Strategies for enrollment of African Americans into cancer genetic studies.
The enrollment of ethnically diverse populations in genetic and genomic research is vital to the parity of benefits resulting from research with biological specimens. Herein, we discuss strategies that may effectively improve the recruitment of African Americans into genetics studies. Specifically, we show that engaging physicians, genetic counselors, and community members is essential to enrolling participants into genetic studies. We demonstrate the impact of utilizing African American genetic counselors on study enrollment rates and implementing a two-page consent form that improved on a lengthy and inefficient consenting process. Lastly, we provided participants with the option of donating saliva instead of blood for study purposes. Descriptive statistics were used. Using the aforementioned strategies, recruitment goals for the Genetic Basis of Breast Cancer Subtype Study at Howard University (HU) were met. Our overall results yielded 182 participants in 18 months. Recruitment strategies that involve the engagement of physicians, genetic counselors, and community members may help researchers increase the enrollment of ethnically diverse and hard-to-reach participants into genetic studies.


Targeted clearance of mitochondria by an autophagy-tethering compound (ATTEC) and its potential therapeutic effects.
Increased mitochondrial damage plays a critical role in many neurodegeneration-related diseases such as Parkinson's disease (PD) and Down syndrome (DS). Thus, enhancement of mitochondrial degradation by small molecule compounds may provide promising new strategies to tackle these diseases. Here, we explored the strategy to induce clearance of mitochondria by targeting them to the autophagy machinery by autophagy-tethering compounds (ATTECs). We provided the proof-of-concept evidence demonstrating that the bifunctional compound (mT1) binding to both the outer mitochondrial membrane protein TSPO and the autophagosome protein LC3B simultaneously may enhance the engulfment of damaged mitochondria by autophagosomes and subsequent autophagic degradation of them. In addition, preliminary experiments suggest that mT1 attenuated disease-relevant phenotypes in both a PD cellular model and a DS organoid model. Taken together, we demonstrate the possibility of degrading mitochondria by bifunctional ATTECs, which confirms the capability of degrading organelles by ATTECs and provides potential new strategies in the intervention of mitochondria-related disorders.


Pseudohypertrophic myopathy in cysticerosis.
A patient with diffuse involvement of the central nervous system and pseudohypertrophic muscular changes induced by cysticerci is described. Electromyographic and pathologic changes are reported for the first time. Electromyographic examination demonstrated numerous short-duration, low-amplitude motor unit potentials in proximal muscles. Biopsy showed swelling of muscle fibers, fiber atrophy with fibrosis, and cellular infiltration separate from inflammatory exudate surrounding numerous cysts.


[Corrigendum] Repression of Smad4 by miR‑205 moderates TGF‑β-induced epithelial‑mesenchymal transition in A549 cell lines.
Following the publication of this article, an interested reader drew to the authors' attention that, in Fig. 6B on p. 706, various of the data panels appeared to show overlapping data. After having carefully re‑examined the manuscript, raw data and laboratory records, the authors were able to identify the correct data for the figure concerned. Essentially, some of the data panels in Fig. 6 had been erroneously selected from photographs taken of the same data, but with different fields of view. In addition, the authors repeated some of the contentious experiments and obtained similar results, thereby corroborating the results and conclusions reported in this study. Therefore, the errors made with the assembly of Fig. 6 did not have an adverse bearing on the overall conclusions reported in the study. A revised version of Fig. 6, presenting the correct data for Fig. 6B, is shown on the next page. The authors are grateful to the Editor of International Journal of Oncology for allowing them the opportunity to publish this Corrigendum, and all of the authors agree to the publication of this Corrigendum. The authors sincerely apologize for this mistake, and apologize to the readership of the Journal for any inconvenience caused. [the original article was published in International Journal of Oncology 49: 700‑708, 2016; DOI: 10.3892/ijo.2016.3547].


The distribution of polyphenols in the tea plant (Camellia sinensis L.).
1. Methods for the separation and determination of the polyphenolic components of the tea plant by thin-layer chromatography and colorimetric reactions have been devised. 2. High concentrations of catechins, flavonols and depsides were found to be restricted to the young vegetative and floral shoots, whereas leucoanthocyanins or flavylogens were characteristic of the more bulky axial tissues of the plant. 3. In the young shoots cell growth was correlated with an increasing degree of flavonoid B-ring hydroxylation. 4. Maximal flavylogen concentrations occurred in the outer protective layers of stem and of seed coat. 5. Mature leaves were shown to contain derivatives of the flavones apigenin and luteolin. 6. Developing seedlings showed a steady increase in polyphenol complexity; flavylogens were concentrated at shoot and root apices and accumulated at the stem base. 7. It is postulated that the flavanols (leucoanthocyanins and catechins), because they can co-polymerize, are of use to the plant for protection of wood and bark against infection and decay.


Effect of silymarin on streptozotocin-nicotinamide-induced type 2 diabetic nephropathy in rats.
Diabetic nephropathy is the major cause of end-stage renal disease worldwide. Silymarin is a flavonoid mixture obtained from Silybum marianum. Various preclinical and clinical studies have revealed that it has antidiabetic activity. The objective of this study was to evaluate the effect of silymarin on type 2 diabetic nephropathy in rats. Non-insulin-dependent diabetes mellitus was induced in overnight-fasted male albino Wistar rats by an intramuscular injection of streptozotocin and nicotinamide. Eighteen rats with diabetic nephropathy and 6 rats without induced nephropathy were divided into 4 groups, each containing 6 animals. Group 1 was the normal control and group 2 was the DM control. Groups 3 and 4 were rats with diabetic nephropathy that received 60 mg/kg and 120 mg/kg of silymarin for 60 days. At the end of the study period, the diabetic control group had significantly higher blood glucose, glycosylated hemoglobin, urine volume, serum uric acid, and urine albumin levels when compared to the normal control group. Silymarin-treated groups showed significantly lower levels of blood glucose, glycosylated hemoglobin, urine volume, serum creatinine, serum uric acid, and urine albumin, when compared to the diabetic control group. Histopathological studies reports strongly supported the protective effect of silymarin. These findings suggest that silymarin has protective effects for kidneys affected by type 2 diabetes mellitus. If the safety and efficacy is confirmed in humans, silymarin will be a good medication to prevent nephropathy-induced premature death in diabetic patients.


In vitro synergistic activity of the sulbactam/avibactam combination against extensively drug-resistant Acinetobacter baumannii.
Introduction. The therapeutic options to treat Acinetobacter baumannii infections are very limited.Aim. Our aim was to evaluate the activity of sulbactam combined directly with avibactam or the ampicillin-sulbactam/ceftazidime-avibactam combination against extensively drug-resistant A. baumannii isolates.Methodology. Extensively drug-resistant A. baumannii isolates (n=127) collected at several South American hospitals were studied. Synergy with the sulbactam/avibactam combination was assessed in all isolates using the agar dilution method. Avibactam was used at a fixed concentration of 4 mg l-1. A disc diffusion synergy test was also performed. Synergy by a time-kill experiment was performed in a selected isolate.Results. Synergy with sulbactam/avibactam was demonstrated in 124 isolates and it showed MIC values ≤4 mg l-1. This synergy was not detected in the three New Delhi metallo-β-lactamase-harbouring isolates. Similar results were observed with the disc diffusion synergy test of ampicillin-sulbactam/ceftazidime-avibactam. In the time-kill experiments, sulbactam/avibactam showed a rapid synergistic and bactericidal activity in ampicillin-sulbactam-resistant isolates.Conclusions. This study demonstrated that the sulbactam/avibactam combination displayed synergistic activity against A. baumannii isolates. This synergy was observed when both inhibitors were also used as part of the commercially available combinations: ampicillin-sulbactam and ceftazidime-avibactam.


Molecular characterization and virulence of Beauveria spp. from the pine processionary moth, Thaumetopoea pityocampa (Lepidoptera: Thaumetopoeidae).
The pine processionary moth Thaumetopoea pityocampa (Den. & Schiff.) is one of the most harmful pests to pine species in Mediterranean countries including Turkey. Caterpillars of T. pityocampa are not only significantly harmful to forest trees but also responsible for various allergic reactions in humans and animals. In this study, in order to find a more effective and safe biological control agent against T. pityocampa, we investigated fungal pathogens of T. pityocampa in the Black Sea Region of Turkey and tested their pathogenicity on it. Five different fungi were isolated and identified based on their morphological and molecular characteristics including ITS and partial sequence of EF1-[alpha]. Based on these characteristics, four isolates were identified as Beauveria bassiana cf. Clade C (Rehner and Buckley in Mycologia 97:84-98, 2005) and one isolate was identified as Beauveria bassiana. Among these isolates, B. bassiana KTU-24, B. bassiana cf. Clade C KTU-66 and KTU-67 showed the highest virulence with 100% mortality within 10 days after application. B. bassiana isolate KTU-24 produced the highest mycosis value with %100. Consequently, B. bassiana KTU-24 seems to be good candidate for further investigation as a possible biological control agent against this pest.


[Actual status of laparoscopic cholecystectomy].
Since the first laparoscopic cholecystectomy in 1988, the management of gall-bladder disease has changed importantly. This technique was rapidly popularized in the U.S. as well as in Europe. Multiple studies have proved its feasibility, safeness and great advantages. Analyze usefulness and recent advances of endoscopic surgery in the management of gallbladder disease. We did a review of the recent medical literature to determine the actual status of laparoscopic cholecystectomy. Laparoscopic cholecystectomy is the most common surgical procedure performed in the digestive tract. During the year 2001, 1,100,000 cholecystectomies were done in the U.S., 85% were done laparoscopically. In Mexico cholecystectomy in government hospitals is done laparoscopically in 50% of the cases, while in private hospitals it reaches 90%. There are multiple prospective controlled studies showing superiority of laparoscopic cholecystectomy in times of recovery, costs, return to normal activity, pain, morbidity, esthetics among other advantages. Laparoscopic cholecystectomy is the gold standard for the treatment of the great majority of cases of gallbladder disease, nevertheless in developing countries open cholecystectomy is still done frequently.


