Reliability and Validity of the HD-PRO-TriadTM, a Health-Related Quality of Life Measure Designed to Assess the Symptom Triad of Huntington's Disease.
Huntington's disease (HD), is a neurodegenerative disorder that is associated with cognitive, behavioral, and motor impairments that diminish health related quality of life (HRQOL). The HD-PRO-TRIADTM is a quality of life measure that assesses health concerns specific to individuals with HD. Preliminary psychometric characterization was limited to a convenience sample of HD participants who completed measures at home so clinician-ratings were unavailable. The current study evaluates the reliability and validity of the HD-PRO-TRIADTM in a well-characterized sample of individuals with HD. Four-hundred and eighty-two individuals with HD (n = 192 prodromal, n = 193 early, and n = 97 late) completed the HD-PRO-TRIADTM questionnaire. Clinician-rated assessments from the Unified Huntington Disease Rating Scales, the short Problem Behaviors Assessment, and three generic measures of HRQOL (WHODAS 2.0, RAND-12, and EQ-5D) were also examined. Internal reliability for all domains and the total HD-PRO-TRIADTM was excellent (all Cronbach's α >0.93). Convergent and discriminant validity were supported by significant associations between the HD-PRO-TRIADTM domains, and other patient reported outcome measures as well as clinician-rated measures. Known groups validity was supported as the HD-PRO-TRIADTM differentiated between stages of the disease. Floor and ceiling effects were generally within acceptable limits. There were small effect sizes for 12-month change over time and moderate effect sizes for 24-month change over time. Findings support excellent internal reliability, convergent and discriminant validity, known groups validity, and responsiveness to change over time. The current study supports the clinical efficacy of the HD-PRO-TRIADTM. Future research is needed to assess the test-retest reliability of this measure.


The motor domain determines the large step of myosin-V.
Class-V myosin proceeds along actin filaments with large ( approximately 36 nm) steps. Myosin-V has two heads, each of which consists of a motor domain and a long (23 nm) neck domain. In accordance with the widely accepted lever-arm model, it was suggested that myosin-V steps to successive (36 nm) target zones along the actin helical repeat by tilting its long neck (lever-arm). To test this hypothesis, we measured the mechanical properties of single molecules of myosin-V truncation mutants with neck domains only one-sixth of the native length. Our results show that the processivity and step distance along actin are both similar to those of full-length myosin-V. Thus, the long neck domain is not essential for either the large steps or processivity of myosin-V. These results challenge the lever-arm model. We propose that the motor domain and/or the actomyosin interface enable myosin-V to produce large processive steps during translocation along actin.


A prospective study on educational level and adaptation to cancer, within one year after the diagnosis, in an older population.
Socio-economic status (SES) has often been associated with health disparities and mortality in cancer patients, yet systematic research into the role of SES in the course of the disease is lacking. This prospective study intends to examine the role of SES (i.e. educational level in this study) in psychological and physical adaptation to cancer. Ninety-nine cancer patients were followed from a community-based survey. Pre- and post-morbid data on patients' quality of life (QoL) were available. Adaptation was defined by looking at the level and pattern of scores on QoL scales from pre- to post-disease assessments. Results show some non-significant trends that more high-educated patients managed to adapt completely to cancer in relation to role and physical functioning when compared with low-educated participants. Furthermore, the greater part of high-educated patients who completely adapted in physical functioning achieved this result more rapidly without an initial deterioration. Unexpectedly, these differences were not significant when tested in a regression model. Hence, although there are some indications for differences in adaptation to role and physical functioning between educational groups, we did not find any evidence that proved such a relation. For the group as a whole, it is very interesting to see that based on our operationalization of adaptation, only a small percentage of patients deteriorated from pre- to post-disease assessments.


