular (LV) pressure-volume responses during dynamic exercise. To assess LV haemodynamic responses to dynamic exercise in patients with HFpEF. Twenty subjects with normal ejection fraction (EF) and exertional dyspnoea underwent invasive haemodynamic assessment during dynamic exercise to evaluate suspected HFpEF. LV end-diastolic pressure was elevated at rest (>15 mm Hg, n=18) and with exercise (≥20 mm Hg, n=20) in all subjects, consistent with HFpEF. Heart rate (HR), blood pressure, arterial elastance and cardiac output increased with exercise (all p<0.001). Minimal and mean LV diastolic pressures increased by 43-56% with exercise (both p<0.0001), despite a trend towards a reduction in LV end-diastolic volume (p=0.08). Diastolic filling time was abbreviated with increases in HR and the proportion of diastole that elapsed prior to estimated complete relaxation increased (p<0.0001), suggesting inadequate relaxation reserve relative to the shortening of diastole. LV diastolic chamber elastance acutely increased 50% during exercise (p=0.0003). Exercise increases in LV filling pressures correlated with changes in diastolic relaxation rates, chamber stiffness and arterial afterload but were not related to alterations in preload volume, HR or cardiac output. In patients with newly diagnosed HFpEF, LV filling pressures increase during dynamic exercise in association with inadequate enhancement of relaxation and acute increases in LV chamber stiffness. Therapies that enhance diastolic reserve function may improve symptoms of exertional intolerance in patients with hypertensive heart disease and early HFpEF.


Bone marrow transplantation without conditioning regimen in Omenn syndrome: a case report.
OS is a non-SCID immunodeficiency characterized by a poor outcome even after BMT. We report here a case of BMT without preparative conditioning regimen, and with a successful engraftment in a five-month-old infant with OS. The patient was transplanted with 15 x 10(8) bone marrow mononuclear cells/kg, from his HLA matched brother, without preparative regimen and GVHD prophylaxis. Immunological status was assessed before and after the BMT, and the engraftment was monitored with microchimerism analysis. Six days after BMT, an acute GVHD involving first the skin, then the liver and gut, complicated the post-transplantation course. An excellent engraftment was confirmed by donor chimerism over 95% respectively at day post-transplantation 30, 60, 90, and 150. The cellular immunity of the patient was restored, and infectious complications decreased after BMT. Later the patient experienced chronic GVHD, and he died on day post-transplantation 246 from GVHD. BMT without conditioning regimen for OS is feasible, but there must be a megadose cell transplantation, and appropriate prophylactic immunosuppressive treatment to prevent acute GVHD.


Perceptions of the social determinants of health by two groups more and less affiliated with public health in Canada.
Despite strong academic recognition of the SDOH both in Canada and internationally, acknowledgement and uptake of the SDOH in health policy and public consciousness have remained weak. This paper aims to discern reasons for limited action on the SDOH by examining the perceptions of the SDOH held by two groups more and less affiliated with public health in Canada.We conducted formal consultation with group members on their interpretation of the SDOH and their thoughts on the nature and basis of differences between those more and less aligned with the SDOH as a basis for action. Thematic analysis was used to evaluate the views of the two groups. Group 1 (community/public health workers) felt overwhelmed when confronted with questions regarding action on the SDOH within the context of their professional lives. They suggested an expanded list of health determinants that included factors such as voluntarism and happiness, transcending traditional notions of "root causes." Furthermore, they did not articulate value-based reasons why others would oppose the SDOH; rather, in line with their professional roles, they adopted a value-neutral and pragmatic approach to working to improve health. Group 2 (child and youth advocacy organization members) seemed rooted in the 1986 Ottawa Charter for Health Promotion framework, with their recommendations aligned with strategies such as building healthy public policy and reorienting health services. Neither group made reference to issues of social justice or inequity when they made suggestions for improving health. We found that two groups with different affiliations to formal public health could discuss the SDOH without acknowledging the inequitable distribution of power and resources that lies at its root. We also found that those working in public health had difficulty moving beyond individual actions that they or their clients could take to improve health. For a group more focused on advocacy than direct service provision, the Ottawa Charter framework seemed more easily suited to their recommendations for action than suggesting actions that would address the SDOH. Our findings indicate that there remains work to be done in terms of translating the SDOH concept into action in Canada.


Tenosynovial fibroma.
Tenosynovial fibroma or angiofibroma of tendon sheath is a distinctive clinicopathological entity occurring mainly in young and middle-aged men and affecting dominantly the distal extremities. Fingers, hands and wrists are the site of 80 per cent of cases. Palmar aspects of hands and plantar aspects of foot are preferentially involved. The trunk and neck are seldom affected. They are generally small, firm, sometimes painful lesions attached to tendon sheath and/or tendon. The lesion must be distinguished from a variety of benign lesions including nodular fasciitis, angiomyoma and giant-cell tumour of tendon sheath. It can also be confused with sarcoma, including synovial sarcoma, because of the presence in it of characteristic slit-like spaces which have been identified as vascular rather than synovial spaces by virtue of the Factor VIII content of their lining cells.


Use of hepatobiliary scintigraphy in the diagnosis of extrahepatic biliary obstruction in dogs and cats: 25 cases (1982-1989).
Twenty-five animals (21 dogs and 4 cats) in which hepatobiliary scintigraphy (HBS) was performed between 1982 and 1989 were included in a retrospective study to determine the utility of HBS for diagnosis of extrahepatic biliary obstruction. Final diagnoses, which were based on liver biopsy results and surgical findings in all animals, were hepatocellular disease alone (n = 17), hepatocellular disease and extrahepatic biliary obstruction (n = 7), and normal liver (n = 1). Hepatobiliary scintigraphy was performed by use of 99mTc-diisopropyl iminodiacetic acid in all cases. All 7 cases of extrahepatic biliary obstruction were confirmed at surgery. In animals with biliary obstruction, HBS failed to demonstrate radiolabel within either the gallbladder or intestine at any time. Using nonvisualization of the intestine by 180 minutes as the scintigraphic criterion for diagnosis of biliary obstruction, sensitivity was 83% and specificity was 94% in this series. Hepatobiliary scintigraphy was concluded to be an accurate indicator of extrahepatic biliary obstruction in this group of animals. High serum bilirubin concentration at the time HBS was performed did not appear to reduce the diagnostic usefulness of the scintigraphic findings.


Anti-virus effect of traditional Chinese medicine Yi-Fu-Qing granule on acute respiratory tract infections.
Yi-Fu-Qing granule is a traditional Chinese medicine for the treatment of acute respiratory tract infections. The present study sought to investigate the anti-virus effects of Yi-Fu-Qing granule on acute respiratory infections with respiratory syncytial virus (RSV) and human adenoviruses type 3 (Ad3). The cytotoxicity of Yi-Fu-Qing granule was evaluated by the neutral red assay on HeLa cells. The antiviral effect of Yi-Fu-Qing granule was tested by observing the cytopathogenic effect (CPE) with a compound mixture of Isatis leaf as the positive control drug. The results indicated that the highest non-toxicity concentration of Yi-Fu-Qing granule on Hela cells was 1:100. The CPE reduction assay showed that Yi-Fu-Qing granule inhibited RSV and Ad3 replication at a concentration of 1:100. Thus, Yi-Fu-Qing granule may have a significant antivirus effect on acute respiratory tract infections with RSV and Ad3 infections and this could prove useful for further antivirus research on acute respiratory tract infections.


Diagnostic value of thyroglobulin washout in fine-needle aspiration samples for diagnosis and follow-up of differentiated thyroid cancer.
Our goal was to assess the effectiveness of fine-needle aspiration thyroglobulin (FNA-Tg) in detecting malignant lymph nodes (LNs) in patients with differentiated thyroid cancer (DTC). We also aimed to determine the factors that affect the accuracy of FNA-Tg. We conducted a retrospective cohort study using the laboratory, ultrasonographic, histopathological, FNA cytology (FNA-C), and FNA-Tg results of 176 DTC patients. We used receiver operating characteristic analysis to identify the cutoff value of FNA-Tg, and binary regression analysis to compare FNA-Tg with other diagnostic parameters. Spearman correlation was utilized to identify factors that influence FNA-Tg. Our study revealed that a cutoff value of 3.14 ng/mL for FNA-Tg had a sensitivity of 91.8% and a specificity of 96.6% in detecting malignant LNs in the entire group. In the subgroup with thyroid tissue, the optimal cutoff value for FNA-Tg was determined to be 15.5 ng/mL. Additionally, FNA-C had a sensitivity of 82.4% and a specificity of 99.4% for the entire group. The combined use of FNA-Tg and FNA-C yielded a sensitivity of 100% and a specificity of 96%, which was found to be more effective than using either test alone. Serum Tg positivity and serum thyroid-stimulating hormone were positively correlated with FNA-Tg levels in detecting malignant LNs. Our study demonstrated that FNA-Tg is a reliable method for detecting LN metastases in DTC patients, with a 3.14 ng/mL cutoff value. However, each center should take into account factors such as serum thyroid-stimulating hormone, serum Tg, and the presence of thyroid tissue when interpreting FNA-Tg results and determining the appropriate cutoff level.


Temporal multiplexing to simulate multifocal intraocular lenses: theoretical considerations.
Fast tunable lenses allow an effective design of a portable simultaneous vision simulator (SimVis) of multifocal corrections. A novel method of evaluating the temporal profile of a tunable lens in simulating different multifocal intraocular lenses (M-IOLs) is presented. The proposed method involves the characteristic fitting of the through-focus (TF) optical quality of the multifocal component of a given M-IOL to a linear combination of TF optical quality of monofocal lenses viable with a tunable lens. Three different types of M-IOL designs are tested, namely: segmented refractive, diffractive and refractive extended depth of focus. The metric used for the optical evaluation of the temporal profile is the visual Strehl (VS) ratio. It is shown that the time profiles generated with the VS ratio as a metric in SimVis resulted in TF VS ratio and TF simulated images that closely matched the TF VS ratio and TF simulated images predicted with the M-IOL. The effects of temporal sampling, varying pupil size, monochromatic aberrations, longitudinal chromatic aberrations and temporal dynamics on SimVis are discussed.