Mental disorders in adolescent suicide. DSM-III-R axes I and II diagnoses in suicides among 13- to 19-year-olds in Finland.
The prevalence of mental disorders (DSM-III-R Axes I and II) among adolescent suicide victims (n = 53) was investigated in a nationwide psychological autopsy study in Finland. The data were collected comprehensively through interviews of the victims' relatives and attending health care personnel and from official records. Following independent assessment by two psychiatrists, the DSM-III-R diagnoses were assigned in consensus meetings. A large majority of the victims (94%) suffered from a mental disorder. The most prevalent disorders were depressive disorders (51%) and alcohol abuse or dependence (26%). The prevalence of adjustment disorders (21%) was higher than in most studies from other countries. Personality disorder was diagnosed in 32% of the cases. Comorbidity was found in 51% of the victims. The results indicate a strong relatedness between adolescent suicide and the presence of depression, antisocial behavior, and alcohol abuse.


[Isolation and Characterization of Multipotent Precursor Cells from Murine Adipose Tissue using a Clinically Approved Cell Separation System].
Recent studies underscored the clinical potential of adipose-derived multipotent stem-/precursor cells (ASPCs). One of the main hurdles en route to clinical application was to isolate cells without having to perform expansion cultures outside the OR. A new generation of clinically approved, commercially available cell separation systems claims to provide ASPCs ready for application without further expansion cultures. However, it is unclear if the new systems yield sufficient cells of adequate quality for the use in autologous murine models. The aim of this study was to isolate and characterize adipose-derived precursor cells taken from the inguinal fat pat of wistar rats using InGeneron's clinically approved ARC™-cell separation system. We isolated cells from the inguinal fat pad of 3 male Wistar rats according to the manufacturer's protocol. In order to reduce the influence of the atmospheric oxygen on the multipotent precursor cells, one half of the cell suspension was cultivated under hypoxia (2% O2) simulating physiological conditions for ASPCs. As a control, the other half of the cells were cultivated under normoxia (21% O2). Cell surface markers CD90, CD29, CD45 and CD11b/c were analyzed by FACS, and osteogenic and adipogenic differentiation of the ASPCs was performed. Finally, cellular growth characteristics were assessed by evaluation of the cumulative population doublings and CFU assay, and metabolic activity was evaluated by WST-1 assay. Processing time was 90 (± 12) min. 1 g of adipose tissue yielded approximately 60 000 plastic adhering cells. Both groups showed a high expression of the mesenchymal stem cell markers CD90 and CD29 while they were negative for the leucocyte markers CD45 and CD11b/c. A strong osteogenic differentiation and a sufficient adipogenic differentiation potential was proven for all ASPCs. Under hypoxia, ASPCs showed increased proliferation characteristics and CFU efficiency as well as a significantly increased metabolic activity. This study showed that sufficient multipotent ASPCs of appropriate quality can be isolated from the inguinal fat pad of Wistar rats using the ARC™-cell separation system. As shown in previous studies, cultivation of cells under hypoxic conditions increased their stemness. Our findings will enable future studies that focus on autologous transplantation of ASPCs in a rat model, which most closely resembles a possible clinical application.


The changing epidemiology of meningococcal disease in the United States, 1992-1996.
New meningococcal vaccines are undergoing clinical trials, and changes in the epidemiologic features of meningococcal disease will affect their use. Active laboratory-based, population-based US surveillance for meningococcal disease during 1992-1996 was used to project that 2400 cases of meningococcal disease occurred annually. Incidence was highest in infants; however, 32% of cases occurred in persons >/=30 years of age. Serogroup C caused 35% of cases; serogroup B, 32%; and serogroup Y, 26%. Increasing age (relative risk [RR], 1.01 per year), having an isolate obtained from blood (RR, 4.5), and serogroup C (RR, 1.6) were associated with increased case fatality. Among serogroup B isolates, the most commonly expressed serosubtype was P1.15; 68% of isolates expressed 1 of the 6 most common serosubtypes. Compared with cases occurring in previous years, recent cases are more likely to be caused by serogroup Y and to occur among older age groups. Ongoing surveillance is necessary to determine the stability of serogroup and serosubtype distribution.


Genetic approach to evaluate specificity of small molecule drug candidates inhibiting PLK1 using zebrafish.
During the preclinical drug discovery process it remains a challenge to enable early elimination of candidate molecules that may have non-specific, off-target activities. Here, we use whole zebrafish embryo assays coupled with genetic analysis to address this issue. PLK1 (Polo-like kinase 1) is one of the key regulators that control mitotic entry, spindle assembly, chromosome segregation, and cytokinesis in the cell cycle. Since plk1 expression is abnormally up-regulated in several tumors, it is regarded as a good target for cancer therapy. A number of small-molecule inhibitors targeting PLK1 have been developed as reagents and anticancer drug candidates. It will be interesting to determine if these inhibitors indeed specifically target PLK1 in vivo. Bioinformatics analysis revealed that the zebrafish and human genomes share high homology across all PLK family members. In particular, PLK1 has a nearly identical 3-D structure between zebrafish and human. We selected three published PLK1 inhibitors, LFM-A13, ON01910, and thiazole-carboxamide 10A in our assay. When added at 2-cell stage, all of these inhibitors prevented embryos from dividing and caused cells to fuse into one large cell. When added at the later stage during zygotic mRNA transcription program initiation, embryos survived for 3 days but showed different phenotypes for each compound. Embryos treated with LFM-A13 appeared relatively normal. Embryos treated with ON01910 failed to properly develop trunk and tail regions while the head structure was unaffected. Embryos treated with thiazole-carboxamide 10A had a shorter body axis and deformed head structure. To determine which inhibitor is more selectively targeting PLK1, we inhibited PLK1 activity using anti-sense morpholino. Comparative analysis indicated that thiazole-carboxamide 10A could faithfully phenocopy zebrafish embryos genetically deficient of plk1. These findings demonstrate that these three PLK1 inhibitors, although well established by in vitro studies, have different off-target activities in vivo, and that thiazole-carboxamide 10A appears most specific to PLK1. Our studies suggest that zebrafish should be generally useful as an efficient in vivo model to evaluate specificity of small molecules designed to regulate any conserved target proteins through comparative analysis of genetic phenotypes.


Hispolon induces apoptosis through JNK1/2-mediated activation of a caspase-8, -9, and -3-dependent pathway in acute myeloid leukemia (AML) cells and inhibits AML xenograft tumor growth in vivo.
Hispolon is an active phenolic compound of Phellinus igniarius, a mushroom that was recently shown to have antioxidant and anticancer activities in various solid tumors. Here, the molecular mechanisms by which hispolon exerts anticancer effects in acute myeloid leukemia (AML) cells was investigated. The results showed that hispolon suppressed cell proliferation in the various AML cell lines. Furthermore, hispolon effectively induced apoptosis of HL-60 AML cells through caspases-8, -9, and -3 activations and PARP cleavage. Moreover, treatment of HL-60 cells with hispolon induced sustained activation of JNK1/2, and inhibition of JNK by JNK1/2 inhibitor or JNK1/2-specific siRNA significantly abolished the hispolon-induced activation of the caspase-8/-9/-3. In vivo, hispolon significantly reduced tumor growth in mice with HL-60 tumor xenografts. In hispolon-treated tumors, activation of caspase-3 and a decrease in Ki67-positive cells were observed. Our results indicated that hispolon may have the potential to serve as a therapeutic tool to treat AML.


C-Reactive Protein Is an Important Biomarker for Prognosis Tumor Recurrence and Treatment Response in Adult Solid Tumors: A Systematic Review.
A systematic literature review was done to determine the relationship between elevated CRP and prognosis in people with solid tumors. C-reactive protein (CRP) is a serum acute phase reactant and a well-established inflammatory marker. We also examined the role of CRP to predict treatment response and tumor recurrence. MeSH (Medical Subject Heading) terms were used to search multiple electronic databases (PubMed, EMBASE, Web of Science, SCOPUS, EBM-Cochrane). Two independent reviewers selected research papers. We also included a quality Assessment (QA) score. Reports with QA scores <50% were excluded. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) methodology was utilized for this review (S1 PRISMA Checklist). 271 articles were identified for final review. There were 45% prospective studies and 52% retrospective. 264 had intermediate QA score (≥50% but <80%); Seven were adequate (80% -100%); A high CRP was predictive of prognosis in 90% (245/271) of studies-80% of the 245 studies by multivariate analysis, 20% by univariate analysis. Many (52%) of the articles were about gastrointestinal malignancies (GI) or kidney malignancies. A high CRP was prognostic in 90% (127 of 141) of the reports in those groups of tumors. CRP was also prognostic in most reports in other solid tumors primary sites. A high CRP was associated with higher mortality in 90% of reports in people with solid tumors primary sites. This was particularly notable in GI malignancies and kidney malignancies. In other solid tumors (lung, pancreas, hepatocellular cancer, and bladder) an elevated CRP also predicted prognosis. In addition there is also evidence to support the use of CRP to help decide treatment response and identify tumor recurrence. Better designed large scale studies should be conducted to examine these issues more comprehensively.


Effect of allergic rhinitis on the use and cost of health services by children with asthma.
Allergic rhinitis (AR) is common among children with asthma and exacerbates asthma symptoms. To assess the incremental utilization and cost of asthma-related health services due to concomitant AR among asthmatic children. Asthma-related claims were extracted from the Korean National Health Insurance (NHI) claims database, which covers 97% of the population. Per-capita utilization and costs of asthma-related services were determined from the societal perspective. Of 319,714 children (1-14 years old) with chronic asthma in 2003, 195,026 had concomitant AR (prevalence 610 per 1,000 asthmatic children). Children with AR had 1.14 times more outpatient visits, 1.30 times more emergency department (ED) visits, and 1.49 times more hospitalizations than children without AR. More children with AR used general hospitals (7.17%) than children without AR (3.23%). The ratios of unit pharmaceutical costs per outpatient visit, ED visit, and admission between children with and without AR were 1.27, 1.20, and 1.14. Total annual expenditure combining direct health care, transportation, and caregivers' costs, were $273 and $217 for children with and without AR, respectively. Health service utilization and costs for asthma were greater for asthmatic children with AR. More frequent ED visits and admissions among asthmatic children with AR suggest poorer control and more frequent exacerbations. Higher unit cost of pharmaceuticals during visits, tendency to receive asthma care from a higher-level facility, and greater risk of ED visit or admission all contributed to the additional economic burden of AR.


(Poly)phenols: The Missing Piece in the Puzzle of Inflammation.
Despite researchers' and clinicians' exponential understanding of chronic diseases' complexity, ranging from cancer, diabetes, and neurodegenerative disorders, we still have a lot of unanswered questions on pathobiology mechanisms, wherein inflammation is central [...].