The impact of COVID-19 on the tuberculosis control activities in Addis Ababa.
The first COVID-19 case was reported in Ethiopia on 13th March 2020 and series of announcements of set of measures, proclamation and directives have been enacted to fight the coronavirus pandemic. These have implications for the regular health services including the TB control program. This brief communication assesses the impact of the COVID-19 response on the TB control activities of Addis Ababa health centers based on research project data. We compared the patient flows in pre-COVID-19 period (quarter 1, Q1) and during COVID-19 (quarter 2, Q2 and quarter 3, Q3) of 2020 at 56 health centers in Addis Ababa from all 10 sub-cities per sub-city. The patient flow declined from 3,473 in Q1 to 1,062 in Q2 and 1,074 in Q3, which is a decrease by 62-76% and 52-80% in Q2 and Q3 respectively as compared to that of Q1. In Q2, Kolfe keranio and Kirkos sub-cities recorded the biggest decline (76 and 75% respectively) whereas Yeka sub-city had the least decline (62%). In Q3, Kirkos sub-city had the biggest decline (80%) and Addis ketema sub-city had the lowest (52%). We conclude that the series of measures, state of emergency proclamation and government directives issued to counter the spread of COVID-19 and the public response to these significantly affected the TB control activities in Addis Ababa city as attested by the decrease in the patient flow at the clinics. Health authorities may inform the public that essential health services are still available and open to everyone in need of these services.


Ovarian tissue collection for cryopreservation in pediatric age: laparoscopic technical tips.
As the number of young girls subjected to chemo and radiotherapy is steadily increasing it is our duty to try to preserve their future fertility and ovarian function. A possibility is to collect ovarian samples, cryopreserve them and reimplant the tissue when the treatments are over. We report our 11 year experience with the use of laparoscopy to collect ovarian tissue samples. In particular we focus on the details of the surgical technique. The procedure was performed in 54 patients affected by malignancies or pathologies requiring chemo or radiotherapy, with good results. Cryopreservation seems to be a good option to preserve future fertility although it is still an experimental method.


Influence of type of cigarette on peripheral versus central lung cancer.
Adenocarcinoma has replaced squamous cell carcinoma as the most common cell type of lung cancer in the United States. It has been proposed that this shift is due to the increased use of filter and lower-tar cigarettes, resulting in increased delivery of smoke to peripheral regions of the lungs, where adenocarcinoma usually occurs. We reviewed radiologic data to evaluate the hypothesis that tumors in smokers of cigarettes with lower-tar yield are more likely to occur peripherally than tumors in smokers of higher-yield cigarettes. At two urban academic medical centers, we reviewed computed tomographic scans, chest radiographs, and medical records to assign tumor location (peripheral or central) for 330 smokers diagnosed with carcinoma of the lung between 1993 and 1999. We compared the proportion of tumors in a peripheral versus central location by lifetime filter use and average lifetime tar rating (< 21 and > or = 21 mg). Tumor location (69% peripheral and 31% central) was unrelated to cigarette filter use. Smokers of cigarettes with lower-tar ratings were more likely than those with higher ratings to have peripheral rather than central tumors (odds ratio, 1.76; 95% confidence interval, 0.89-3.47). When restricted to subjects with adenocarcinoma or squamous cell carcinoma, the odds ratio (95% confidence interval) was 2.31 (1.05-5.08). Among cigarette smokers with lung cancer, use of cigarettes with lower-tar yield was associated with preferential occurrence of tumors in peripheral sites. Our findings support the hypothesis that changes in smoking associated with lower-tar cigarettes have led to a shift in the location of smoking-related lung cancer.