Regulated Acyl-CoA Synthetase Short-Chain Family Member 2 Accumulation during Spermatogenesis.
Acyl-CoA synthetase short-chain family member 2 (ACSS2) activity provides a major source of acetyl-CoA to drive histone acetylation. This study aimed to unravel the ACSS2 expression during mouse spermatogenesis, where a dynamic and stage-specific genome-wide histone hyperacetylation occurs before histone eviction. In this experimental study, ACSS2 expression levels during spermatogenesis were verified by Immunodetection. Testis paraffin-embedded sections were used for IHC staining with anti-H4 pan ac and anti-ACSS2. Co-detection of ACSS2 and H4K5ac was performed on testis tubular sections by immunofluorescence. Proteins extracts from fractionated male germ cells were subjected to western-blotting and immunoblot was probed with anti- ACSS2 and anti-actin. The resulting data showed that the commitment of progenitor cells into meiotic divisions leads to a robust accumulation of ACSS2 in the cell nucleus, especially in pachytene spermatocytes (P). However, ACSS2 protein drastically declines during post-meiotic stages, when a genome-wide histone hyperacetylation is known to occur. The results of this study are in agreement with the idea that the major function of ACSS2 is to recycle acetate generated after histone deacetylation to regenerate acetyl-CoA which is required to maintain the steady state of histone acetylation. Thus, it is suggested that in spermatogenic cells, nuclear activity of ACSS2 maintains the acetate recycling until histone hyperacetylation, but disappears before the acetylation-dependent histone degradation.


Analysis of the 3' ends of tRNA as the cause of insertion sites of foreign DNA in Prochlorococcus.
The purpose of this study was to investigate the characteristics of transfer RNA (tRNA) responsible for the association between tRNA genes and genes of apparently foreign origin (genomic islands) in five high-light adapted Prochlorococcus strains. Both bidirectional best BLASTP (basic local alignment search tool for proteins) search and the conservation of gene order against each other were utilized to identify genomic islands, and 7 genomic islands were found to be immediately adjacent to tRNAs in Prochlorococcus marinus AS9601, 11 in P. marinus MIT9515, 8 in P. marinus MED4, 6 in P. marinus MIT9301, and 6 in P. marinus MIT9312. Monte Carlo simulation showed that tRNA genes are hotspots for the integration of genomic islands in Prochlorococcus strains. The tRNA genes associated with genomic islands showed the following characteristics: (1) the association was biased towards a specific subset of all iso-accepting tRNA genes; (2) the codon usages of genes within genomic islands appear to be unrelated to the codons recognized by associated tRNAs; and, (3) the majority of the 3' ends of associated tRNAs lack CCA ends. These findings contradict previous hypotheses concerning the molecular basis for the frequent use of tRNA as the insertion site for foreign genetic materials. The analysis of a genomic island associated with a tRNA-Asn gene in P. marinus MIT9301 suggests that foreign genetic material is inserted into the host genomes by means of site-specific recombination, with the 3' end of the tRNA as the target, and during the process, a direct repeat of the 3' end sequence of a boundary tRNA (namely, a scar from the process of insertion) is formed elsewhere in the genomic island. Through the analysis of the sequences of these targets, it can be concluded that a region characterized by both high GC content and a palindromic structure is the preferred insertion site.


Nanotopography - potential relevance in the stem cell niche.
Understanding signals in the niche that regulate stem cell behaviours is important for applications such as tissue engineering, and limitations in ex vivo/in vitro recapitulation of some stem cell niches, particularly the bone marrow, have led researchers to attempt to delineate signalling mechanisms present in vivo using a reductionist approach. This is especially important as 'stemness' is not solely an intrinsic property of stem cells but a result of the reciprocal interactions between stem cells and their niches. Physical stimuli such as mechanical stiffness and topography are known to significantly impact stem cell behaviours; being translated through adhesions, intracellular tension and mechanotransduction, which can alter gene expression and thus cell fate. In this review general properties of the stem cell niche are initially described, using intestinal and bone marrow niches as examples. The lesser-described physical stimuli of nanotopography and the mechanisms by which stem cells respond and interact with it are described, including biochemical and physical mechanotrasduction, chemical and physical signal integration and adhesion mechanisms in both anchorage-dependent and -independent cells. Specific examples of nanotopographical influence over stem cell differentiation are highlighted and parallels drawn between the stem cell niche and these 'synthetic'in vitro observations. Ultimately if the complex stem cell niche is to be mimicked in vitro or stem cells exploited for medical applications the physical microenvironment, including nanotopography, must be optimised.


An embedded intracranial seizure monitor for objective outcome measurements and rhythm identification.
Providing clinicians with objective outcomes of neuromodulation therapy is a key unmet need, especially in emerging areas such as epilepsy and mood disorders. These diseases have episodic behavior and circadian/multidien rhythm characteristics that are difficult to capture in short clinical follow-ups. This work presents preliminary validation evidence for an implantable neuromodulation system with integrated physiological event monitoring, with an initial focus on seizure tracking for epilepsy. The system was developed to address currently unmet requirements for patients undergoing neuromodulation therapy for neurological disorders, specifically the ability to sense physiological data during stimulation and track events with seconds-level granularity. The system incorporates an interactive software tool to enable optimal configuration of the signal processing chain on an embedded implantable device (the Picostim-DyNeuMo Mk-2) including data ingestion from the device loop recorder, event labeling, generation of filter and classification parameters, as well as summary statistics. When the monitor parameters are optimized, the user can wirelessly update the system for chronic event tracking. The simulated performance of the device was assessed using an in silico model with human data to predict the real-time device performance at tracking recorded seizure activity. The in silico performance was then compared against its performance in an in vitro model to capture the full environmental constraints such as sensing during stimulation at the tissue electrode interface. In vitro modeling demonstrated comparable results to the in silico model, providing verification of the software tool and model. This study provides validation evidence of the suitability of the proposed system for tracking longitudinal seizure activity. Given its flexibility, the event monitor can be adapted to track other disorders with episodic and rhythmic symptoms represented by bioelectrical behavior.Clinical relevance-An implantable neuromodulation system is presented that enables chronic tracking of physiological events in disease. This physiological monitor provides the basis for longitudinal assessments of therapy outcomes for patients, such as those with epilepsy where objective identification of patient seizure activity and rhythms might help guide therapy optimization. The system is configurable for other disease states such as Parkinson's disease and mood disorders.


[Contextualized editorial practices: Carlos Augusto Monteiro and the journal Revista de Saúde Pública].
This text is part of a series of interviews that seek to explore diverse editing and publication experiences and the similar difficulties Latin America journals face, in order to begin to encounter contextualized solutions that articulate previously isolated efforts. In this interview, carried out in July 2015 in the Instituto de Salud Colectiva [Institute of Collective Health] of the Universidad Nacional de Lanús, Carlos Augusto Monteiro speaks to us about funding, work processes, technological innovations, and establishing teams and roles. He analyzes the importance of Latin American journals as a platform for spreading research relevant to national agendas, and the connection between journal performance, the quality of graduate training programs and research quality.


Selective cognitive processing of drug cues in heroin dependence.
Previous studies provide evidence for the selective processing of disorder related stimuli on anxiety, depression, and eating disorders. There exist some preliminary indications that selective processing of drug cues may be involved in drug craving and relapse that deserve further investigation. In order to investigate the role of processing bias in an abnormal motivational system, the attentional bias for drug related stimuli was studied in a heroin dependent population. Heroin dependent participants (n = 21) and control participants (n = 30) performed a supra- and subliminal heroin Stroop task and heroin craving was assessed. Heroin dependent participants showed a considerable attentional bias for supraliminally presented heroin cues. However, there was no evidence for a preattentive bias on the subliminal presented cues. Reaction time on heroin cues was significantly predicted by heroin craving-levels. Results indicate that selective processing may be related to motivational induced states in general. The finding are discussed in the context of selective information processing in general psychopathology and in motivational processes as addiction specifically.


Minimal effective dose of bedaquiline administered orally and activity of a long acting formulation of bedaquiline in the murine model of leprosy.
Bedaquiline (BDQ), by targeting the electron transport chain and having a long half-life, is a good candidate to simplify leprosy treatment. Our objectives were to (i) determine the minimal effective dose (MED) of BDQ administered orally, (ii) evaluate the benefit of combining two inhibitors of the respiratory chain, BDQ administered orally and clofazimine (CFZ)) and (iii) evaluate the benefit of an intramuscular injectable long-acting formulation of BDQ (intramuscular BDQ, BDQ-LA IM), in a murine model of leprosy. To determine the MED of BDQ administered orally and the benefit of adding CFZ, 100 four-week-old female nude mice were inoculated in the footpads with 5x103 bacilli of M. leprae strain THAI53. Mice were randomly allocated into: 1 untreated group, 5 groups treated with BDQ administered orally (0.10 to 25 mg/kg), 3 groups treated with CFZ 20 mg/kg alone or combined with BDQ administered orally 0.10 or 0.33 mg/kg, and 1 group treated with rifampicin (RIF) 10 mg/kg. Mice were treated 5 days a week during 24 weeks. To evaluate the benefit of the BDQ-LA IM, 340 four-week-old female swiss mice were inoculated in the footpads with 5x103 to 5x101 bacilli (or 5x100 for the untreated control group) of M. leprae strain THAI53. Mice were randomly allocated into the following 11 groups treated with a single dose (SD) or 3 doses (3D) 24h after the inoculation: 1 untreated group, 2 treated with RIF 10 mg/kg SD or 3D, 8 treated with BDQ administered orally or BDQ-LA IM 2 or 20 mg/kg, SD or 3D. Twelve months later, mice were sacrificed and M. leprae bacilli enumerated in the footpad. All the footpads became negative with BDQ at 3.3 mg/kg. The MED of BDQ administered orally against M. leprae in this model is therefore 3.3 mg/kg. The combination of CFZ and BDQ 10-fold lower than this MED did not significantly increase the bactericidal activity of CFZ. The BDQ-LA IM displayed similar or lower bactericidal activity than the BDQ administered orally. We demonstrated that the MED of BDQ administered orally against M. leprae was 3.3 mg/kg in mice and BDQ did not add significantly to the efficacy of CFZ at the doses tested. BDQ-LA IM was similar or less active than BDQ administered orally at equivalent dosing and frequency but should be tested at higher dosing in order to reach equivalent exposure in further experiments.