Mapping BOLD Activation by Pharmacologically Evoked Tremor in Swine.
Harmaline-induced tremor is one of the most commonly utilized disease models for essential tremor (ET). However, the underlying neural networks involved in harmaline-induced tremor and the degree to which these are a representative model of the pathophysiologic mechanism of ET are incompletely understood. In this study, we evaluated the functional brain network effects induced by systemic injection of harmaline using pharmacological functional magnetic resonance imaging (ph-fMRI) in the swine model. With harmaline administration, we observed significant activation changes in cerebellum, thalamus, and inferior olivary nucleus (ION). In addition, inter-regional correlations in activity between cerebellum and deep cerebellar nuclei and between cerebellum and thalamus were significantly enhanced. These harmaline-induced effects gradually decreased with repeated administration of drug, replicating the previously demonstrated 'tolerance' effect. This study demonstrates that harmaline-induced tremor is associated with activity changes in brain regions previously implicated in humans with ET. Thus, harmaline-induction of tremor in the swine may be a useful model to explore the neurological effects of novel therapeutic agents and/or neuromodulation techniques for ET.


Molecularly precise self-assembly of theranostic nanoprobes within a single-molecular framework for in vivo tracking of tumor-specific chemotherapy.
Structural heterogeneity and the lack of in vivo real-time tracking of drug release are the utmost barriers for nanocarrier-mediated prodrugs in targeted therapy. Herein, we describe the strategy of molecularly precise self-assembly of monodisperse nanotheranostics for BP n -DCM-S-CPT (n = 0, 5 and 20) with fixed drug loadings (36%, 23% and 16%) and constant release capacities, permitting in vivo real-time targeted therapy. We focus on regulating the hydrophilic fragment length to construct stable, well-defined nanostructured assemblies. Taking the bis-condensed dicyanomethylene-4H-pyran (DCM) derivative as the activatable near-infrared (NIR) fluorophore, it makes full use of two terminal conjunctions: the hydrophobic disulfide-bridged anticancer prodrug camptothecin (CPT) and the hydrophilic oligomer-bridged biotin segment serving as an active targeting unit. From the rational design, only BP20-DCM-S-CPT forms uniform and highly stable self-assemblies (ca. 80 nm, critical micelle concentration = 1.52 μM) with several advantages, such as structural homogeneity, fixed drug loading efficiency, real-time drug release tracking and synergistic targeting (passive, active and activatable ability). More importantly, in vitro and in vivo experiments verify that the surface-grafted biotins of nanoassemblies are directly exposed to receptors on cancer cells, thus markedly facilitating cellular internalization. Notably, through synergistic targeting, BP20-DCM-S-CPT displays excellent tumor-specific drug release performance in HeLa tumor-bearing nude mice, which has significantly enhanced in vivo antitumor activity and nearly eradicates the tumor (IRT = 99.7%) with few side effects. For the first time, the specific molecularly precise self-assembly of BP20-DCM-S-CPT within a single-molecular framework has successfully achieved a single reproducible entity for real-time reporting of drug release and cancer therapeutic efficacy in living animals, providing a new insight into amphiphilic nanotheranostics for clinical translation.


Continuous Positive Airway Pressure Treatment May Improve Optic Nerve Function in Obstructive Sleep Apnea: An Electrophysiological Study.
Obstructive sleep apnea (OSA) is a sleep disorder frequently associated with optic nerve diseases. Moreover, untreated patients with severe OSA may show optic nerve dysfunction as documented by electrophysiological studies using visual evoked potentials (VEP). Because continuous positive airway pressure (CPAP) treatment has proved to restore the physiologic nocturnal breathing, thus preventing nocturnal hypoxemia and reducing inflammation, in this study we tested whether 1-year CPAP treatment may modify VEP responses in patients with severe OSA. VEP were recorded at baseline and after 1 year of CPAP treatment in 20 patients with severe OSA, divided in two groups on the basis of CPAP adherence, and compared to a healthy control group. Patients with good adherence to CPAP therapy (CPAP+; n = 10) showed VEP P100 amplitude significantly higher than patients with poor adherence to CPAP therapy (CPAP-; n = 10). Moreover, the CPAP+ group showed VEP responses similar to those in the control group (n = 26). Considering the mean difference of VEP responses between baseline and follow-up, the CPAP+ group showed a significant increase in VEP P100 amplitude and a significant decrease in VEP P100 latency compared to the CPAP- group. This study documented that CPAP therapy significantly improves VEP in patients with OSA who are adherent to the treatment. We hypothesize that CPAP treatment, minimizing the metabolic, inflammatory and ischemic consequences of OSA, may normalize the altered VEP responses in patients with OSA by restoring and preserving optic nerve function.


Mechanistic studies on the dehydrogenases of methylotrophic bacteria. 2. Kinetic studies on the intramolecular electron transfer in trimethylamine and dimethylamine dehydrogenase.
E.p.r. spectroscopy of the trimethylamine and dimethylamine dehydrogenases of Hyphomicrobium X indicates that the substrate-reduced forms of these enzymes exist in the triplet state, which arise through interaction of a reduced [4Fe-4S] cluster and flavosemiquinone, with e.p.r. signals which differ in detail from those of the trimethylamine dehydrogenase of bacterium W3A1. Under certain conditions the intramolecular electron transfer between the flavoquinol form of 6-S-cysteinyl-FMN and the [4Fe-4S] cluster in all three dehydrogenases was much slower than the preceding reduction of the flavin to the flavoquinol form. Trimethylamine dehydrogenases from both organisms show a time-dependent broadening of the e.p.r. signals centred around g = 2 after mixing with trimethylamine. The broadening of the e.p.r. signals could be correlated with an unexpected dependence of the rate of formation of the triplet state on substrate concentration. A model which accounts in a qualitative manner for the substrate dependence of the formation of the triplet state in the trimethylamine dehydrogenase of Hyphomicrobium X is proposed. The binding of the substrate to the reduced form of the enzyme seems to result in a conformational change of the enzyme to a form in which the rate of intramolecular electron transfer is decreased. This finding may be correlated with the observation of hyperbolic substrate inhibition for both trimethylamine dehydrogenases. The results indicate the transfer of an electron to the [4Fe-4S] cluster to be an obligatory step in catalysis and suggest that the transfer of electrons from these enzymes to electron acceptors is mediated solely through the [4Fe-4S] cluster.


Faculty Development- Is Some Better Than None?
This article was migrated. The article was marked as recommended. Introduction: With the advent of competency-based medical education there is an emphasis on formative workplace based assessment. The quality of these assessments is a concern for medical educators and their trainees. Faculty development (FD) strategies to improve assessment quality have resulted in some success. However, few faculty participate, and those who do are likely more motivated to improve, making it difficult to demonstrate a conclusive benefit. To address these weaknesses, we designed a FD initiative to improve the quality of completed in-training evaluation reports (ITERs). All faculty within a division participated. We hypothesized that clinical supervisors would improve their ITER quality based on feedback, regardless of their own motivation to do so, with a simple, point-in-time intervention. Methods: In this three-phase study, two independent raters used the Completed Clinical Evaluation Report Rating (CCERR) to assess the quality of ITERs completed by all faculty in the Division of Orthopedic Surgery at the University of Ottawa. In phase one, ITERs from the previous nine months were evaluated. In phase two, the participants were aware that their ITERs were being evaluated, but they did not receive feedback. In phase three, participants received regular feedback on their performance in the form of their mean CCERR scores. Mean CCERR scores from the different phases of the study were compared. Results: CCERR scores were similar for all three phases (one: 17.56 ± 1.02, two: 17.65 ± 0.96, three: 17.54 ± 0.75, p=0.98). Discussion and Conclusions: There was no evidence in our study that participants' improved their ITER quality despite being aware that they were being evaluated and/or receiving feedback. Potentially, this was related to a lack of motivation. Alternatively, the intensity and/or frequency of the feedback may have been inadequate to create change. These results raise concerns that some faculty development may not necessarily be better than none.


Purification, characterization, and molecular cloning of the gene of a seed-specific antimicrobial protein from pokeweed.
A small cysteine-rich protein with antimicrobial activity was isolated from pokeweed (Phytolacca americana) seeds and purified to homogeneity. The protein inhibits the growth of several filamentous fungi and gram-positive bacteria. The protein was highly basic, with a pI higher than 10. The entire amino acid sequence of the protein was determined to be homologous to antimicrobial protein (AMP) from Mirabilis jalapa. The cDNA encoding the P. americana AMP (Pa-AMP-1) and chromosomal DNA containing the gene were cloned and sequenced. The deduced amino acid sequence shows the presence of a signal peptide at the amino terminus, suggesting that the protein is synthesized as a preprotein and secreted outside the cells. The chromosomal gene shows the presence of an intron located within the region encoding the signal peptide. Southern hybridization showed that there was small gene family encoding Pa-AMP. Immunoblotting showed that Pa-AMP-1 was only present in seeds, and was absent in roots, leaves, and stems. The Pa-AMP-1 protein was secreted into the environment of the seeds during germination, and may create an inhibitory zone against soil-borne microorganisms. The disulfide bridges of Pa-AMP-1 were identified. The three-dimensional modeling of Pa-AMP-1 indicates that the protein has a small cystine-knot folding, a positive patch, and a hydrophobic patch.


IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells: evidence that IDH1 may regulate lipogenesis in hepatic cells.
The mRNA level for cytosolic NADP-dependent isocitrate dehydrogenase (IDH1) increases 2.3-fold, and enzyme activity of NADP-isocitrate dehydrogenase (IDH) 63%, in sterol-deprived HepG2 cells. The mRNA levels of the NADP- and NAD-dependent mitochondrial enzymes show limited or lack of regulation under the same conditions. Nucleotide sequences that are required, and sufficient, for the sterol regulation of transcription are located within a 67 bp region of an IDH1-secreted alkaline phosphatase promoter-reporter gene. The IDH1 promoter is fully activated by the expression of SREBP-1a in the cells and, to a lesser degree, by that of SREBP-2. A 5'-end truncation of 23 bp containing a CAAT and a GC-Box results in 6.5% residual activity. The promoter region involved in the activation by the sterol regulatory element binding proteins (SREBPs) is located at nucleotides -44 to -25. Mutagenesis analysis identified within this region the IDH1-SRE sequence element GTGGGCTGAG, which binds the SREBPs. Similar to the promoter activation, electrophoretic mobility shifts of probes containing the IDH1-SRE element exhibit preferential binding to SREBP-1a, as compared with SREBP-2. These results indicate that IDH1 activity is coordinately regulated with the cholesterol and fatty acid biosynthetic pathways and suggest that it is the source for the cytosolic NADPH required by these pathways.