A Systematic Review on Transplantation Studies of the Retinal Pigment Epithelium in Animal Models.
The retinal pigment epithelium (RPE) and the adjacent light-sensitive photoreceptors form a single functional unit lining the back of the eye. Both cell layers are essential for normal vision. RPE degeneration is usually followed by photoreceptor degeneration and vice versa. There are currently almost no effective therapies available for RPE disorders such as Stargardt disease, specific types of retinitis pigmentosa, and age-related macular degeneration. RPE replacement for these disorders, especially in later stages of the disease, may be one of the most promising future therapies. There is, however, no consensus regarding the optimal RPE source, delivery strategy, or the optimal experimental host in which to test RPE replacement therapy. Multiple RPE sources, delivery methods, and recipient animal models have been investigated, with variable results. So far, a systematic evaluation of the (variables influencing) efficacy of experimental RPE replacement parameters is lacking. Here we investigate the effect of RPE transplantation on vision and vision-based behavior in animal models of retinal degenerated diseases. In addition, we aim to explore the effect of RPE source used for transplantation, the method of intervention, and the animal model which is used. In this study, we systematically identified all publications concerning transplantation of RPE in experimental animal models targeting the improvement of vision (e.g., outcome measurements related to the morphology or function of the eye). A variety of characteristics, such as species, gender, and age of the animals but also cell type, number of cells, and other intervention characteristics were extracted from all studies. A risk of bias analysis was performed as well. Subsequently, all references describing one of the following outcomes were analyzed in depth in this systematic review: a-, b-, and c-wave amplitudes, vision-based, thickness analyses based on optical coherence tomography (OCT) data, and transplant survival based on scanning laser ophthalmoscopy (SLO) data. Meta-analyses were performed on the a- and b-wave amplitudes from electroretinography (ERG) data as well as data from vision-based behavioral assays. original research articles met the inclusion criteria after two screening rounds. Overall, most studies were categorized as unclear regarding the risk of bias, because many experimental details were poorly reported. Twenty-three studies reporting one or more of the outcome measures of interest were eligible for either descriptive (thickness analyses based on OCT data; n = 2) or meta-analyses. RPE transplantation significantly increased ERG a-wave (Hedges' g 1.181 (0.471-1.892), n = 6) and b-wave (Hedges' g 1.734 (1.295-2.172), n = 42) amplitudes and improved vision-based behavior (Hedges' g 1.018 (0.826-1.209), n = 96). Subgroup analyses revealed a significantly increased effect of the use of young and adolescent animals compared to adult animals. Moreover, transplanting more cells (in the range of 105 versus in the range of 104) resulted in a significantly increased effect on vision-based behavior as well. The origin of cells mattered as well. A significantly increased effect was found on vision-based behavior when using ARPE-19 and OpRegen® RPE. This systematic review shows that RPE transplantation in animal models for retinal degeneration significantly increases a- and b- wave amplitudes and improves vision-related behavior. These effects appear to be more pronounced in young animals, when the number of transplanted cells is larger and when ARPE-19 and OpRegen® RPE cells are used. We further emphasize that there is an urgent need for improving the reporting and methodological quality of animal experiments, to make such studies more comparable.


Changing incidence of Candida bloodstream infections among NICU patients in the United States: 1995-2004.
Recent reports suggest that candidemia caused by fluconazole-resistant strains is increasing in certain adult populations. We evaluated the annual incidence of neonatal candidemia and the frequency of disease caused by different species of Candida among neonates in the United States. The study included neonates admitted to 128 NICUs participating in the National Nosocomial Infections Surveillance system from January 1, 1995, to December 31, 2004 (study period). Reports of bloodstream infection (BSI) with Candida spp.; Candida BSIs, patient admissions, patient-days, and central venous catheter days were pooled by birth weight category. The number of Candida BSIs per 100 patients (attack rate) and per 1000 patient-days (incidence density) was determined. Both overall and species-specific rates were calculated; data were pooled over time to determine the differences by birth weight category and by year to determine trends over time. From the 130,523 patients admitted to NICUs during the study period, there were 1997 Candida spp. BSIs reported. Overall, 1472 occurred in the <1000-g birth weight group. Candida albicans BSIs were most common, followed by Candida parapsilosis, Candida tropicalis, Candida lusitaniae, Candida glabrata, and only 3 Candida krusei. Among neonates <1000 g, incidence per 1000 patient-days decreased from 3.51 during 1995-1999 to 2.68 during 2000-2004 but remained stable among heavier neonates. No increase in infections by species that tend to demonstrate resistance to fluconazole (C glabrata or C krusei) was observed. Although Candida BSI is a serous problem among neonates <1000 g, incidence has declined over the past decade, and disease with species commonly resistant to azoles was extremely rare.