The effect of strict volume control on cardiac biomarker and arterial stiffness in peritoneal dialysis patients.
Arterial stiffness is a risk marker for cardiovascular events in peritoneal dialysis (PD) patients. Strict volume control strategy has been shown to result in better cardiac functions and control of hypertension in these patients. The aim of the study was to identify the determinants of arterial stiffness and evaluate the changes in cardiac biomarkers in PD patients under strict volume control strategy. 58 PD patients were enrolled into this prospective observational study. Arterial stiffness determined by aortic pulse wave velocity (PWV), echocardiography, ambulatory blood pressure and NT-pro-BNP levels were measured at baseline and at first year. The mean age of the patients was 46.4 ± 14 years. 30 patients were on automated PD (APD) and 28 on continuous ambulatory PD (CAPD) group. In both groups, there were significant differences in PWV values at baseline and at the end of the study. A similar decrease was observed with NT-proBNP and PWV levels. In addition, a significant improvement was found in echocardiographic parameters in all patients. Comparison of APD and CAPD groups with respect to change in one year, showed no difference in echocardiographic findings, while the reduction in PWV, NTproBNP and blood pressure values was higher in the CAPD group. In PD patients, strict volume control leads to a reduction in NT-pro-BNP levels, better control of blood pressure and significant improvements in cardiac functions and arterial stiffness.


The synthesis and characterization of nonperipherally tetra terminal alkynyl substituted phthalocyanines and glycoconjugation via the click reaction.
In order to obtain nonperipherally tetra terminal alkynyl substituted phthalocyanines (Pcs), new 3-pent-4-ynyloxy phthalonitrile (3) was prepared by the nucleophilic displacement reaction of 3-nitrophthalonitrile (1) and 4-pentyn-1-ol (2) and then cyclotetramerization was attained in the presence of zinc acetate, cobalt acetate, and/or DBU in n-pentanol without protection/deprotection. For the first time, the glycoconjugation of the nonperipherally tetra terminal alkynyl substituted zinc phthalocyanine (ZnPc) (6) can be easily achieved via the click reaction in a high yield. The electronic absorption spectrum of the glucopyranosyl substituted ZnPc (10) derivative showed a red-shifted Q band at 751 nm in dichloromethane due to the protonation of the meso nitrogens of the Pc macrocycle. Deacylation yielded ZnPc (11) bearing glucose substituents at nonperipheral positions with an improved water-solubility and non-aggregation in DMSO. The chemical structures of the new compounds were characterized by (1)H NMR, (13)C NMR, FT-IR, UV-Vis, mass spectrometry and elemental analysis. Moreover, the phthalonitrile compound was characterized using X-ray.


Mercury exposure is associated with negative effects on turtle reproduction.
Mercury (Hg), a ubiquitous and highly toxic bioaccumulative contaminant, can maternally transfer and elicit deleterious effects on adult reproduction and offspring phenotype in fish, amphibians, and birds. However, the effects of Hg on reproduction remain largely unstudied in reptiles. We evaluated the consequences of maternally transferred Hg on a long-lived aquatic omnivore, the common snapping turtle (Chelydra serpentina). We collected eggs and tissues from gravid female turtles along a broad Hg contamination gradient in a river in central Virginia. We incubated eggs in the laboratory, quantified embryonic mortality, infertility, and hatching success of each clutch, and assessed all hatchlings and dead embryos for gross morphological malformations. As predicted, Hg concentrations in eggs were strongly and positively correlated with Hg levels in female tissues. We found that Hg in eggs was negatively correlated with hatching success, and this effect was driven by both increased egg infertility and embryonic mortality. In comparison to previous effect-based studies on other amniotes, our findings suggest that C. serpentina may be more resilient to Hg exposure and perhaps better suited for long-term monitoring of bioavailability of Hg than as indicators of adverse effects.


Hemostasis in hypertensive disorders of pregnancy.
We studied parameters of hemostasis reported to be altered with "pure" preeclampsia in hypertensive disorders of pregnancy. Plasma fibronectin, antithrombin, and alpha-2 antiplasmin were measured in normal pregnancies (N = 26) and in pregnancies complicated by preeclampsia (N = 19), hypertension (N = 11), and chronic hypertension with superimposed preeclampsia (N = 11). Preeclampsia, both pure and superimposed, was associated with high fibronectin (P less than .001), low antithrombin III (P less than .001), and low alpha-2 antiplasmin (P less than .05) levels, suggesting endothelial injury, clotting, and fibrinolysis, respectively. Alpha-2 antiplasmin was increased with chronic hypertension (P less than .001), regardless of whether there was superimposed preeclampsia. Fibronectin appeared to be more closely linked with preeclampsia than antithrombin III or alpha-2 antiplasmin and may prove valuable in detecting preeclampsia when evaluating hypertension in pregnancy.


Gene Dosage Dependent Aggravation of the Neurological Phenotype in the 5XFAD Mouse Model of Alzheimer's Disease.
In the present report, we extend previous findings in the 5XFAD mouse model with regard to a characterization of behavioral deficits and neuropathological alterations. We demonstrate that these mice develop a robust age-dependent motor phenotype and spatial reference memory deficits when bred to homozygosity, leading to a strongly reduced age of onset of behavioral symptoms. At postnatal day sixteen, abundant AβPP was detected in subiculum and cortical pyramidal neurons. From six weeks on, intraneuronal Aβ could be detected which was much more abundant in homozygous mice. The same gene-dosage effect was seen on memory and motor deficits. While at 2 months of age neither heterozygous nor homozygous 5XFAD mice show any neurological phenotype except for alterations in anxiety behavior, at 5 months they were clearly evident. Interestingly, despite abundant motor deficiencies, homozygous 5XFAD mice were able to perform the acquisition training of the Morris water maze task with no difference in the swimming performance between the groups. Therefore the aggravated spatial memory and spatial reference memory deficits of the homozygous mice correlated with the elevated soluble and insoluble Aβ levels. Homozygous 5XFAD mice represent a model with several advantages in comparison to the heterozygous mice, developing amyloid pathology much more rapidly together with a neurological phenotype. These advantages allow reducing the number of animals for Alzheimer's disease research.


Perfectionism in obsessive-compulsive and eating disorders.
The main aims of this article are twofold. First, to assess perfectionism dimensions in obsessive-compulsive disorder and eating disorders in comparison with psychiatric control (depression/anxiety) and non-clinical control groups. Second, to examine if perfectionism is specifically related to these different clinical conditions. Thirty-nine outpatients with obsessive-compulsive disorder, 24 outpatients with eating disorders, 65 outpatients with a diagnosis of depression and/or anxiety, and 70 non-clinical participants completed the Portuguese version of the Multidimensional Perfectionism Scale. Compared to non-clinical subjects, individuals of all clinical samples had significantly higher scores on Multidimensional Perfectionism Scale total score, Self-Oriented and Socially-Prescribed Perfectionism. There were no significantly differences in Self-Oriented Perfectionism and Multidimensional Perfectionism Scale total score in all the three clinical samples. Subjects from the eating disorders sample had significantly higher scores of Socially-Prescribed Perfectionism in comparison to obsessive-compulsive disorder and psychiatric control samples. Perfectionism showed to be related with this broad range of psychopathologies. However, the differences between eating disorders versus obsessive-compulsive disorder and psychiatric control on Socially-Prescribed Perfectionism warrant further investigation in order to clarify the specificity of this perfectionism dimension in eating disorders.


Butyrate production in phylogenetically diverse Firmicutes isolated from the chicken caecum.
Sixteen butyrate-producing bacteria were isolated from the caecal content of chickens and analysed phylogenetically. They did not represent a coherent phylogenetic group, but were allied to four different lineages in the Firmicutes phylum. Fourteen strains appeared to represent novel species, based on a level of ≤ 98.5% 16S rRNA gene sequence similarity towards their nearest validly named neighbours. The highest butyrate concentrations were produced by the strains belonging to clostridial clusters IV and XIVa, clusters which are predominant in the chicken caecal microbiota. In only one of the 16 strains tested, the butyrate kinase operon could be amplified, while the butyryl-CoA:acetate CoA-transferase gene was detected in eight strains belonging to clostridial clusters IV, XIVa and XIVb. None of the clostridial cluster XVI isolates carried this gene based on degenerate PCR analyses. However, another CoA-transferase gene more similar to propionate CoA-transferase was detected in the majority of the clostridial cluster XVI isolates. Since this gene is located directly downstream of the remaining butyrate pathway genes in several human cluster XVI bacteria, it may be involved in butyrate formation in these bacteria. The present study indicates that butyrate producers related to cluster XVI may play a more important role in the chicken gut than in the human gut.


Orthopedic Treatment for Class II Malocclusion with Functional Appliances and Its Effect on Upper Airways: A Systematic Review with Meta-Analysis.
Aim of this systematic review was to assess the effects of orthopedic treatment for Class II malocclusion with Functional Appliances (FAs) on the dimensions of the upper airways. Eight databases were searched up to October 2020 for randomized or nonrandomized clinical studies on FA treatment of Class II patients with untreated control groups. After duplicate study selection, data extraction, and risk of bias assessment according to Cochrane guidelines, random effects meta-analyses of mean differences (MDs) and their 95% confidence intervals (CIs) were performed, followed by subgroup/meta-regression analyses and assessment of the quality of evidence. A total of 20 nonrandomized clinical studies (4 prospective/16 retrospective) including 969 patients (47.9% male; mean age 10.9 years) were identified. Orthopedic treatment with FAs was associated with increased oropharynx volume (MD = 2356.14 mm3; 95% CI = 1276.36 to 3435.92 mm3; p < 0.001) compared to natural growth. Additionally, significant increases in nasopharynx volume, minimal constricted axial area of pharyngeal airway, and airway were seen, while removable FAs showed considerably greater effects than fixed FAs (p = 0.04). Finally, patient age and treatment duration had a significant influence in the effect of FAs on airways, as had baseline matching and sample size adequacy. Clinical evidence on orthopedic Class II treatment with FAs is associated with increased upper airway dimensions. However, the quality of evidence is very low due to methodological issues of existing studies, while the clinical relevance of increases in airway dimensions remains unclear.