Defining core gonorrhea transmission utilizing spatial data.
Spatial distribution of repeat and singly occurring gonorrhea in Baltimore, Maryland, was examined to identify clusters of core transmitters. Gonorrhea reported between 2001 and 2002 was geocoded and mapped. Those with more than one gonorrhea infection separated by more than 14 days during the 2-year period were considered repeaters. Other cases were treated as isolated events. Six definitions of core transmission were examined by census tracts with the highest quintiles of 1) cases for 2001, 2) cases for 2002, 3) rates for 2001, 4) rates for 2002, 5) counts of repeaters over the 2-year period, and 6) proportion of total cases that were repeaters. Of the 6,108 gonorrhea cases analyzed, 9% were repeaters. Repeaters were more likely to be female and younger. Core areas identified by definitions based on overall disease burden agreed well with each other but had poor agreement with definitions based upon repeat infections. Repeaters clustered to a greater extent at smaller distances than did singly occurring gonorrhea cases. Repeat gonorrhea infections are prevalent in Baltimore and likely represent behavior consistent with core transmission. Census tracts of core transmission defined by geographic distribution of repeat infections may indicate foci of highest risk sexual behaviors and high transmission.


Evinacumab for Homozygous Familial Hypercholesterolemia.
Homozygous familial hypercholesterolemia is characterized by premature cardiovascular disease caused by markedly elevated levels of low-density lipoprotein (LDL) cholesterol. This disorder is associated with genetic variants that result in virtually absent (null-null) or impaired (non-null) LDL-receptor activity. Loss-of-function variants in the gene encoding angiopoietin-like 3 (ANGPTL3) are associated with hypolipidemia and protection against atherosclerotic cardiovascular disease. Evinacumab, a monoclonal antibody against ANGPTL3, has shown potential benefit in patients with homozygous familial hypercholesterolemia. In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned in a 2:1 ratio 65 patients with homozygous familial hypercholesterolemia who were receiving stable lipid-lowering therapy to receive an intravenous infusion of evinacumab (at a dose of 15 mg per kilogram of body weight) every 4 weeks or placebo. The primary outcome was the percent change from baseline in the LDL cholesterol level at week 24. The mean baseline LDL cholesterol level in the two groups was 255.1 mg per deciliter, despite the receipt of maximum doses of background lipid-lowering therapy. At week 24, patients in the evinacumab group had a relative reduction from baseline in the LDL cholesterol level of 47.1%, as compared with an increase of 1.9% in the placebo group, for a between-group least-squares mean difference of -49.0 percentage points (95% confidence interval [CI], -65.0 to -33.1; P<0.001); the between-group least-squares mean absolute difference in the LDL cholesterol level was -132.1 mg per deciliter (95% CI, -175.3 to -88.9; P<0.001). The LDL cholesterol level was lower in the evinacumab group than in the placebo group in patients with null-null variants (-43.4% vs. +16.2%) and in those with non-null variants (-49.1% vs. -3.8%). Adverse events were similar in the two groups. In patients with homozygous familial hypercholesterolemia receiving maximum doses of lipid-lowering therapy, the reduction from baseline in the LDL cholesterol level in the evinacumab group, as compared with the small increase in the placebo group, resulted in a between-group difference of 49.0 percentage points at 24 weeks. (Funded by Regeneron Pharmaceuticals; ELIPSE HoFH ClinicalTrials.gov number, NCT03399786.).


The ventral hippocampus and nucleus accumbens as neural substrates for cocaine contextual memory reconsolidation.
Drug craving triggered by cues that were once associated with drug intoxication is a major contributor to continued drug-seeking behaviors. Addictive drugs engage molecular pathways of associative learning and memory. Reactivated memories are vulnerable to disruption by interference with the process of reconsolidation, hence targeting reconsolidation could be a strategy to reduce cue-induced drug craving and relapse. Here we examined the circuitry of cocaine contextual memory reconsolidation and explored neuroplasticity following memory reactivation. Mice underwent chemogenetic inhibition of either nucleus accumbens (NA) neurons or the glutamatergic projection neurons from the ventral hippocampus (vHPC) to NA using inhibitory designer receptors exclusively activated by designer drugs (iDREADD). Mice underwent cocaine conditioned place preference followed by reactivation of the cocaine contextual memory. Clozapine-N-oxide (CNO) was administered after memory reactivation to inhibit either NA neurons or the accumbens-projecting vHPC neurons during the reconsolidation period. When retested 3 days later, a significant reduction in the previously established preference for the cocaine context was found in both conditions. FosTRAP2-Ai14 mice were used to identify neurons activated by cocaine memory recall and to evaluate plasticity in NA medium spiny neurons (MSNs) and vHPC pyramidal neurons upon recall of cocaine memories. Results indicate a significant increase in dendritic spine density in NA MSNs activated by cocaine memory recall, particularly of the thin spine type. Sholl analysis indicated longer dendritic length and more branching of NA MSNs after cocaine memory recall than without memory reactivation. vHPC neurons showed increased spine density, with the most robust change in stubby spines. These results implicate a circuit involving glutamatergic projections from the vHPC onto NA neurons which is necessary for the reconsolidation of cocaine memories. Interruption of cocaine memory reconsolidation reduced drug-seeking behavior.


Diluting power of thick limbs of Henle. I. Peritubular hypertonicity blocks basolateral Cl- channels.
This paper provides the results of experiments intended to assess the mechanism responsible for the suppression of net salt absorption and the attendant spontaneous voltage (Ve, mV) that occurs when isolated thick ascending limbs of Henle (TAL) are exposed to a hypertonic environment. In isolated mouse medullary (MTAL) and cortical (CTAL) segments, as well as in rabbit MTAL segments, increases in peritubular osmolality with urea produced a graded suppression of Ve. This effect was evaluated in further detail in isolated mouse MTAL segments, where 600 mM peritubular urea produced a reversible reduction in Ve and a reversible reduction in the transcellular electrical conductance (Gc; mS.cm-2). There was no detectable effect on the paracellular conductance (Gs; mS.cm-2). Simultaneously, 600 mM peritubular urea also produced hyperpolarization of the voltage across basolateral membranes (mV). Moreover, 600 mM peritubular urea produced virtually the same magnitude reduction in Gc either in the absence or presence of 10(-4) M luminal furosemide. Thus we conclude that peritubular urea hypertonicity directly suppresses the Cl- conductance of basolateral membranes (mS.cm-2).


An Instrument for High-throughput Testing of Heart Tissue In Vitro.
Cardiac trabeculae are small samples of heart muscle tissue that can be dissected and studied in vitro to better understand the underlying physiology of cardiac muscle. However, instruments for such experimentation often (1) involve delicate mounting of the muscle, (2) constrain investigations to one muscle at a time and, thus, (3) cannot retain the muscle in the same experimental configuration for post-experimental assessment including imaging analysis. Here, we present a novel device that allows trabeculae to be secured by a visible-light photo-initiated hydrogel, manipulated via a force sensor, and stimulated while being imaged. We use our robust, accurate image registration techniques to measure cantilever and gel deformation during trabecula contraction and thereby provide a measure of trabecula force production during twitches. A variety of experiments can then be conducted, with the potential for the trabecula to be fixed in place using hydrogel for further post-experiment analysis, as well as longitudinal evaluation. The device has multiple wells making it amenable to high-throughput testing.Clinical Relevance- These methods may allow longitudinal and high-throughput studies of cardiac tissue samples in health and disease.


Implementation evaluation of a medical student-led intervention to enhance students' engagement with research: Findings and lessons learned.
Medical colleges globally have student organizations that serve to enable students' involvement in research. However, details of their approach and activities are seldom published to serve as learning for student organizations in other settings. The Student Research Forum (SRF), a student organization based at a private medical school in Pakistan aims to facilitate students in acquiring research skills. Following the observation of a downward trajectory of student initiative and interest, SRF leadership restructured the organization and improve its impact. This study describes the development and implementation evaluation of the interventions. The operational framework was revised using the Theory of Change by the core group. Major interventions included enhanced social media and outreach coordination, research workshops, journal clubs, and mentorship to increase research output, mentorship opportunities, and knowledge of medical research; ultimately improving quality in research. The outcomes generated over the course of the study's duration from July 2019 to September 2021 were analyzed using the process metrics of reach, adoption, and efficacy. As a result of the interventions, SRF expanded its reach by conducting a total of 41 events during the duration of the study, facilitated by social media growth on each of SRF's online platforms, with a 300% increase in followers on Facebook, and a nationwide network of 91 student ambassadors. An annual workshop series taught research skills to more than 3800 participants. Students leading their own events, SRF featuring international speakers, and the abstracts submitted to SRF's annual conference, along with the conference's reach of 10,000 students, are seen as improvements in the ToC-informed interventions' adoption. The efficacy of the interventions manifested as the REACH program allocated 56 research projects to vetted applicants. The applied interventions have accelerated SRF's progress towards achieving its long-term outcome of increased quality in research as translated by increased research output quantity, mentorship, and knowledge of medical research. Further evaluation is required to assess the success of the ToC. As SRF continues to grow, a continued analysis of the implementation outcomes is imperative to gauge its effectiveness.


Exploring a Bayesian hierarchical approach for developing safety performance functions for a mountainous freeway.
While rural freeways generally have lower crash rates, interactions between driver behavior, traffic and geometric characteristics, and adverse weather conditions may increase the crash risk along some freeway sections. This paper examines the safety effects of roadway geometrics on crash occurrence along a freeway section that features mountainous terrain and adverse weather. Starting from preliminary exploration using Poisson models, Bayesian hierarchical models with spatial and random effects were developed to efficiently model the crash frequencies on road segments on the 20-mile freeway section of study. Crash data for 6 years (2000-2005), roadway geometry, traffic characteristics and weather information in addition to the effect of steep slopes and adverse weather of snow and dry seasons, were used in the investigation. Estimation of the model coefficients indicates that roadway geometry is significantly associated with crash risk; segments with steep downgrades were found to drastically increase the crash risk. Moreover, this crash risk could be significantly increased during snow season compared to dry season as a confounding effect between grades and pavement condition. Moreover, sites with higher degree of curvature, wider medians and an increase of the number of lanes appear to be associated with lower crash rate. Finally, a Bayesian ranking technique was implemented to rank the hazard levels of the roadway segments; the results confirmed that segments with steep downgrades are more crash prone along the study section.