The IL23R A/Gln381 allele promotes IL-23 unresponsiveness in human memory T-helper 17 cells and impairs Th17 responses in psoriasis patients.
We and others have shown that the minor, nonconserved allele Gln381 of the Arg381Gln single-nucleotide polymorphism (rs11209026G>A) of the IL-23 receptor gene (IL23R) protects against psoriasis. Moreover, we have recently shown impaired IL-23-induced IL-17A production and STAT-3 phosphorylation in Th17 cells generated in vitro from healthy individuals heterozygous for the protective A allele (GA). However, the biological effect of this variant has not been determined in homozygous carriers of the protective A allele (AA), nor in psoriatic patients. Here we expand our functional investigation of the IL23R Arg381Gln gene variant to include AA homozygous individuals. By using isolated memory CD4+ T cells, we found attenuated IL-23-induced Th17 response in heterozygous individuals. Moreover, we found that AA homozygous individuals were strikingly unresponsive to IL-23, with minimal or no IL-17A and IL-17F production and failure of human memory Th17 cell survival/expansion. Finally, IL-23-induced Th17 response was also attenuated in age- and sex-matched GA versus GG psoriatic patients undergoing systemic treatment. Taken together, our data provide evidence for an allele-dosage effect for IL-23R Gln381 and indicate that common gene alleles associated with complex diseases might have biological effects of considerable magnitude in homozygous carriers.


Relationship Between Optic Nerve Protrusion Measured by OCT and MRI and Papilledema Severity.
To develop measures of optic nerve protrusion length (NPL) from optical coherence tomography (OCT) and magnetic resonance imagining (MRI) and compare these measures with papilledema severity in idiopathic intracranial hypertension (IIH). Optical coherence tomography and MRI scans were obtained from 11 newly diagnosed untreated IIH patients (30 ± 10 years; body mass index [BMI] 36 ± 4 kg/m2). Optic nerve protrusion length was measured for each eye using OCT and MRI independently. The relationship between the NPL measures and their association with the Frisen scale for papilledema severity were assessed. Two different OCT-based measures of NPL were derived to assess the influence of the retinal thickness on the association with papilledema severity. Additional OCT scans from 11 healthy subjects (38 ± 7 years) were analyzed to establish reliability of the NPL measurement. Optical coherence tomography and MRI measurements of NPL were significantly linearly correlated (R = 0.79, P < 0.0001). Measurements of NPL from OCT and MRI were significantly associated with Frisen papilledema grade (P < 0.0001). Mean OCT measurement of NPL in the papilledema cohort was significantly larger than in the healthy cohort (0.62 ± 0.24 vs. 0.09 ± 0.03 mm, P < 0.0001). Significant linear correlation between OCT and MRI measurements of NPL supports the reliability of the OCT-based measurements of NPL in papilledema. Significant association between the papilledema grade and OCT- and MRI-based measurements of NPL highlights the potential of NPL as an objective and more sensitive marker of papilledema severity than the Frisen scale.


Complexation of carboxylate on smectite surfaces.
We report a first principles molecular dynamics (FPMD) study of carboxylate complexation on clay surfaces. By taking acetate as a model carboxylate, we investigate its inner-sphere complexes adsorbed on clay edges (including (010) and (110) surfaces) and in interlayer space. Simulations show that acetate forms stable monodentate complexes on edge surfaces and a bidentate complex with Ca2+ in the interlayer region. The free energy calculations indicate that the complexation on edge surfaces is slightly more stable than in interlayer space. By integrating pKas and desorption free energies of Al coordinated water calculated previously (X. Liu, X. Lu, E. J. Meijer, R. Wang and H. Zhou, Geochim. Cosmochim. Acta, 2012, 81, 56-68; X. Liu, J. Cheng, M. Sprik, X. Lu and R. Wang, Geochim. Cosmochim. Acta, 2014, 140, 410-417), the pH dependence of acetate complexation has been revealed. It shows that acetate forms inner-sphere complexes on (110) in a very limited mildly acidic pH range while it can complex on (010) in the whole common pH range. The results presented in this study form a physical basis for understanding the geochemical processes involving clay-organics interactions.