Assessment of Biopharmaceutical Performance of Supersaturating Formulations of Carbamazepine in Rats Using Physiologically Based Pharmacokinetic Modeling.
There is an overgrowing emphasis on supersaturating drug delivery systems (SDDS) with increase in number of poorly water-soluble compounds. However, biopharmaceutical performance from these formulations is limited by phase transformation to stable crystalline form due to their high-energy physical form. In the present study, in vitro kinetic solubility in water and dissolution in biorelevant medium integrated with in silico physiologically based pharmacokinetic (PBPK) modeling was used to predict biopharmaceutical performance of SDDS of poorly water-soluble compound, carbamazepine (CBZ). GastroPlus™ with advanced compartmental absorption and transit model was used as a simulation tool for the study. Wherein, the model was developed using physicochemical properties of CBZ and disposition parameters obtained after intravenous administration of CBZ (20 mg/kg) into Sprague-Dawley (SD) rats. Biorelevant medium was selected by screening different dissolution media for their capability to predict oral plasma concentration-time profile of marketed formulation of CBZ. In vivo performance of SDDS was predicted with the developed model and compared to observed plasma concentration-time profile obtained after oral administration of SDDS into SD rats (20 mg/kg). The predictions, with strategy of using kinetic solubility and dissolution in the selected biorelevant medium, were consistent with observed biopharmaceutical performance of SDDS. Additionally, phase transformation of CBZ during gastrointestinal transit of formulations was evaluated and correlated with in vivo dissolution deconvoluted by Loo-Reigelman analysis.


Raloxifene inhibits the overexpression of TGF-β1 in cartilage and regulates the metabolism of subchondral bone in rats with osteoporotic osteoarthritis.
Overexpression of transforming growth factor-beta 1 (TGF-β1) and subchondral bone remodelling play key roles in osteoarthritis (OA). Raloxifene (RAL) reduces the serum level of TGF-β1 in postmenopausal women. However, the effect of RAL on TGF-β1 expression in articular cartilage is still unclear. Therefore, we aimed to investigate the protective effect of RAL on osteoporotic osteoarthritis via affecting TGF-β1 expression in cartilage and the metabolism of subchondral bone. Osteoporotic osteoarthritis was induced by a combination of anterior cruciate transection (ACLT) and ovariectomy (OVX). Rats were divided into five groups (n = 12): The sham group, the ACLT group, the OVX group, the ACLT + OVX group, and the RAL group (ACLT + OVX + RAL, 6.25 mg/kg/day for 12 weeks). Assessment was performed by histomorphology, microcomputed tomography (micro-CT) scan, immunohistochemistry, and tartrate-resistant acid phosphatase (TRAP) staining. We found that severe cartilage degeneration was shown in the ACLT + OVX group. The histomorphological scores, the levels of TGF-β1, and its related catabolic enzymes and osteoclasts numbers in the ACLT + OVX group were higher than those in other groups (p < 0.05). Furthermore, structure model index (SMI) and trabecular spacing (Tb.Sp) were decreased (p < 0.05), while bone mineral density (BMD), bone volume fraction (BV/TV), and trabecular number (Tb.N) were increased by RAL compared with the ACLT + OVX group (p < 0.05). Our findings demonstrated that RAL in clinical doses retards the development of osteoporotic osteoarthritis by inhibiting the overexpression of TGF-β1 in cartilage and regulating the metabolism of subchondral bone. These results provide support for RAL in the expansion of clinical indication for prevention and treatment in postmenopausal osteoarthritis.


Inhibitory RNA in epilepsy: research tools and therapeutic perspectives.
Since its discovery a decade ago, RNA interference (RNAi) has been developed not only into powerful experimental tools but also into promising novel therapeutics. In contrast to conventional antiepileptic drugs (AEDs) that target specific proteins such as ion channels or receptors, RNAi-based therapeutics exploit an endogenous regulatory mechanism of gene expression and thereby are poised to prevent or reverse pathogenetic mechanisms involved in seizure development. Therapeutic RNAi has been widely explored for dominant targets involved in neurodegenerative diseases; however, their use for epilepsy therapy has received less attention. This review discusses potential RNAi-based targets that are of interest for epilepsy therapy, including adenosine kinase (ADK), the key negative regulator of the brain's endogenous anticonvulsant adenosine. Overexpression of ADK, and the resulting adenosine deficiency, are pathologic hallmarks of the sclerotic epileptic brain, and have been implicated in seizure generation. Therefore, RNAi-strategies aimed at reducing ADK (and increasing adenosine) are based on a direct neurochemical rationale that has recently been explored experimentally using ex vivo and in vivo gene therapy approaches. Technical issues and challenges remain before those promising tools can be developed into future therapeutics for epilepsy.


Relationships of temperature and sodium chloride concentration to the survival of Vibrio parahaemolyticus in broth and fish homogenate.
The interaction of temperature and NaCl concentration in affecting the survival of three strains of Vibrio parahaemolyticus was studied in Trypticase soy broth and fish homogenate. Cells of V. parahaemolyticus suspended in Trypticase soy broth without NaCl were quite unstable and readily killed. The presence of NaCl appeared to be protective to the cells at 48 +/- 1 C, with the optimal concentration strain-dependent for the 3 to 12% range tested. Temperatures of 5 +/- 1, -5 +/- 1, and -18 +/- 1 C reduced the number of viable organisms per milliliter regardless of the NaCl concentration. In the presence of NaCl, viable cells, in numbers ranging up to 580 per ml, were still detected at the end of 30 days of storage. Similar results were obtained for cells suspended in fish homogenate, except that fish homogenate itself was protective as compared with Trypticase soy broth. This protection was significantly lower than that provided by NaCl in any amount tested.


Trends in sexually transmitted diseases and condom use patterns among commercial sex workers in Fukuoka City, Japan 1990-93.
To investigate trends in sexually transmitted diseases (STDs) among female commercial sex workers and in their condom use patterns during the period from 1990 to 1993 in Fukuoka, Japan. The study group consisted of a total of 824 commercial sex workers who attended an STD clinic to undergo screening for STDs including chlamydia, gonorrhoea, syphilis, hepatitis B and HIV-1 infection during the period from 1990 to 1993. For detection of Chlamydia trachomatis and Neisseria gonorrhoeae, endocervical smear specimens were taken from the women. Blood samples were obtained for serological diagnosis of syphilis, hepatitis B and HIV-1. Commercial sex workers who visited the clinic during the period from November to December of 1993 were interviewed concerning past (1990 and 1991) and recent (1992 and 1993) condom use patterns. The annual detection rates of C trachomatis and N gonorrhoeae declined significantly from 16.3% in 1990 to 12.2% in 1993 (P < 0.0001) and from 1.5% in 1990 to 0.8% in 1993 (P = 0.0096), respectively. There was a remarkable reduction in the annual syphilis infection rate, from 7.5% in 1990 to 0.5% in 1993 (P = 0.0011). The positive rate for the hepatitis B surface antigen in the women ranged from only 0.6% to 1.9% and none were found to be positive for HIV-1 during the 4-year period. During the same period, there was a significant increase in the proportion of commercial sex workers always using condoms from 6.3% in 1990-91 to 25.3% in 1992-93 (P = 0.0023). The prevalences of chlamydia, gonorrhoea, and syphilis infections decreased significantly among commercial sex workers in Fukuoka from 1990 through 1993, and no commercial sex workers were HIV-1 seropositive. The reductions in the prevalence of major STDs may be related to the increased use of condoms.


Recovery of steroidal glucosiduronic acids from organic solvents containing anionic liquid ion-exchangers.
Solutions of anionic liquid ion-exchangers in organic solvents are potentially useful for extracting steroidal glucosiduronic acids from biological fluids and for purifying mixtures of these acids by chromatography. If a glucosiduronic acid is to be isolated in pure form after either of these procedures, it is necessary to separate it from the ion-exchanger. Separation from an organic solution of tetraheptylammonium chloride may be accomplished by extraction with water under the following conditions, which promote transfer of a glucosiduronate to the aqueous phase: (1) an appropriate solvent (diluent) as the organic phase, (2) the presence in the two-phase mixture of an anion such as myristate or dodecyl sulphate to combine with the tetraheptylammonium ion, and (3) an increase of the pH of the aqueous phase in association with the presence of myristate or dodecyl sulphate. The foregoing factors apply also to removal of glucosiduronates from organic solutions of ion exchangers that are hydrochlorides of tertiary, secondary, or primary amines. Since these amines exert progressively less solubilizing effect for glucosiduronates as the pH of the aqueous phase is increased, the conjugates can be released from the organic phase by adjusting the pH to 10 and omitting the myristate or dodecyl sulphate.