The association between sleep and early pubertal development in Chinese children: a school population-based cross-sectional study.
There is an increasing tendency toward early pubertal development, and sleep might be related to pubertal onset. We aimed to investigate the association of sleep duration and bedtime with early pubertal development. This was a cross-sectional study of 8,007 children (53.6% boys) from Qufu city, Shandong province and Zhongshan city, Guangdong province, China. Data on sleep duration and bedtime were obtained by questionnaire. Early pubertal development was the primary outcome and it was evaluated by the pediatrician according to Tanner staging. Logistic regression models were used to separately examine the association between sleep duration or bedtime and early pubertal development, controlling body mass index (BMI), dietary pattern, soft drink, feeding pattern and mother's BMI. In boys, short sleep duration was strongly related to early pubertal development [OR (95%CI): 4.26 (1.30, 13.94)], and this association was intensified after adjusted BMI, dietary pattern, soft drink, feeding pattern and mother's BMI. In girls, OR (95%CI) was 1.62 (1.04, 2.51), and increased after controlling BMI. Bedtime was associated with early pubertal development on weekdays [OR (95%CI): 6.39 (1.54, 26.45) in boys and 1.93 (1.23, 3.05) in girls], but not on weekends [OR (95%CI): 2.49 (0.61, 10.21) in boys; 1.31 (0.76, 2.25) in girls]. This study underscores the positive association between the risk of early pubertal development and insufficient sleep duration and late bedtime.


Plasma uric acid level indicates tubular interstitial leisions at early stage of IgA nephropathy.
Hyperuricemia appeared to be a common symptom in IgA nephropathy (IgAN), even in those with normal eGFR. IgAN was characterized by variation of pathological features, especially variable tubulointerstitial lesions. Since tubular reabsorption and excretion appeared to be more important in determination of plasma uric acid levels in persons without obvious decrease of glomerular filtration rate, we took advantage of our IgAN cohort to investigate whether plasma uric acid level associated with tubular interstitial lesions, and could be considered as a maker for tubular interstitial lesions, especially at early stage with normal eGFR. 623 IgAN patients were involved in the present study. Morphological changes were evaluated with Oxford classification scoring system as well as Beijing classification system of IgAN. Statistical analysis was done with SPSS 13.0. We found that plasma uric acid level associated with percentage of interstitial fibrosis/tubular atrophy. Higher plasma uric acid levels indicated higher tubulointerstitial scores, either with Oxford system (P = 0.012) or with Beijing classification system (P = 4.8*10-4) in the whole cohort. We also found that in the subgroup of 258 IgAN cases with normal baseline eGFR (eGFR > =90 ml/min/1.73 M2), higher plasma uric acid associated with more severe tubulointerstitial lesions with Beijing scoring system (P = 3.4*10-5). The risk of having more than 10% tubulointerstitial lesions in patients with hyperuricemia increased 58% compared with normal uric acid level. In subgroup with normal eGFR, only hyperuricemia predicted tubulointerstitial leisions, and the risk of having more tubulointerstitial changes increased 100%. Among these patients, hyperuricemia was associated with more tubulointerstitial lesions with a specificity of 60.3%. Specificity increased to 65% among those patients with eGFR > =90 ml/min/1.73 m2. Plasma uric acid levels indicate tubular interstitial lesions in IgAN and hyperuricemia may be considered as a marker for tubulointerstitial lesions.


A possible link between cognitive development in 5 years old children and prenatal oxidative stress.
To study the impact of oxidative damage associated with particulate matter< 2.5 µm (PM2.5) during prenatal period on the cognitive development in five years old children. Two cohorts of children aged five years, born in the years 2013 and 2014, were studied for their cognitive development in the polluted district Karvina and the control district Ceske Budejovice. Exposure to PM2.5 in the ambient air was measured for each mother during the 3rd trimester of pregnancy. Oxidative damage was determined from the level of biomarkers at delivery in mothers´ and newborns´ urine as 8-oxo-7,8-dihydro-2´-deoxyguanosine (8-oxodG) and in plasma as 15-F2t-isoprostane levels (15-F2t-IsoP). The Bender Visual Motor Gestalt Test (BG test) and the Raven Colored Progressive Matrices (RCPM test) were used as psychological cognitive tests. Average concentrations of PM2.5 ± SD in the 3rd trimester of mothers´ pregnancies were 37.7 ± 14.7 µg/m3 and 17.1 ± 4.8 µg/m3 in Karvina and Ceske Budejovice, respectively (p < 0.001). The maternal level of 15-F2t-IsoP in plasma at the time of delivery was significantly associated with the results of the RCPM test (p < 0.05) and the BG test (p < 0.05) in five years old children. Lipid peroxidation in maternal plasma at the time of delivery has an adverse effect on the results of psychological cognitive tests in five years old children.


Assessment of Functional Pain Score by Comparing to Traditional Pain Scores.
Pain assessments, such as the Numerical Pain Scale (NPS) and Wong-Baker FACEs (FACEs), offer methods to quantify pain with simplistic descriptions on a scale of 0-10 or facial expressions. These tools have limitations and deliver insufficient information to the provider developing a pain management plan. A new Functional Pain Scale (FPS) assesses other scopes of pain, including the loss of function in activities of daily living, sleep habits, and communication. Although NPS and FACEs are traditionally used in clinical practice, FPS provides a functional assessment to help patients self-report their pain to their providers. Aim: Our study attempts to show a comparative data analysis of the FPS to NPS and FACEs. The purpose of our study is not to demonstrate FPS's superiority over NPS and FACEs but to fill the gaps of information necessary to communicate the type of pain a patient has to their provider. Due to its descriptive nature and clear scores, FPS should be implemented within electronic medical records (EMR) to help providers assess patients' pain and evaluate the efficacy of interventions selected based on that pain. A prospective, observational, single-center, cohort study was performed, with simultaneously administered surveys to compare pains scores on a new FPS to the common NPS and FACEs. The target sample was postoperative orthopedic patients above 18 years of age who can read and speak English. Patients were surveyed on all three pain scales: FPS, NPS, and FACEs and were asked to rate their pain perioperatively after their respective orthopedic procedures. Spearman correlation method was used to test for correlation between the three pain scales and Wilcoxon rank-sum test was used to compare means between FPS and NPS. FPS has a strong correlation with FACEs (r = 0.647, p<0.05) and with NPS (r = 0.634, p<0.05). There is a significant difference in mean scores between FPS and NPS. Conclusion and study implications: The most reliable marker of pain is patient self-reporting. In routine assessment, because pain is one-dimensional, we as providers need to better define the range of 0-10. This can only be done via an algorithm regarding which functions are lost as pain intensities increase. FPS fits those requirements by offering suitable descriptions with each pain score. The implications of the study include a chance to remedy the opioid crisis that plagues healthcare. We need tools that assess and educate patients about their pain level and appropriately convey that information to providers. Furthermore, this study is a chance for innovative tools to be implemented to better change healthcare practice. If FPS gains traction, it can improve pain communication between patients and providers.


IFITM5 pathogenic variant causes osteogenesis imperfecta V with various phenotype severity in Ukrainian and Vietnamese patients.
Osteogenesis imperfecta (OI) covers a spectrum of bone fragility disorders. OI is classified into five types; however, the genetic causes of OI might hide in pathogenic variants of 20 different genes. Often clinical OI types mimic each other. This sometimes makes it impossible to identify the OI type clinically, which can be a risk for patients. Up to 90% of OI types I-IV are caused by pathogenic variants in the COL1A1/2 genes. OI type V is caused by the c.-14C > T pathogenic variant in the 5'UTR of the IFITM5 gene and is characterized by hyperplastic callus formation and the ossification of interosseous membranes. In the current study, we performed IFITM5 5'UTR region mutational analysis using Sanger sequencing on 90 patients who were negative for COL1A1/2 pathogenic variants. We also investigated the phenotypes of five patients with genetically confirmed OI type V. The proportion of OI type V patients in our cohort of all OI patients was 1.48%. In one family, there was a history of OI in at least three generations. Phenotype severity differed from mild to extremely severe among patients, but all patients harbored the same typical pathogenic variant. One patient had no visible symptoms of OI type V and was suspected to have had OI type IV previously. We also identified a case of extremely severe hyperplastic callus in a 15-year-old male, who has hearing loss and brittleness of teeth. OI type V is underlined with some unique clinical features; however, not all patients develop them. The phenotype spectrum might be even broader than previously suspected, including typical OI features: teeth brittleness, bluish sclera, hearing loss, long bones deformities, and joint laxity. We suggest that all patients negative for COL1A1/2 pathogenic variants be tested for the presence of an IFITM5 pathogenic variant, even if they are not expressing typical OI type V symptoms. Further studies on the pathological nature and hyperplastic callus formation mechanisms of OI type V are necessary.


Hunter-gatherer human nature and health system safety: an evolutionary cleft stick?
The stunning archaeological find of a new species of human dubbed the hobbit, formally named Homo floresiensis, is a reminder that humans and hobbits are evolved for transient lives, subsisting in an environment radically different from that of contemporary societies. Although the problems facing health systems are well documented, few scholars have taken an evolutionary-level approach to understanding them. By considering the nature of humans as adapted not for modern societies but for hunter-gatherer existence, and examining what humans were evolved for, new light can be shed on contemporary behaviours exposed by the medical inquiries into what is going wrong in acute health systems. Investigation of two of these inquiries shows how health professionals under pressure typically default to tribal behaviours, have recourse to hierarchies and engage in turf protection routines. Those who have conducted studies into iatrogenic harm or presided over the medical inquiries have argued that culture change is the solution to health care's ills. This is likely to be much harder to institute than some people realize, especially given our underlying hunter-gatherer nature. This is an evolutionary cleft stick that has not been factored in by those optimistic about health sector reform. The implications are that we need a deep understanding of human nature in addressing health system problems and to recognize that profound culture change is more challenging than many believe. Paradoxically, it is when humans are faced with seemingly intractable problems that a collective way forward might emerge.