Metabolizable lanthanum-coordination nanoparticles as efficient radiosensitizers for solid tumor therapy.
The clinical potential of radiotherapy cannot be realised as expected due to the inherent radioresistance of tumors. To overcome these problems, radiosensitizers containing heavy metal elements have been used in radiotherapy as efficient radiation dose enhancers. In the present study, we report the design and preparation of novel lanthanum-coordination nanoparticles, and their application as nano-sized radiosensitizers in radiotherapy against solid tumors. Via a simple one-pot hydrothermal route, these nanoparticles were fabricated without any expensive chemical reagents. The polyvinylpyrrolidone molecules used in a typical synthesis could highly enhance the dispersity and bio-compatibility of these nanoparticles. In vitro toxicity studies demonstrated that these nanoparticles had low cytotoxicity, negligible hemolysis, and no effect on blood coagulation. Upon exposure to high energy X-ray radiation, these nanoparticles possessed excellent radiosensitization effects and induced serious cellular death both in vitro and in vivo. In addition, time-dependent bio-distribution and long-term toxicity results for these nanoparticles after intravenous administration indicated their high bio-compatibility. More importantly, these metabolizable nanoparticles could be cleared up after intravenous administration along with time passing. These significant findings promise the prospective use of these nanoparticles as vigorous X-ray radiation-mediated therapeutic agents in coming cancer treatments.


Autologous strain-specific cytolytic T lymphocyte responses directed against human immunodeficiency virus type 1 Env.
The Env glycoprotein of human immunodeficiency virus is critical for the pathogenesis of the acquired immunodeficiency syndrome, and has been the prime target for candidate HIV-1 vaccines. Cytolytic T lymphocytes (CTLs) may be important for the immunologic control of HIV infection and HIV-1 Env-specific cytolytic T cells have been isolated from infected individuals and seronegative recipients of HIV-1 vaccines. Most prior studies have used assays that detect Env-specific CTLs directed against standard laboratory viral variants. These studies may be limited because the Env proteins of these laboratory strains (for example, LAI and MN) may differ significantly from the Env proteins from primary HIV-1 strains, and a single amino acid change can abrogate the recognition of HIV-1 Env by some CTL clones. Therefore, this study measured CTL activity directed against HIV-1 Env representing the infected individual's (autologous) HIV-1 viral variants. For two HIV-1-infected individuals, recombinant vaccina viruses expressing cloned HIV-1 env genes were constructed. Using an in vitro stimulation method, strain-specific CTL activity directed against autologous HIV-1 Env was detected in both individuals. From one subject, strain-specific CTL clones directed against autologous and HIV-1LAI Env were characterized. Therefore, some infected individuals have Env-specific CTLs directed against autologous strains of HIV-1. Detection and characterization of autologous Env-specific CTL activity may have important implications relative to the current HIV-1 vaccine development strategies focusing on Env derived from laboratory strains of HIV-1.


Autoimmunity in thyroid disease.
The autoimmune thyroid diseases, Graves' disease and autoimmune hypothyroidism, represent the two ends of a disease spectrum where an immune response is directed against the thyroid gland. In Graves' disease, antibodies directed against the thyrotropin receptor (TSH-R) lead to the development of glandular overactivity, while in autoimmune hypothyroidism, cell-mediated and humoral thyroid injury leads to destruction of thyroid tissue and thyroid hormone deficiency. The mechanisms by which these diseases develop are unknown, although it is likely that both diseases occur in genetically susceptible individuals exposed to a permissive environment. A number of environmental factors have been postulated to be involved in the development of autoimmune thyroid disease. There is, however, no direct evidence to support clear causality. Susceptibility loci within immune response genes have been identified although a significant component of the genetic predisposition to disease remains unknown. This review will focus on some of the studies designed to identify genes that confer susceptibility to the autoimmune disease process within the thyroid gland.


Tolerance and chimerism after renal and hematopoietic-cell transplantation.
We describe a recipient of combined kidney and hematopoietic-cell transplants from an HLA-matched donor. A post-transplantation conditioning regimen of total lymphoid irradiation and antithymocyte globulin allowed engraftment of the donor's hematopoietic cells. The patient had persistent mixed chimerism, and the function of the kidney allograft has been normal for more than 28 months since discontinuation of all immunosuppressive drugs. Adverse events requiring hospitalization were limited to a 2-day episode of fever with neutropenia. The patient has had neither rejection episodes nor clinical manifestations of graft-versus-host disease.