DNA methylation abnormalities of imprinted genes in congenital heart disease: a pilot study.
Congenital heart disease (CHD) is resulted from the interaction of genetic aberration and environmental factors. Imprinted genes, which are regulated by epigenetic modifications, are essential for the normal embryonic development. However, the role of imprinted genes in the etiology of CHD remains unclear. After the samples were treated with bisulfate salt, imprinted genes methylation were measured by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. T test and One-way ANOVA were performed to evaluate the differences among groups. Odds ratios (ORs) were performed to evaluate the incidence risk of CHD in relation to methylation levels. We investigated the alterations of imprinted gene germline differential methylation regions (gDMRs) methylation in patients with CHD. Eighteen imprinted genes that are known to affect early embryonic development were selected and the methylation modification genes were detected by massarray in 27 CHD children and 28 healthy children. Altered gDMR methylation level of 8 imprinted genes was found, including 2 imprinted genes with hypermethylation of GRB10 and MEST and 6 genes with hypomethylation of PEG10, NAP1L5, INPP5F, PLAGL1, NESP and MEG3. Stratified analysis showed that the methylation degree of imprinted genes was different in different types of CHD. Risk analysis showed that 6 imprinted genes, except MEST and NAP1L5, within a specific methylation level range were the risk factors for CHD CONCLUSION: Altered methylation of imprinted genes is associated with CHD and varies in different types of CHD. Further experiments are warranted to identify the methylation characteristics of imprinted genes in different types of CHD and clarify the etiologies of imprinted genes in CHD.


Inhibitory effect of 6-formylpterin on HIF-1alpha protein accumulation.
Hypoxia-inducible factor-1 (HIF-1) is a main regulator of metabolic adaptation to hypoxia. HIF-1alpha is induced by hypoxia, or by hypoxia-mimicking reagents, such as desferrioxamine (DFX), under a normoxic condition. A xanthine oxidase inhibitor, 6-formylpterin (6FP), is reported to exert its functions on reactive oxygen species (ROS) modulation. In this study, we investigated the effect of 6FP on HIF-1alpha expression under a DFX-treated or hypoxic condition. 6FP decreased HIF-1alpha expression at the protein level, but not at the mRNA level, in a dose-dependent manner, and this suppressive effect was reversed by the antioxidant, N-acetyl-L-cysteine (NAC). Furthermore, the ROS generated by 6FP was reversed with NAC coincubation. These findings suggest that intracellular ROS generated by 6FP decreased the HIF-1alpha protein accumulation under a DFX-treated or hypoxic condition.


Conservation and divergence of YODA MAPKKK function in regulation of grass epidermal patterning.
All multicellular organisms must properly pattern cell types to generate functional tissues and organs. The organized and predictable cell lineages of the Brachypodium leaf enabled us to characterize the role of the MAPK kinase kinase gene BdYODA1 in regulating asymmetric cell divisions. We find that YODA genes promote normal stomatal spacing patterns in both Arabidopsis and Brachypodium, despite species-specific differences in those patterns. Using lineage tracing and cell fate markers, we show that, unexpectedly, patterning defects in bdyoda1 mutants do not arise from faulty physical asymmetry in cell divisions but rather from improper enforcement of alternative cellular fates after division. These cross-species comparisons allow us to refine our understanding of MAPK activities during plant asymmetric cell divisions.


Regulated ectopic expression of cyclin D1 induces transcriptional activation of the cdk inhibitor p21 gene without altering cell cycle progression.
Cyclin D1 plays a key regulatory role during the G1 phase of the cell cycle and its gene is amplified and overexpressed in many cancers. To address the relationship between cyclin D1 and other cell cycle regulatory proteins, we established human glioma and rodent fibroblast cell lines in which cyclin D1 expression could be regulated ectopically with tetracycline. In both of these cell lines, we found that ectopic expression of cyclin D1 in asynchronously growing cells was accompanied by increased levels of the p53 tumor suppressor protein and the cyclin/cdk inhibitor p21. Despite the induction of these cell cycle inhibitory proteins, cyclin D1-associated cdk kinase remained activated and the cells grew essentially like that of the parent cells. Although growth parameters were unchanged in these cells, morphological changes were clearly identifiable and anchorage independent growth was observed in NIH3T3 cells. In a first step toward elaborating the mechanism for cyclin D1-mediated induction of p21 gene expression we show that co-expression of E2F-1 and DP-1 can specifically transactivate the p21 promoter. In support of these findings and a direct effect of E2F on induction of p21 gene expression a putative E2F binding site was identified within the p21 promoter. In summary, our results demonstrate that ectopic expression of cyclin D1 can induce gene expression of the cdk inhibitor p21 through an E2F mechanism the consequences of which are not to growth arrest cells but possibly to stabilize cyclin D1/cdk function.


Paradoxical hypertrichosis after laser therapy: a review.
Laser hair removal is a safe and effective procedure for the treatment of unwanted body hair but is not exempt from side effects. A rare but significant adverse effect with this treatment modality is paradoxical hypertrichosis. To evaluate the potential etiologies, risk factors, related laser types, and treatment options for the development of excess hair after laser therapy. An analysis of previously published case studies and review articles along with our own experience was used to gather information regarding this phenomenon. Paradoxical hypertrichosis has a low incidence, ranging from 0.6% to 10%, and most commonly occurs on the face and neck. All laser and light sources have the potential to cause hair induction, especially in individuals with darker skin types (III-VI); with dark, thick hair; and with underlying hormonal conditions. Possible causes include the effect of inflammatory mediators and subtherapeutic thermal injury causing induction of the hair cycle. Treatment for paradoxical hypertrichosis is laser therapy of the affected area. Paradoxical hypertrichosis is a rare side effect of laser hair removal; the pathogenesis of this event remains widely unknown. We recommend further large-scale studies to investigate this effect. The authors have indicated no significant interest with commercial supporters.


Conduction and block by organic cations in a K+-selective channel from sarcoplasmic reticulum incorporated into planar phospholipid bilayers.
A collection of organic cations has been used to probe the gross structural features of the ionic diffusion pathway in a K+-selective channel from sarcoplasmic reticulum (SR). Channels were incorporated into planar phospholipid bilayer membranes, and single-channel currents were measured in the presence of ammonium-derived cations in the aqueous phases. Small monovalent organic cations are able to permeate the channel: the channel conductance drops sharply for cations having molecular cross sections larger than 18-20 A2. Impermeant or poorly permeant cations such as tetraethylammonium, choline, and glucosamine, among others, block K+ conduction through the channel. This block is voltage dependent and can be described by a one-site, one-ion blocking scheme. 19 monovalent organic cations blocks primarily from the trans side of the membrane (the side defined as zero voltage), and much more weakly, if at all, from the cis side (to which SR vesicles are added). These blockers all appear to interact with a site located at 63% (average value) of the electric potential drop measured from the trans side. Furthermore, block by 1,3-bis[tris(hydroxymethyl)-methylamino] propane (BTP) shows that the presence of a blocking ion increases the duration of the apparent open state, as expected for a scheme in which the blocking site can be reached only when the channel is open. The results lead to a picture of the channel containing a wide (at least 50 A2) nonselective trans entry in series with a narrow (20 A2) constriction.


Vascular dysfunction in diabetes: The endothelial progenitor cells as new therapeutic strategy.
The vascular endothelium is a critical determinant of diabetes-associated vascular complications, and improving endothelial function is an important target for therapy. Diabetes mellitus contributes to endothelial cell injury and dysfunction. Endothelial progenitor cells (EPCs) play a critical role in maintaining endothelial function and might affect the progression of vascular disease. EPCs are essential to blood vessel formation, can differentiate into mature endothelial cells, and promote the repair of damaged endothelium. In diabetes, the circulating EPC count is low and their functionality is impaired. The mechanisms that underlie this reduced count and impaired functionality are poorly understood. Knowledge of the status of EPCs is critical for assessing the health of the vascular system, and interventions that increase the number of EPCs and restore their angiogenic activity in diabetes may prove to be particularly beneficial. The present review outlines current thinking on EPCs' therapeutic potential in endothelial dysfunction in diabetes, as well as evidence-based perspectives regarding their use for vascular regenerative medicine.


Why wet feels wet? A neurophysiological model of human cutaneous wetness sensitivity.
Although the ability to sense skin wetness and humidity is critical for behavioral and autonomic adaptations, humans are not provided with specific skin receptors for sensing wetness. It has been proposed that we "learn" to perceive the wetness experienced when the skin is in contact with a wet surface or when sweat is produced through a multisensory integration of thermal and tactile inputs generated by the interaction between skin and moisture. However, the individual roles of thermal and tactile cues and how these are integrated peripherally and centrally by our nervous system is still poorly understood. Here we tested the hypothesis that the central integration of coldness and mechanosensation, as subserved by peripheral A-nerve afferents, might be the primary neural process underpinning human wetness sensitivity. During a quantitative sensory test, we found that individuals perceived warm-wet and neutral-wet stimuli as significantly less wet than cold-wet stimuli, although these were characterized by the same moisture content. Also, when cutaneous cold and tactile sensitivity was diminished by a selective reduction in the activity of A-nerve afferents, wetness perception was significantly reduced. Based on a concept of perceptual learning and Bayesian perceptual inference, we developed the first neurophysiological model of cutaneous wetness sensitivity centered on the multisensory integration of cold-sensitive and mechanosensitive skin afferents. Our results provide evidence for the existence of a specific information processing model that underpins the neural representation of a typical wet stimulus. These findings contribute to explaining how humans sense warm, neutral, and cold skin wetness.


Common misconceptions and future intention to smoke among secondary school students in Malaysia.
The prevalence of smoking among secondary school children continues to remain unchanged over the last 3 decades even though awareness regarding the health effects of smoking is increasing. Common misconceptions about smoking and parental influence could be factors influencing future intentions to smoke among these students. Hence, we looked at the common misconceptions as well as student perceptions about their future intention to smoke among Form 4 students in Shah Alam, Malaysia. This study was conducted by distribution of a questionnaire developed as part of the Global Youth Tobacco Survey to Form 4 student in 3 schools at Shah Alam. Prevalence of smoking (current smokers) was 7.5%. Almost half of the children came from families where one or both parents smoked and a third of the parents had no discussion regarding consequences of smoking with them. A large number of students were classified as "triers" as they had tried smoking and were unsure of whether they would not be smoking in the future. Contrary to our expectations, students generally felt smoking did make one feel more uncomfortable and helped one to reduce body weight. Most students seemed to be aware of the ill-effects of smoking on health. They felt they had received adequate information from school regarding the effects on smoking on health. Our study showed that even though Form 4 students in Shah Alam were knowledgeable about ill-effects of smoking and were taught so as part of their school curriculum, the prevalence of smoking was still high. Students in the "trier group" represent a potential group of future smokers and strategies targeting tobacco control may be aimed at tackling these vulnerable individuals. Efforts are also needed to help educate secondary school children about common misconceptions and dispel myths associated with cigarette smoking.