Concealed metabolic reprogramming induced by different herbicides in tomato.
Herbicide application is a common procedure in agriculture, whose potentially adverse effects are assessed mainly with respect to weeds or in terms of residues and environmental impact. However, recent evidence has highlighted possible effects of pesticide treatments on plant metabolism, with potential implications for fruit quality. Therefore, the goal of this study was to investigate the impact of four different herbicides on the metabolic processes in industrial tomato plants. To this aim, plants were treated either with the selective herbicides metribuzin and rimsulfuron or with the non-selective herbicides glyphosate and pelargonic acid. Thereafter, leaves were analyzed using a metabolomics approach, and 247 differential compounds were selected by multivariate statistics and used to examine the changes at the molecular level. Data interpretation via the PlantCyc Pathway Tool revealed that the tested herbicides induced distinctive responses to the treatments, with the phytohormone profile (gibberellins and jasmonates) and secondary metabolism (including stress-related compounds, such as phenylpropanoids and glucosinolates) showing the largest modulation. Surprisingly, such metabolic reprogramming also affected several aspects of the fruits even though the herbicides were applied several weeks before, thus opening the possibility of effects on food quality. To date, these hidden effects have been largely underestimated even though they deserve to be carefully considered since they may affect the qualitative and quantitative traits of the yield.


Activity of glutaraldehyde at low concentrations (less than 2%) against poliovirus and its relevance to gastrointestinal endoscope disinfection procedures.
The activity of glutaraldehyde (GTA) at low concentrations (less than 2%) against poliovirus was assessed by a suspension procedure. The inactivation kinetics showed that concentrations of less than or equal to 0.10% were effective against purified poliovirus at pH 7.2; a 1 log10 reduction was obtained in 70 min with 0.02% GTA, and a 3 log10 reduction was obtained in 30 min with 0.10% GTA. GTA activity at low concentrations was greatly enhanced at alkaline pH, but was completely abolished at acid pH. In contrast, the inactivation assays on poliovirus RNA showed that it was highly resistant to GTA at concentrations up to 1.0% at pH 7.2. At pH 8.3 a low inactivation was noticed with 1.0% GTA. Our results are of relevance to hospital practice in digestive endoscopy investigations because there has been an increasing tendency to use low concentrations of GTA and very short contact times in disinfection procedures.


Multifactorial role of long non-coding RNAs (LncRNAs) in hematopoiesis.
Human genome project unveiled that only 1.5.-2.0.% of the genome is protein coding. ENCODE and related studies showed that most part of the genome transcribed into RNAs, and most of them do not code for a functional proteins, hence the name non-coding RNAs (ncRNAs). ncRNAs are small ncRNAs (less than 200 nucleotides) and long ncRNAs (longer than 200 nucleotides up to 10 kb). They act as a direct link between highly ordered chromosome structures, gene expression and serve as a bridge between genome and chromatin modification complexes as guides, scaffolds, and decoys. Highly regulated hematopoietic differentiation is required for formation of all types of blood cells. Among a variety of lncRNAs only few hematopoitic lncRNAs have been studied extensivelyand most of them are not functionally characterized. The role of these lncRNAs remains partially undetermined but their involvement in the regulation of various genes and protein synthesis has been proved even in hematopoiesis. So, the present review is a mere effort to highlight the role of lncRNAs involved in the development and regulation of hematopoiesis.


Photoreceptor shedding is initiated by light in the frog retina.
Frogs maintained on a diurnal light-dark cycle (14 hours light and 10 hours darkness) shed their rod photoreceptor outer segment tips shortly after the onset of light. Shedding is synchronous and occurs in about 25 percent of the rod photoreceptors each day. Prolonged exposure to total darkness decreases the amount of shedding, after which exposure to light results in a large burst of synchronous shedding. Thus in the frog retina, the synchronous shedding of rod outer segment tips is shown to be directly related to light stimulation.


Advances in the molecular understanding of GABA(B) receptors.
The molecular nature of the metabotropic GABA(B) receptor was for some time a mystery, however it was recently discovered that two related G-protein-coupled receptors have to heterodimerize to form the functional GABA(B) receptor at the cell surface. This review discusses the most recent findings in the rapidly expanding field of GABA(B) receptor research, and includes a summary of all splice variants of both receptor subunits identified to date. It also evaluates emerging evidence that certain splice variants might play a role in determining pharmacologically distinguishable receptors, and reviews receptor localization at the sub-cellular level and involvement in neuronal development.


Poland's anomaly. Natural history and long-term results of chest wall reconstruction in 33 patients.
Poland's anomaly is an uncommon congenital aberration of the chest wall characterized by absence of the pectoralis major muscle and other nearby musculoskeletal components. In this series, a wide spectrum of thoracic deformities was associated with the Poland anomaly, ranging from segmental agenesis of the ribs, sternum, and nearby muscles, to simple aplasia of the pectoralis major muscle. Although little disability was associated with the syndrome, the patients primarily sought operative correction due to the asymmetry and their perception of adverse cosmesis. Over a 10-year period, 53 operations were performed on 27 individuals with the goal of correcting the abnormal contour of the chest wall. The most successful reconstructions involved the use of the latissimus dorsi muscle, which was detached and transferred to the anterior chest wall while preserving the neurovascular pedicle. In women, this was accompanied by insertion of a mammary prosthesis. Reconstruction of the so-called "herniation" of the lung with rib grafts or alloplastic materials was found to be unnecessary, and the use of custom-made chest wall prostheses is not recommended, since four of five of these devices had to be removed due to migration, erosion of local tissues, and adverse cosmesis.


Development and validation of a prognostic nomogram for patients with laryngeal cancer with synchronous or metachronous lung cancer.
The objective of this study was to examine the independent prognostic factors of laryngeal cancer with synchronous or metachronous lung cancer (LCSMLC), and to generate and verify a clinical prediction model. In this study, laryngeal cancer alone and LCSMLC were defined using the Surveillance, Epidemiology, and End Results (SEER) database. Risk factors of patients with LCSMLC were analyzed through univariate and multivariate logistic regression analysis. Independent prognostic factors were selected by Cox regression analyses, on the basis of which a nomogram was constructed using R code. Kaplan-Meier survival analyses were applied to test the application of a risk stratification system. Finally, we conducted a comparison of the American Joint Committee on Cancer (AJCC) staging system of laryngeal cancer with the new model of nomogram and risk stratification. For further validation of the nomogram, data from patients at two Chinese independent institutions were also analyzed. According to the eligibility criteria, 32 429 patients with laryngeal cancer alone and 641 patients with LCSMLC from the SEER database (the training cohort) and additional 61 patients from two Chinese independent institutions (the external validation cohort) were included for final analyses. Compared with patients with laryngeal cancer who did not have synchronous or metachronous lung cancer, age, sex, race, primary site of laryngeal cancer, grade, and stage were risk factors for LCSMLC, while marriage, surgery, radiation therapy, and chemotherapy are not their risk factors. Age, two cancers' interval, pathological type, stage, surgery, radiation, primary lung site, and primary throat site were independent prognostic predictors of LCSMLC. The risk stratification system of high-, medium-, and low-risk groups significantly distinguished the prognosis in different patients with LCSMLC, regardless of the training cohort or the validation cohort. Compared with the 6th AJCC TNM stage of laryngeal cancer, the new model of nomogram and risk stratification showed an improved net benefit. Age, sex, race, primary site of laryngeal cancer, grade, and stage were risk factors for LCSMLC. An individualized clinical prognostic predictive model by nomogram was generated and validated, which showed superior prediction ability for LCSMLC.


Immunomodulatory drugs increase endothelial tissue factor expression in vitro.
Immunomodulatory compounds such as thalidomide (THL) and lenalidomide (LEN) represent treatment options for multiple myeloma. Venous thromboembolism is a potential complication of immunomodulatory treatment in myeloma patients. The optimal thromboprophylactic strategy to prevent this drug-induced hypercoagulable state is debated. It is the aim of this study to investigate i) the effect of immunomodulatory treatment on endothelial cell tissue factor (TF) expression and function, ii) the regulation of the observed TF activity, and iii) the modulating effect of low molecular weight heparin and aspirin on TF activity in vitro. These aims were addressed in an in vitro culture model, human umbilical vein endothelial cells, using TF activity and antigen assays as well flow cytometry, real time PCR and electron microscopy. At THL and LEN concentrations resembling those observed in myeloma patients in vivo and in the presence of tumor necrosis factor-α (TNFα) we observed significantly increased TF activity in human umbilical vein endothelial cells in vitro. Concordant changes were detected for tissue factor mRNA and TF whole cell antigen. Dalteparin and a mixture of monoclonal anti-TF antibodies inhibited TF activity by 100% and more than 80% respectively, while aspirin's inhibitory effect was only approximately 30%. In the presence of TNFα we detected the generation of endothelial cell-derived microparticles which expressed TF activity. Our in vitro data support the hypothesis that THL and LEN induce a hypercoagulable state through increased endothelial TF expression.


The Role of Social Workers in Interprofessional Primary Healthcare Teams.
In Ontario, Canada, social workers are employed in a number of primary healthcare (PHC) settings such as Community Health Centres (CHCs) and Family Health Teams (FHTs). However, many aspects of social work practice within PHC settings are unknown. The objectives of our study are to determine the amount of social work services provided in CHCs and FHTs, identify the types of services that social workers provide in CHCs and FHTs and ascertain the methods social workers use to deliver services in CHCs and FHTs. An analysis of a cross-sectional data set obtained from a survey conducted in June 2016 in Ontario was performed. The majority of practices (84.2%) had a social worker, although several practices also hosted other types of mental health workers. In virtually all practices with social workers, they (and individuals designated as mental healthcare providers) were also involved in practice level efforts to support mental healthcare delivery. In several practices, the care they delivered extended beyond that related directly to mental healthcare, ranging from preventive care and health promotion (64.5%) to palliative care (16.8%). In several practices, these workers also offered group appointments related to healthy behaviour (43.6%) and self-management (~33%). Interestingly, the role of social workers in practices where they were the sole designated mental healthcare worker was not meaningfully different from practices where other mental health professionals work. In PHC, social workers deliver or support the delivery of mental healthcare, but their role extends beyond that domain to encompass a broader set of services that contribute to the individual's health and wellbeing.