MLS-2384, a new 6-bromoindirubin derivative with dual JAK/Src kinase inhibitory activity, suppresses growth of diverse cancer cells.
Janus kinase (JAK) and Src kinase are the two major tyrosine kinase families upstream of signal transducer and activator of transcription (STAT). Among the seven STAT family proteins, STAT3 is constitutively activated in many diverse cancers. Upon activation, JAK and Src kinases phosphorylate STAT3, and thereby promote cell growth and survival. MLS-2384 is a novel 6-bromoindirubin derivative with a bromo-group at the 6-position on one indole ring and a hydrophilic group at the 3'-position on the other indole ring. In this study, we investigated the kinase inhibitory activity and anticancer activity of MLS-2384. Our data from in vitro kinase assays, cell viability analyses, western blotting analyses, and animal model studies, demonstrate that MLS-2384 is a dual JAK/Src kinase inhibitor, and suppresses growth of various human cancer cells, such as prostate, breast, skin, ovarian, lung, and liver. Consistent with the inactivation of JAK and Src kinases, phosphorylation of STAT3 was inhibited in a dose-dependent manner in the cancer cells treated with MLS-2384. STAT3 downstream proteins involved in cell proliferation and survival, such as c-Myc and Mcl-1, are downregulated by MLS-2384 in prostate cancer cells, whereas survivin is downregulated in A2058 cells. In these two cancer cell lines, PARP is cleaved, indicating that MLS-2384 induces apoptosis in human melanoma and prostate cancer cells. Importantly, MLS-2384 suppresses tumor growth with low toxicity in a mouse xenograft model of human melanoma. Taken together, MLS-2384 demonstrates dual JAK/Src inhibitory activity and suppresses tumor cell growth both in vitro and in vivo. Our findings support further development of MLS-2384 as a potential small-molecule therapeutic agent that targets JAK, Src, and STAT3 signaling in multiple human cancer cells.


Case study: complications associated with anticoagulant therapy.
A 42 year old male with gram negative pneumonia complicated by deep venous thrombosis was followed throughout his hospital stay and for two weeks following discharge. The treatment course is divided into five treatment periods, each with accompanying commentary. Drug interactions and neutralizations as well as dietary factors contributed to a complicated course. Laboratory determinations were used to directly evaluate therapeutic anticoagulant effects, and dosage regimens were adjusted to achieve desired anticoagulant levels.


The internal/external issue what is an outer object? Another person as object and as separate other in object relations models.
The question of what we mean by the term outer object has its roots in the epistemological foundation of psychoanalysis. From the very beginning, Freud's view was Kantian, and psychoanalysis has kept that stance, as it seems. The author reviews the internal/external issue in Freud's thinking and in the central object relations theories (Klein, Winnicott, and Bion). On this background he proposes a simple model to differentiate the concept of object along one central dimension: internal object, external object, and actual person. The main arguments are: (1) there is no direct, unmediated perception of the actual person--the experience of the other is always affected by the perceiver's subjectivity; (2) in intense transference reactions and projections, the perception of the person is dominated by the qualities of an inner object--and the other person "becomes" an external object for the perceiver; (3) when this distortion is less dominating, the other person to a higher degree remains a separate other--a person in his or her own right. Clinical material illustrates these phenomena, and a graphical picture of the model is presented. Finally with the model as background, the author comments on a selection of phenomena and concepts such as unobjectionable transference, "the third position," mourning and loneliness. The way that the internal colours and distorts the external is of course a central preoccupation of psychoanalysis generally. (Spillius et al., 2011, p. 326)


Arabinose confers protection against intestinal injury by improving integrity of intestinal mucosal barrier.
There is a growing amount of research that highlights the significant involvement of metabolic imbalance and the inflammatory response in the advancement of colitis. Arabinose is a naturally occurring bioactive monosaccharide that plays a crucial role in the metabolic processes and synthesis of many compounds in living organisms. However, the more detailed molecular mechanism by which the administration of arabinose alleviates the progression of colitis and its associated carcinogenesis is still not fully understood. In the present study, arabinose is recognized as a significant and inherent protector of the intestinal mucosal barrier through its role in preserving the integrity of tight junctions within the intestines. Also, it is important to note that there is a positive correlation between the severity of inflammatory bowel disease (IBD) and colorectal cancer (CRC), as well as chemically-induced colitis in mice, and lower levels of arabinose in the bloodstream. In two mouse models of colitis, caused by dextran sodium sulfate (DSS) or by spontaneous colitis in IL-10-/- mice, damage to the intestinal mucosa was reduced by giving the mice arabinose. When arabinose is administrated to model with colitis, it sets off a chain of events that help keep the lysosomes together and stop cathepsin B from being released. During the progression of intestinal epithelial injury, this process blocks myosin light chain kinase (MLCK) from damaging tight junctions and causing mitochondrial dysfunction. In summary, the results of the study have provided evidence supporting the beneficial effects of arabinose in mitigating the progression of colitis. This is achieved through its ability to avoid dysregulation of the intestinal barrier. Consequently, arabinose may hold promise as a therapeutic supplementation for the management of colitis.


Catalytic subunit of human telomerase reverse transcriptase is an independent predictor of survival in patients undergoing curative resection of hepatic colorectal metastases: a multicenter analysis.
To determine the role of the catalytic subunit of human telomerase reverse transcriptase (hTERT) in predicting survival after resection of hepatic colorectal metastases (CRM). Two hundred one patients who underwent curative resection of hepatic CRM between 1990 and 2000 were identified from a multicenter database. The CRM were analyzed for hTERT nucleolar expression by standard immunohistochemical techniques. hTERT expression and known clinicopathologic factors of survival were examined. With a median follow-up of 80 months, 152 patients (75.6%) had died; the 5-year overall survival was 30.7%. On univariate analysis, number of metastases greater than two (P = .0005), extrahepatic disease (P = .0054), disease-free interval less than 12 months (P = .006), carcinoembryonic antigen level greater than 200 ng/mL (P = .0071), and positive hTERT nucleolar staining (P < .0001) were associated with decreased survival. On multivariate analysis, three factors independently predicted survival: number of metastases (relative risk [RR] = 1.74; P = .0011); disease-free interval (RR = 1.70; P = .0035); and positive hTERT nucleolar staining (RR = 2.03; P < .0001). Patients with none or one of these factors had a 5-year survival rate of 48%, whereas those with two or three of these factors had a 5-year survival of 15% (P < .0001). hTERT nucleolar expression is associated with worse survival after resection of hepatic CRM. hTERT expression in conjunction with number of hepatic metastases and disease-free interval may permit more accurate prediction of survival after resection of hepatic CRM.


Recognition of insulin-like-growth-factor-binding proteins in serum and amniotic fluid by an antiserum against a low-molecular-mass insulin-like-growth-factor-inhibitor/binding protein.
An antiserum (R8) raised against a purified specific low-Mr (16,000-18,000) insulin-like-growth-factor (IGF)-inhibitor/binding protein, which is immunologically related to the native growth hormone (GH)-dependent Mr-150,000 IGF-binding protein in serum, has been used to probe a possible additional relationship to the predominant non-GH-dependent IGF-binding protein (Mr approximately 30,000) of human amniotic fluid. Amniotic-fluid fractions and an IGF-inhibitory fraction of serum were analysed by covalent cross-linking, ligand-blotting and immunoblotting techniques. Western blotting of the serum fraction using the R8 antiserum gave five immunoreactive (ir) bands, of which at least three (Mr 38,000, 34,000 and 23,000) possessed IGF-binding activity, as indicated by ligand (125I-IGF-I) blotting. Western blotting of two differently prepared amniotic-fluid fractions, which both showed potent IGF-inhibitory bioactivity, gave several (Mr range 14,500-73,000) ir bands, of which two (Mr 28,000 and 17,000) were most prominent. Ligand-blotting analysis gave a single intensely labelled band at Mr 28,000, consistent with the major presence of the Mr-28,000-30,000 amniotic-fluid IGF-binding protein. Covalent cross-linking of the amniotic-fluid fractions to 125I-IGF-I gave three specifically cross-linked complexes (Mr 36,000, 32,000 and 23,000), which, assuming a 1:1 binding stoichiometry with IGF (Mr 7500), represent binding proteins of Mr 28,500, 24,500 and 15,500 respectively. The Mr-15,500 binding protein, very similar to the Mr-17,000 ir band, in all likelihood represents the IGF-inhibitor protein. Our results indicate that inhibitor-sized binding proteins and IGF-inhibitor bioactivity are present in human amniotic fluid, and that the IGF-inhibitor protein (Mr 16,000) and amniotic-fluid IGF-binding protein (Mr 28,000) are immunologically related. Since the IGF-inhibitor protein is also immunologically and structurally related to the native, GH-dependent, Mr-150,000 binding protein in serum, our data suggest a heretofore-unrecognized immunological similarity between the Mr-150,000 binding protein and the amniotic-fluid binding protein and its serum analogue, the Mr approximately 30,000, non-GH-dependent, binding protein.


Scaling up diabetes prevention in Victoria, Australia: policy development, implementation, and evaluation.
OBJECTIVE The Australian lifestyle intervention program Life! is only the second reported, large-scale diabetes prevention program. This article describes the genesis and the successful establishment of Life! and its key outcomes for participants and implementation. RESEARCH DESIGN AND METHODS Life!, a behavior-change intervention, comprises six group sessions over 8 months. The Victorian Department of Health funded Diabetes Australia-Victoria to implement the program. Experience of the Greater Green Triangle diabetes prevention implementation trial was used for intervention design, workforce development, training, and infrastructure. Clinical and anthropometric data from participants, used for program evaluation, were recorded on a central database. RESULTS Life! has a statewide workforce of 302 trained facilitators within 137 organizations. Over 29,000 Victorians showed interest in Life!, and 15,000 individuals have been referred to the program. In total, 8,412 participants commenced a Life! program between October 2007 and June 2011, and 37% of the original participants completed the 8-month program. Participants completing sessions 1 to 5 lost an average of 1.4 kg weight (P < 0.001) and waist circumference of 2.5 cm (P < 0.001). Those completing six sessions lost an average of 2.4 kg weight (P < 0.001) and waist circumference of 3.8 cm (P < 0.001). The weight loss of 2.4 kg represents 2.7% of participants' starting body weight. CONCLUSIONS The impact of Life! is attributable to applying available evidence for the system's design of the intervention and collaboration between policy makers, implementers, and evaluators using the principles of continuous quality improvement to support successful, large-scale recruitment and implementation.