Maturation of the human scar: an observational study.
The natural history of scar maturation in humans has never been formally described from either a clinical or a histologic standpoint. The maturation of incisional scars was observed in 58 healthy male volunteers who each had 2 x 1-cm incisional wounds created on the inner aspect of both upper arms. The resulting scars were photographed digitally at monthly intervals for 12 months and excised for histologic analysis at specific time points. All histologic specimens were stained using Masson's trichrome and reviewed together with the corresponding digital clinical scar images to produce macroscopic and microscopic descriptions of the maturation process. Three distinct groups, each displaying a different rate of longitudinal progression of scar maturation, were identified from within the study group. The majority of volunteers belonged to a "representative" subset but distinct "poor" and "excellent" subsets were also identified. The poor subset invariably contained volunteers younger than 30 years of age, whereas the majority of the excellent subset comprised subjects older than 55 years of age. Scar maturation occurs as a series of defined macroscopic and microscopic stages over the course of 1 year. The rate of scar maturation varied within the study group, with older subjects (>55 years) displaying accelerated maturation, whereas a prolonged high turnover state and a retarded rate of maturation were observed in younger subjects (<30 years).


The smooth and bumpy road of trastuzumab administration: from intravenous (IV) in a hospital to subcutaneous (SC) at home.
Trastuzumab has become standard of care in the treatment of early and metastatic HER2-positive breast cancer. Initially trastuzumab could only be administered intravenously (IV), however since a few years there is also a subcutaneous (SC) formulation. The efficacy and the safety profile of both formulations is the comparable. The administration logistics however have an impact on the patients, the health care professionals (HCPs), the hospital and the government. The preference for the patients (89%) and the HCPs (77%) is in favour of the SC formulation. The patient chair time per cycle, as defined by the time between entry and exit of infusion chair, is between 53 and 122 minutes shorter for SC administration. Also, the time actively dedicated by the HCP on preparation and administration SC, is between 17 and 50 minutes shorter per cycle. These time savings may increase the capacity of an oncological day clinic and reduce waiting lists. An additional benefit is that the use of SC formulation reduces the consumables and the waste. When the SC form was given at home instead of in the hospital the safety profile remained the same, but the satisfaction rate improved further for both the patients and the HCPs. The next and final step will be potentially to invest in teaching the patients to self-administer the medication. The home administration and the education of the patients and the HCPs will have a cost price and it will be interesting to see how the hospital financial authorities and the government will deal with this situation in the time of budgetary restrictions.


Information geometry for multiparameter models: new perspectives on the origin of simplicity.
Complex models in physics, biology, economics, and engineering are oftensloppy, meaning that the model parameters are not well determined by the model predictions for collective behavior. Many parameter combinations can vary over decades without significant changes in the predictions. This review uses information geometry to explore sloppiness and its deep relation to emergent theories. We introduce themodel manifoldof predictions, whose coordinates are the model parameters. Itshyperribbonstructure explains why only a few parameter combinations matter for the behavior. We review recent rigorous results that connect the hierarchy of hyperribbon widths to approximation theory, and to the smoothness of model predictions under changes of the control variables. We discuss recent geodesic methods to find simpler models on nearby boundaries of the model manifold-emergent theories with fewer parameters that explain the behavior equally well. We discuss a Bayesian prior which optimizes the mutual information between model parameters and experimental data, naturally favoring points on the emergent boundary theories and thus simpler models. We introduce a 'projected maximum likelihood' prior that efficiently approximates this optimal prior, and contrast both to the poor behavior of the traditional Jeffreys prior. We discuss the way the renormalization group coarse-graining in statistical mechanics introduces a flow of the model manifold, and connect stiff and sloppy directions along the model manifold with relevant and irrelevant eigendirections of the renormalization group. Finally, we discuss recently developed 'intensive' embedding methods, allowing one to visualize the predictions of arbitrary probabilistic models as low-dimensional projections of an isometric embedding, and illustrate our method by generating the model manifold of the Ising model.


Efficacy of pipobroman in the treatment of polycythemia vera: long-term results in 163 patients.
Polycythemia vera (PV) is a myeloproliferative disorder, characterized by the expansion of the red cell mass. Our purpose was to evaluate the efficacy of pipobroman (PB) in the long-term control of PV and to assess early and late events. From June 1975 to December 1997, 163 untreated patients with PV (median age 57 years, range 30-82) were treated with PB in a single Institute for a median follow-up of 120 months. The diagnosis was made according to the Polycythemia Vera Study Group criteria. PB was given at the dose of 1 mg/kg/day until hematologic response (hematocrit < 45% and platelets < 400x109/L) and of 0.3-0.6 mg/kg/day as maintenance therapy. Hematologic remission was achieved in 94% of patients in a median time of 13 weeks (range 6-48). Median overall survival was 215 months, with a standardized mortality ratio of 1.7. The cumulative risk of death was 11%, 22%, and 26% at 7, 10, and 12 years, respectively. The incidence of thrombotic events was 18.4x105 person-year and the cumulative risk was 6%, 11%, 16%, and 20% at 3, 7, 10, and 12 years respectively. Acute leukemia occurred in 11 patients, myelofibrosis in 7, and solid tumors in 11. The 10-year cumulative risk of leukemia, myelofibrosis, and solid tumors was 5%, 4%, and 8%, respectively. In the logistic analysis age over 65 (p = 0.0001) and thrombotic events at diagnosis (p = 0.001) were significantly correlated with a higher risk of death. Female gender (p = 0.02) and age over 65 (p = 0.01) significantly influenced the occurrence of thrombotic complications. Age was the only significant risk factor for leukemia (p = 0.04) and for solid tumors (p = 0.03), while the duration of PB treatment did not influence these risks. No significant risk factor was demonstrated for myelofibrosis. This study demonstrates in a large series of patients, observed for a long period, that pipobroman is effective in the long-term control of PV. The risk of early thrombotic complications at 3 years is 6% and the 10-year risk of acute leukemia, late myelofibrosis, and solid tumors is 5%, 4%, and 8%, respectively. The duration of pipobroman treatment did not correlate with these events.


Optimal [Formula: see text] ratio for predicting 15 km performance among elite male cross-country skiers.
The aim of this study was 1) to validate the 0.5 body-mass exponent for maximal. oxygen uptake [Formula: see text] as the optimal predictor of performance in a 15 km classical-technique skiing competition among elite male cross-country skiers and 2) to evaluate the influence of distance covered on the body-mass exponent for [Formula: see text] among elite male skiers. Twenty-four elite male skiers (age: 21.4±3.3 years [mean ± standard deviation]) completed an incremental treadmill roller-skiing test to determine their [Formula: see text]. Performance data were collected from a 15 km classical-technique cross-country skiing competition performed on a 5 km course. Power-function modeling (ie, an allometric scaling approach) was used to establish the optimal body-mass exponent for [Formula: see text] to predict the skiing performance. The optimal power-function models were found to be [Formula: see text] and [Formula: see text], which explained 69% and 81% of the variance in skiing speed, respectively. All the variables contributed to the models. Based on the validation results, it may be recommended that [Formula: see text] divided by the square root of body mass (mL · min(-1) · kg(-0.5)) should be used when elite male skiers' performance capability in 15 km classical-technique races is evaluated. Moreover, the body-mass exponent for [Formula: see text] was demonstrated to be influenced by the distance covered, indicating that heavier skiers have a more pronounced positive pacing profile (ie, race speed gradually decreasing throughout the race) compared to that of lighter skiers.


Safety of selective serotonin reuptake inhibitor use prior to coronary artery bypass grafting.
Selective serotonin reuptake inhibitors (SSRIs) have been shown to increase bleeding risks. This study examined the association of perioperative coronary artery bypass grafting (CABG) bleeding risks and SSRI use prior to CABG. SSRI may be associated with increased bleeding risks after CABG resulting in elevated reoperation rates due to bleeding complications. Patients who underwent CABG between 1999 and 2003 (n = 4794) were identified in a tertiary medical center. SSRI use (n = 246) was determined using inpatient pharmacy records. Outcomes included primary end point of reoperation due to bleeding complications and other secondary measures. Multivariate regression models were constructed to adjust for baseline differences between SSRI and control groups. Reoperation due to bleeding complications among SSRI users was not significantly different (odds ratio [OR]: 1.14 (0.52-2.47); P = 0.75) compared to the control group. Other secondary outcomes and 30-day mortality (2.0% in SSRI vs 2.1% in control group; P = 0.92) between the 2 groups were similar. However, the adjusted total volume of postoperative red blood cell (RBC) units transfused was higher in the SSRI group. We conclude that there is no compelling evidence to limit the use of SSRIs among patients with coronary artery disease who undergo CABG given the current evidence. Further research may be needed on individual SSRI medications.


Programmatic approach to patients with advanced ischemic cardiomyopathy: Integrating microaxial support into strategies for the modern era.
Patients with advanced ischemic cardiomyopathy manifesting as left ventricular dysfunction exist along a spectrum of severity and risk, and thus decision-making surrounding optimal management is challenging. Treatment pathways can include medical therapy as well as revascularization through percutaneous coronary intervention or coronary artery bypass grafting. Additionally, temporary and durable mechanical circulatory support, as well as heart transplantation, may be optimal for select patients. Given this spectrum of risk and the complexity of treatment pathways, patients may not receive appropriate therapy given their perceived risk, which can lead to sub-satisfactory outcomes. In this review, we discuss the identification of high-risk ischemic cardiomyopathy patients, along with our programmatic approach to patient evaluation and perioperative optimization. We also discuss our strategies for therapeutic decision-making designed to optimize both short- and long-term patient outcomes.


An experiment in health careers recruitment: a summer program at Indiana University.
During the summer of 1973, the Indiana University Division of Optometry, via a Special Project Grant from the National Institutes of Health, conducted its first Summer Institute in the Health Related Professions for High School and College Students. Twenty-seven high school students and twenty-nine college students were brought to Indiana University for intensive sessions in career awareness, curriculum and financial counseling, and academic coursework. Assisted by the staffs of Indiana Health Careers, Inc. and the Indiana University Coordinators for School Science, the Institute awakened new interests and goals, relative to the health career prospectus, within the trainees. As a direct consequence of the summer program, four participants in the college institute were matriculated into schools of medicine, pharmacy, and optometry during the semester following the culmination of the Institute; ten more are participating in the followup program for continued guidance and counseling, seeking 1974 entrance into health professions schools and colleges. This experiment in health professions recruitment for minority, disadvantaged, and low-income students proved to be a viable method of increasing the manpower pool of health professionals.