Antithrombotic therapy in patients with prosthetic heart valves.
Patients with mechanical valve prostheses require a lifelong anticoagulant treatment. The combined use of Warfarin and low-dose aspirin appears to reduce the risk of valve thrombosis and systemic embolism at a low risk of bleeding. The management of women with prosthetic heart valves during pregnancy poses a particular challenge, as there are no available controlled clinical trials to provide guidelines for effective antithrombotic therapy. Oral anticoagulants, such as Warfarin, cause foetal embryopathy; unfractionated heparin and low-molecular-weight heparin have been reported to be ineffective in preventing thromboembolic complications. This article discusses the available data and the most recent guidelines in the antithrombotic management of patients with prosthetic valves, and antithrombotic therapy in various clinical situations such as pregnant women with prosthetic heart valves, and patients with prosthetic heart valves undergoing noncardiac surgery.


Noninvasive Oxygenation Strategies in Immunocompromised Patients With Acute Hypoxemic Respiratory Failure: A Pairwise and Network Meta-Analysis of Randomized Controlled Trials.
Acute hypoxemic respiratory failure (AHRF) is a leading cause of intensive care unit (ICU) admission among immunocompromised patients. Invasive mechanical ventilation is associated with increased morbidity and mortality. To evaluate the efficacy of various oxygenation strategies including noninvasive ventilation (NIV), high-flow nasal cannula (HFNC), and conventional oxygen therapy in immunocompromised patients with AHRF. Electronic databases including PubMed, Embase, and the Cochrane Library were reviewed from inception to December 2018. We included all randomized controlled trials (RCTs) comparing different modalities of initial oxygenation strategies in immunocompromised patients with AHRF. Our primary outcome was the need for intubation and invasive mechanical ventilation while secondary outcomes were ICU acquired infections and short- and long-term mortality. Data were extracted separately and independently by 2 reviewers. We performed a Bayesian network meta-analysis to calculate odds ratio (OR) and Bayesian 95% credible intervals (CrIs). Nine RCTs were included (1570 patients, mean age 61.1 ± 13.8 years with 64% male). Noninvasive ventilation was associated with a significantly reduced intubation rate compared with standard oxygen therapy (OR: 0.53; 95% CrI: 0.26-0.91). There were no significant reductions of intubation between NIV versus HFNC (OR: 0.83; 95% CrI: 0.35-2.11) or HFNC versus standard oxygen therapy (OR: 0.65; 95% CrI: 0.26-1.24). There were no significant differences between all groups regarding short-term (28-day or ICU) mortality or long-term (90-day or hospital) mortality or ICU-acquired infections (P > 0.05). Among immunocompromised patients with AHRF, NIV was associated with a significant reduction of intubation compared with standard oxygen therapy. There were no significant differences among all oxygenation strategies regarding mortality and ICU-acquired infections.


Mechanism of fusidic acid inhibition of RRF- and EF-G-dependent splitting of the bacterial post-termination ribosome.
The antibiotic drug fusidic acid (FA) is commonly used in the clinic against gram-positive bacterial infections. FA targets ribosome-bound elongation factor G (EF-G), a translational GTPase that accelerates both messenger RNA (mRNA) translocation and ribosome recycling. How FA inhibits translocation was recently clarified, but FA inhibition of ribosome recycling by EF-G and ribosome recycling factor (RRF) has remained obscure. Here we use fast kinetics techniques to estimate mean times of ribosome splitting and the stoichiometry of GTP hydrolysis by EF-G at varying concentrations of FA, EF-G and RRF. These mean times together with previous data on uninhibited ribosome recycling were used to clarify the mechanism of FA inhibition of ribosome splitting. The biochemical data on FA inhibition of translocation and recycling were used to model the growth inhibitory effect of FA on bacterial populations. We conclude that FA inhibition of translocation provides the dominant cause of bacterial growth reduction, but that FA inhibition of ribosome recycling may contribute significantly to FA-induced expression of short regulatory open reading frames, like those involved in FA resistance.


A comparison of ocular trauma scores in a pediatric population.
Pediatric ocular trauma represents a major concern for ophthalmologists. Delays in presentation, incomplete exams, inaccurate visual acuity (VA) results, and amblyopia can limit accurately predicting final visual outcomes in pediatric eye trauma. We performed a retrospective clinical study to describe the demographics and causes of eye trauma. We also compared 2 ocular trauma scoring systems, one specifically designed for pediatric trauma, to classify injuries and determine which better predicted VA outcomes. A retrospective chart review of 3 years of pediatric globe trauma was performed. Analysis was focused on mechanisms of injury and VA outcomes. Complex factors that may worsen outcomes were recorded. Ocular trauma score (OTS) and pediatric ocular trauma score (POTS) were used to assign Groups 1-5 to each case. Group 1 was poorest prognosis, Group 5 best. Association between Group and final VA was examined. Accuracy of the two systems was compared. 23 children met eligibility criteria (13 male). Initial VA averaged 20/200 (range no light perception (NLP)-20/20). Final VA was 20/150 (range no light perception (NLP)-20/20). Objects of injury were sharp metallic household objects (7), miscellaneous (4), toys (3), BB pellets (2), stick/wood (2), pencil/pen (1).


Induction of antisporozoite antibodies by biting of transgenic Anopheles stephensi delivering malarial antigen via blood feeding.
We produced a transgenic mosquito expressing a rodent malaria vaccine candidate antigen in the salivary gland. Three tandemly repeated amino acid units from the repeat region of circumsporozoite protein of Plasmodium berghei (PbCS3R) fused to red fluorescent protein (monomeric DsRed) was chosen as a vaccine candidate antigen. Immunoblot and fluorescence microscopic analyses showed the transgene expression in the female salivary gland. The transgene product was released from the proboscis as a component of saliva. The monomeric DsRed-fusion expression system could be suitable for transgene secretion in the saliva of female mosquitoes. Mice repeatedly bitten by transgenic mosquitoes raised antibodies against P. berghei sporozoites, and the sera had protective ability against sporozoite invasion of human hepatoma HepG2 cells. These results suggest that transgene products are immunogenically active in saliva, and induce the antibodies to malaria parasite. These findings indicate that this technology has the potential for production of a 'flying vaccinator' for rodent malaria parasites.


Tumor-associated B cells in cutaneous primary melanoma and improved clinical outcome.
B cells often infiltrate the microenvironment of human tumors. B cells can both positively and negatively regulate antitumor immune responses. In several human cancers, higher numbers of CD20(+) TAB are associated with a favorable prognosis, whereas in human primary melanomas, this association is contentious. In this study, we determined the association of TAB numbers in cutaneous primary melanoma tissue samples and patients' overall survival. The CD20 immunohistochemistry on archival nonmetastasized and metastasized cutaneous primary melanoma tissues from 2 independent patient cohorts was performed. One cohort was used in class comparison for metastasis, the most important prognostic factor for overall survival, and the other cohort for a subsequent survival analysis. Survival association was further validated with RNA data from a third independent cohort. Whole tissue sections were read automatically via quantitative digital imaging and analysis. Survival data were analyzed by Cox proportional hazard modeling. We discovered that cutaneous primary melanomas without metastasis contain significantly more TAB than primary melanomas that had metastasized. At time of first diagnosis, a higher number of TAB is associated with a significantly better overall survival in patients with cutaneous primary melanomas of >1 mm Breslow depth. Also, higher CD20/CD19 tumor mRNA levels are correlated with a significantly better overall survival. Thus, our data support TAB numbers as a prognostic biomarker in cutaneous primary melanoma patients with a tumor of >1 mm Breslow depth. For a survey in larger studies, whole tissue section analysis seems to be key to accurate assessment of TAB numbers.


Five year follow up of vertically HIV infected children in a randomised double blind controlled trial of immediate versus deferred zidovudine: the PENTA 1 trial.
A total of 195 children were randomised to zidovudine (immediate) or matching placebo (deferred) in a multicentre double blind trial in vertically HIV infected children with early disease (the PENTA 1 trial). Median follow up in the blinded phase was 1.9 years. Thereafter, individual children were unblinded following the results of adult trials showing a benefit of combination antiretroviral therapy (ART) over monotherapy, but follow up continued and is reported here until December 1998 (total follow up 4.6 years). Median time to starting ART in the deferred group was 2.7 years; 19% of deferred children had not started ART by 1999. Throughout follow up, the percentage of time spent on no ART, monotherapy, dual, and triple ART was 21%, 44%, 29%, and 6% respectively for immediate and 62%, 12%, 18%, and 8% for deferred groups. During the blinded phase eight (7.8%) immediate and 12 (13.3%) deferred children developed AIDS or died (log rank p = 0.24); overall 21 immediate and 20 deferred children progressed. In an analysis including all children regardless of original allocation, the risk of progression to AIDS or death, adjusting for age and time since trial entry was significantly lower during 1997-98 (2.4 per 100 child years) than during 1992-96 (6.6 per 100 child years), most likely a result of increased use of combination ART.