PCNA interacts with Indian mung bean yellow mosaic virus rep and downregulates Rep activity.
Proliferative cell nuclear antigen (PCNA), a conserved plant protein as well as an important replication factor, is induced in response to geminivirus infection in the resting cells of the phloem tissues. The biochemical role of PCNA in rolling circle replication (RCR) of geminivirus DNA has not been explored in detail. The initiation of RCR of the bipartite genome of a geminivirus, Indian mung bean yellow mosaic virus (IMYMV), is mainly controlled by viral protein Rep (or AL1 or AC1). The role of host PCNA in RCR of IMYMV was revealed by studying the physical and functional interactions between recombinant PCNA and recombinant IMYMV Rep. Pea nuclear PCNA as well as recombinant pea PCNA showed binding to recombinant Rep in experiments involving both affinity chromatography and yeast two-hybrid approaches. The contacting amino acid residues of PCNA seemed to be present throughout a wide region of the trimeric protein, while those of Rep appeared to be localized only in the middle part of the protein. The site-specific nicking-closing activity and the ATPase function of IMYMV Rep were impaired by PCNA. These observations lead to interesting speculations about the control of viral RCR and dynamic profiles of protein-protein interactions at the RCR origin of the geminiviruses.


Cell fusion in yeast is negatively regulated by components of the cell wall integrity pathway.
During mating, Saccharomyces cerevisiae cells must degrade the intervening cell wall to allow fusion of the partners. Because improper timing or location of cell wall degradation would cause lysis, the initiation of cell fusion must be highly regulated. Here, we find that yeast cell fusion is negatively regulated by components of the cell wall integrity (CWI) pathway. Loss of the cell wall sensor, MID2, specifically causes "mating-induced death" after pheromone exposure. Mating-induced death is suppressed by mutations in cell fusion genes ( FUS1, FUS2, RVS161, CDC42), implying that mid2Δ cells die from premature fusion without a partner. Consistent with premature fusion, mid2Δ shmoos had thinner cell walls and lysed at the shmoo tip. Normally, Cdc42p colocalizes with Fus2p to form a focus only when mating cells are in contact (prezygotes) and colocalization is required for cell fusion. However, Cdc42p was aberrantly colocalized with Fus2p to form a focus in mid2Δ shmoos. A hyperactive allele of the CWI kinase Pkc1p ( PKC1*) caused decreased cell fusion and Cdc42p localization in prezygotes. In shmoos, PKC1* increased Cdc42p localization; however, it was not colocalized with Fus2p or associated with cell death. We conclude that Mid2p and Pkc1p negatively regulate cell fusion via Cdc42p and Fus2p.


Segmental localization of the rabbit renal proximal tubular Na+-H+ exchange system.
The activity of the Na+-H+ exchanger in rabbit proximal tubule was investigated by using luminal membrane vesicles prepared from "outer cortex" (proximal convoluted tubule) or "outer medulla" (proximal straight tubule). The purity of the preparations was examined by measuring the activity of several marker enzymes, and the degree of cross-contamination and the functional state of the membrane vesicles were assessed by studying Na+-dependent uptake of D-glucose. The Na+ uptake by pars convoluta membrane vesicles exhibited an overshoot in the presence of an intravesicular greater than extravesicular H+ gradient. The overshoot was eliminated by omitting or reversing the transmembranal H+ gradient or by adding amiloride. In contrast, Na+ uptake by pars recta membrane vesicles did not show an overshoot and was independent of H+ gradients and of amiloride. However, Na+ uptake by pars recta membrane vesicles pretreated with monensin exhibited an overshoot. This overshoot apparently was amiloride insensitive. The findings propose that the Na+-H+ exchanger is predominantly operative in the proximal convoluted tubule and is either lacking or of minor significance in the proximal straight tubule.


Fetal-maternal HLA compatibility confers susceptibility to systemic sclerosis.
Systemic sclerosis (SSc) is a disease of unknown origin, which occurs predominantly in women after childbearing years. There are prominent clinical and histopathologic similarities between SSc and chronic graft-versus-host disease (GVHD). GVHD can occur after blood transfusions or after transplantation with HLA-compatible bone marrow. Here we examined the hypothesis that SSc may be caused by fetal cells crossing the placenta into the maternal circulation and providing donor lymphocytes which recognize disparate HLA antigens, resulting in a reaction similar to chronic GVHD. To test the hypothesis we analyzed the inheritance of HLA class I and class II haplotypes in the families of 37 SSc patients and 42 control individuals. Twenty-six (70.2%) SSc patients had HLA class II alleles compatible either for their offspring or mother, compared with only nine (21%) control individuals. The four patients with juvenile onset SSc we analyzed had alleles compatible with their mothers. These results suggest that in some patients, SSc may, indeed, be a form of chronic GVHD caused by fetal or maternal cells which have crossed the placenta during pregnancy and have remained unrecognized by the host due to class II HLA compatibility, and that subsequent activation of these cells by as yet unknown stimuli result in the development of the disease.


Adverse pregnancy outcomes: information from the medical record.
Adverse reproductive outcomes were sought via medical records of 14 central Arkansas hospitals serving a five county area encompassing 28, 102 live births in the 1980 to 1982 study period. This population-based study estimated the overall congenital anomaly case incidence to be 3.5 percent of live births. Information on pregnancy history of the cases or on parental occupations was often not recorded in the medical records of infant or mother, precluding the use of these records for many etiologic investigations. Fetal wastage cases found through hospital sources encompassed 86 percent of the number reported to the Department of Health. Autopsies were performed in only 16 percent of fetal death cases. Many of the fetal death cases not subjected to autopsy had no apparent cause of death listed; reasons for this lack of investigation warrant further study. These pregnancy outcome data have been correlated with agricultural pesticide usage and can be examined in a variety of environmental contexts for development and testing of etiologic hypotheses.


Risk of intracerebral haemorrhage in Chinese patients with atrial fibrillation on warfarin with cerebral microbleeds: the IPAAC-Warfarin study.
Cerebral microbleeds (CMBs), which predict future intracerebral haemorrhage (ICH), may guide anticoagulant decisions for atrial fibrillation (AF). We aimed to evaluate the risk of warfarin-associated ICH in Chinese patients with AF with CMBs. In this prospective, observational, multicentre study, we recruited Chinese patients with AF who were on or intended to start anticoagulation with warfarin from six hospitals in Hong Kong. CMBs were evaluated with 3T MRI brain at baseline. Primary outcome was clinical ICH at 2-year follow-up. Secondary outcomes were ischaemic stroke, systemic embolism, mortality of all causes and modified Rankin Scale ≥3. Outcome events were compared between patients with and without CMBs. A total of 290 patients were recruited; 53 patients were excluded by predefined criteria. Among the 237 patients included in the final analysis, CMBs were observed in 84 (35.4%) patients, and 11 had ≥5 CMBs. The mean follow-up period was 22.4±10.3 months. Compared with patients without CMBs, patients with CMBs had numerically higher rate of ICH (3.6% vs 0.7%, p=0.129). The rate of ICH was lower than ischaemic stroke for patients with 0 to 4 CMBs, but higher for those with ≥5 CMBs. CMB count (C-index 0.82) was more sensitive than HAS-BLED (C-index 0.55) and CHA2DS2-VASc (C-index 0.63) scores in predicting ICH. In Chinese patients with AF on warfarin, presence of multiple CMBs may be associated with higher rate of ICH than ischaemic stroke. Larger studies through international collaboration are needed to determine the risk:benefit ratio of oral anticoagulants in patients with AF of different ethnic origins.


Male-specific expression of the paralog of malaria transmission-blocking target antigen Pfs230, PfB0400w.
Malaria transmission requires that Plasmodium parasites circulating in the vertebrate host develop into male and female gametocytes, which are then taken up by a mosquito to undergo fertilization and further development into infectious sporozoites. To understand the malaria specific events involved in this process, the gene products involved require identification and characterization. This work demonstrates that antibodies generated against the paralog of malaria transmission-blocking antigen Pfs230, PfB0400w, react only with stage V male gametocytes, not gametes or asexual parasites. In contrast, Pfs230 is expressed on the surface of all gametocytes and remains associated with emerged gametes as one of the primary surface antigens for several hours. Consistent with the localization findings, a high molecular weight band is recognized by anti-PfB0400w antibodies on western blots of extracts of late stage gametocytes, not asexual parasites, early (stage II/III) gametocytes, or gametes. PfB0400w mRNA is also not observed in asexual parasites. The transcript levels peak in stage III/IV gametocytes, then sharply decline in gametes. This work identifies a novel male-specific protein with an expression pattern that is distinctly different than its paralog.


Bone turnover and the response to alendronate treatment in postmenopausal osteoporosis.
This study investigated whether bone turnover influences the response to alendronate in women with postmenopausal osteoporosis. One hundred postmenopausal osteoporotic women were randomized to receive either alendronate (10 mg/day) plus calcium (1000 mg/day) (n = 50) or calcium alone (n = 50). Vertebral and radial bone density, measured by DXA, and markers of bone turnover were assessed at baseline and after 1 and 2 years. At the end of treatment, alendronate users showed an increase of 5.0% and 2.3%, respectively, at the lumbar spine and ultradistal radius; in the group treated only with calcium, bone mineral density (BMD) decreased by 1.6% at the lumbar spine and 1.3% at the ultradistal radius. The difference between the two groups was significant (P < 0.001). The patients were divided into high (HT) or low (LT) bone turnover groups, as assessed by 24-hour whole body retention (WBR%) of (99m)Tc-methylene-diphosphonate. The response to alendronate treatment was greater in HT patients compared with LT patients. In fact, at the end of the study period, BMD at the lumbar spine had increased by 7.9% in HT patients and by 3.0% in LT patients; the difference between the two groups was significant (P < 0.001). No significant difference between the two groups was found for BMD at the ultradistal radius. In conclusion, the present study demonstrates that 2-year treatment with alendronate has highly positive effects on bone mass at both the lumbar spine and ultradistal radius. The increase in bone mass, especially at the axial level, is influenced by bone turnover. Therefore, the evaluation of bone turnover may be useful in predicting the response to alendronate treatment.