[Electronic links between hospitals or clinics and pharmacies: structure and operation of WAKASHIO pharmacotherapeusis network].
We developed the WAKASHIO Pharmacotherapeusis Network system. This system electronically links physicians' offices with pharmacies to share clinical records and offers the means for real time bi-directional information input. The system is equipped with individual signature (handwriting) recognition protocols to ensure strict enforcement of security and privacy. The network enables front-line pharmacists to access to pertinent clinical records. We performed a series of tests (a "shakedown cruise") of the system and examined the role of the pharmacist as a counselor for patient compliance with prescribed therapeutic regimens. The results indicated the following: 1) This system provides an unequivocal means of communication between physicians and pharmacists. 2) This system is useful for judicious resolution of potential problems arising from separation of the domains of prescriber and dispenser. 3) A noteworthy finding was that community pharmacists devote substantial time/effort to counseling patients concerning their pharmacotherapeutic regimens. 4) Over 80% of patients responded with statements such as "Now I understand my medicines better," and "I am free of anxiety over my medication now." Thus the system provides a powerful tool to promote patient compliance based on pharmacological knowledge. Our future plans for the system include: 1) implementation of an inquiry/response protocol to enhance risk management; 2) online prescription issuance; and 3) expansion of the database used for patient counseling and improvement of the counseling method. Finally, physician-pharmacist collaboration through the system will contribute to a clear redefinition of their respective roles in community medical care services.


The UCSF Academy of Medical Educators.
The Academy of Medical Educators at the University of California, San Francisco (UCSF), was established in 2000 to (1) foster excellence in teaching, (2) support teachers of medicine, and (3) promote curricular innovation. A membership organization, it recognizes five categories of educational activity: direct teaching, curriculum development and assessment of learner performance, advising and mentoring, educational administration and leadership, and educational research. Excellent medical student teaching and outstanding accomplishment in one or more areas of educational activity qualify a teacher for membership. Candidates prepare a portfolio that is reviewed internally and by national experts in medical education. Currently 37 faculty members, 3% of the entire school of medicine faculty, belong to the academy. The academy's innovations funding program disburses one-year grants to support curricular development and comparisons of pedagogical approaches; through this mechanism, the academy has funded 20 projects at a total cost of $442,300. Three fourths of expended funds support faculty release time. Faculty development efforts include promotion of the use of an educator's portfolio and the establishment of a mentoring program for junior faculty members built around observation of teaching. The Academy of Medical Educators vigorously supports expanded scholarship in education; the academy-sponsored Education Day is an opportunity for educators to present their work locally. Recipients of innovations-funding program grants are expected to present their work in an appropriate national forum and are assisted in doing this through quarterly scholarship clinics. The Academy of Medical Educators has been well received at UCSF and is enhancing the status of medical education and teachers.


Tuberculosis preventive therapy for people living with HIV: A systematic review and network meta-analysis.
Tuberculosis (TB) preventive therapy (TPT) is an essential component of care for people living with HIV (PLHIV). We compared efficacy, safety, completion, and drug-resistant TB risk for currently recommended TPT regimens through a systematic review and network meta-analysis (NMA) of randomized trials. We searched MEDLINE, Embase, and the Cochrane Library from inception through June 9, 2020 for randomized controlled trials (RCTs) comparing 2 or more TPT regimens (or placebo/no treatment) in PLHIV. Two independent reviewers evaluated eligibility, extracted data, and assessed the risk of bias. We grouped TPT strategies as follows: placebo/no treatment, 6 to 12 months of isoniazid, 24 to 72 months of isoniazid, and rifamycin-containing regimens. A frequentist NMA (using graph theory) was carried out for the outcomes of development of TB disease, all-cause mortality, and grade 3 or worse hepatotoxicity. For other outcomes, graphical descriptions or traditional pairwise meta-analyses were carried out as appropriate. The potential role of confounding variables for TB disease and all-cause mortality was assessed through stratified analyses. A total of 6,466 unique studies were screened, and 157 full texts were assessed for eligibility. Of these, 20 studies (reporting 16 randomized trials) were included. The median sample size was 616 (interquartile range [IQR], 317 to 1,892). Eight were conducted in Africa, 3 in Europe, 3 in the Americas, and 2 included sites in multiple continents. According to the NMA, 6 to 12 months of isoniazid were no more efficacious in preventing microbiologically confirmed TB than rifamycin-containing regimens (incidence rate ratio [IRR] 1.0, 95% CI 0.8 to 1.4, p = 0.8); however, 6 to 12 months of isoniazid were associated with a higher incidence of all-cause mortality (IRR 1.6, 95% CI 1.2 to 2.0, p = 0.02) and a higher risk of grade 3 or higher hepatotoxicity (risk difference [RD] 8.9, 95% CI 2.8 to 14.9, p = 0.004). Finally, shorter regimens were associated with higher completion rates relative to longer regimens, and we did not find statistically significant differences in the risk of drug-resistant TB between regimens. Study limitations include potential confounding due to differences in posttreatment follow-up time and TB incidence in the study setting on the estimates of incidence of TB or all-cause mortality, as well as an underrepresentation of pregnant women and children. Rifamycin-containing regimens appear safer and at least as effective as isoniazid regimens in preventing TB and death and should be considered part of routine care in PLHIV. Knowledge gaps remain as to which specific rifamycin-containing regimen provides the optimal balance of efficacy, completion, and safety.


Improved myoelectric prosthesis control using targeted reinnervation surgery: a case series.
Targeted reinnervation is a surgical technique developed to increase the number of myoelectric input sites available to control an upper-limb prosthesis. Because signals from the nerves related to specific movements are used to control those missing degrees-of-freedom, the control of a prosthesis using this procedure is more physiologically appropriate compared to conventional control. This procedure has successfully been performed on three people with a shoulder disarticulation level amputation and three people with a transhumeral level amputation. Performance on timed tests, including the box-and-blocks test and clothespin test, has increased two to six times. Options for new control strategies are discussed.


Blood mononuclear cell nitric oxide production and plasma cytokine levels in healthy gabonese children with prior mild or severe malaria.
Plasmodium falciparum malaria is an important cause of morbidity and mortality in children. Factors that determine the development of mild versus severe malaria are not fully understood. Since host-derived nitric oxide (NO) has antiplasmodial properties, we measured NO production and NO synthase (NOS) activity in peripheral blood mononuclear cells (PBMC) from healthy Gabonese children with a history of prior mild malaria (PMM) or prior severe malaria (PSM) caused by P. falciparum. The PMM group had significantly higher levels of NOS activity in freshly isolated PBMC and higher NO production and NOS activity in cultured PBMC. The investigation of NO-modulating cytokines (e.g., interleukin 12, gamma interferon, tumor necrosis factor alpha [TNF-alpha], and transforming growth factor beta1) as an explanation for differing levels of NOS activity revealed that plasma levels of TNF-alpha were significantly higher in the PSM group. Our results suggest that NOS/ NO and TNF-alpha are markers for prior disease severity and important determinants of resistance to malaria.


Sedentary lifestyle of university students is detrimental to the thoracic spine in men and to the lumbar spine in women.
Sitting for long periods of time and lack of physical activity in young adults can cause postural deterioration leading to rapid onset of fatigue and increase the risk of back pain. We were interested in whether there are gender differences in spinal curvature among university students with a predominantly sedentary lifestyle. 20 sedentary female (age 20 ± 0.73 years) and 39 sedentary male university students (age 20 ± 1.08 years) participated in this study. Their thoracic and lumbar curvatures were assessed while standing and sitting using a Spinal Mouse. In standing, 80.0% of the females and 69.2% of the males had a neutral position of the thoracic spine (33.25° and 35.33°, respectively). However, more males, 30.8%, than females, 10.0%, had hyperkyphosis (54.27° and 47.0°, respectively). Hypokyphosis was found in 10.0% of the females (18.50°) and none in the males. Similarly, 90.0% of the females and 97.4% of the males had neutral position of the lumbar spine (-33.11° and -29.76°, respectively). Increased hyperlordosis was found in 10.0% of the females and 2.6% of the males (-41.0° and -50.0°, respectively). Hypolordosis was not detected in either females or males. In sitting, on the other hand, 70.0% of the females and only 33.3% of the males had a neutral position of the thoracic spine (30.20° and 30.62°, respectively). Increased hyperkyphosis was found in 46.2% of the males (59.76°) and none of the females. 30.0% of the females and 23.1% of the males had light hypokyphosis (47.50° and 46.67°, respectively). Similarly, 70.0% of the females and only 38.5% of the males had a neutral position of the lumbar spine (7.0° and 6.6°, respectively). 35.9% of the males and only 5.0% of the females had a light hypokyphosis (16.14° and 16.0°, respectively). Slightly increased hyperkyphosis was identified in 25.6% of the males and 25.0% of the females (23.9° and 22.5°, respectively). There are significant gender differences in spinal curvature. While in the thoracic spine it was to the detriment of the males when both standing and sitting, in the lumbar spine it is related to the females only when standing. It is therefore necessary to eliminate these spinal deviations in young adults induced by prolonged sitting during university courses by appropriate recovery modalities.


Astragaloside IV: An Effective Drug for the Treatment of Cardiovascular Diseases.
Cardiovascular disease (CVD), the number one cause of death worldwide, has always been the focus of clinical and scientific research. Due to the high number of deaths each year, it is essential to find alternative therapies that are safe and effective with minimal side effects. Traditional Chinese medicine (TCM) has a long history of significant impact on the treatment of CVDs. The mode of action of natural active ingredients of drugs and the development of new drugs are currently hot topics in research on TCM. Astragalus membranaceus is a commonly used Chinese medicinal herb. Previous studies have shown that Astragalus membranaceus has anti-tumor properties and can regulate metabolism, enhance immunity, and strengthen the heart. Astragaloside IV (AS-IV) is the active ingredient of Astragalus membranaceus, which has a prominent role in cardiovascular diseases. AS-IV can protect against ischemic and hypoxic myocardial cell injury, inhibit myocardial hypertrophy and myocardial fibrosis, enhance myocardial contractility, improve diastolic dysfunction, alleviate vascular endothelial dysfunction, and promote angiogenesis. It can also regulate blood glucose and blood lipid levels and reduce the risk of cardiovascular diseases. In this paper, the mechanism of AS-IV intervention in cardiovascular diseases in recent years is reviewed in order to provide a reference for future research and new drug development.