Effects of branched-chain volatile fatty acids on lactation performance and mRNA expression of genes related to fatty acid synthesis in mammary gland of dairy cows.
Branched-chain volatile fatty acids (BCVFA) supplements could promote lactation performance and milk quality by improving ruminal fermentation and milk fatty acid synthesis. This study was conducted to evaluate the effects of BCVFA supplementation on milk performance, ruminal fermentation, nutrient digestibility and mRNA expression of genes related to fatty acid synthesis in mammary gland of dairy cows. A total of 36 multiparous Chinese Holstein cows averaging 606±4.7 kg of BW, 65±5.2 day in milk (DIM) with daily milk production of 30.6±0.72 kg were assigned to one of four groups blocked by lactation number, milk yield and DIM. The treatments were control, low-BCVFA (LBCVFA), medium-BCVFA (MBCVFA) and high-BCVFA (HBCVFA) with 0, 30, 60 and 90 g BCVFA per cow per day, respectively. Experimental periods were 105 days with 15 days of adaptation and 90 days of data collection. Dry matter (DM) intake tended to increase, but BW changes were similar among treatments. Yields of actual milk, 4% fat corrected milk, milk fat and true protein linearly increased, but feed conversion ratio (FCR) linearly decreased with increasing BCVFA supplementation. Milk fat content linearly increased, but true protein content tended to increase. Contents of C4:0, C6:0, C8:0, C10:0, C12:0, C14:0 and C15:0 fatty acids in milk fat linearly increased, whereas other fatty acids were not affected with increasing BCVFA supplementation. Ruminal pH, ammonia N concentration and propionate molar proportion linearly decreased, but total VFA production and molar proportions of acetate and butyrate linearly increased with increasing BCVFA supplementation. Consequently, acetate to propionate ratios linearly increased. Digestibilities of DM, organic matter, CP, NDF and ADF also linearly increased. In addition, mRNA expressions of peroxisome proliferator-activated receptor γ, sterol regulatory element-binding factor 1 and fatty acid-binding protein 3 linearly increased, mRNA expressions of acetyl-coenzyme A carboxylase-α, fatty acid synthase and stearoyl-CoA desaturase quadratically increased. However, lipoprotein lipase mRNA expression was not affected by treatments. The results indicated that lactation performance and milk fat synthesis increased with BCVFA supplementation by improving ruminal fermentation, nutrient digestibility and mRNA expressions of genes related to milk fat synthesis.


A population-based comparative effectiveness study of chemoradiation regimens and sequences in stage III non-small cell lung cancer.
In patients receiving concurrent chemoradiation for locally advanced non-small cell lung cancer (NSCLC), consolidation chemotherapy is frequently given even though several randomized trials have failed to show a benefit. We explored the potential benefits of consolidation chemotherapy using a population-based comparative effectiveness approach. Surveillance, Epidemiology, and End Results-Medicare was used to identify patients with Stage III NSCLC aged ≥65 and diagnosed 2002-2009. We selected patients who received concurrent chemoradiotherapy and determined whether they were (concurrent-consolidation) or were not (concurrent-alone) treated with consolidation chemotherapy. Outcomes were overall and cancer specific survival using a conditional landmark analysis approach. 1688 patients treated with concurrent-alone or concurrent-consolidation were identified with a median follow up of 29 months. Choice of chemotherapy agents did not correlate with outcome. For concurrent-consolidation versus concurrent-alone, the median overall survival was 21 months versus 18 months, respectively (log-rank p=0.008) and the median cancer specific survival was 23 months versus 19 months, respectively (log-rank p=0.03). On multivariate analysis, concurrent-consolidation remained associated with improved overall survival (HR 0.85, p=0.04), and there was a trend for improved cancer specific survival (HR 0.87, p=0.12). Inverse probability of treatment weighting using propensity scores demonstrated similar findings. Importantly, the benefit of concurrent-consolidation held only for patients treated with carboplatin-taxane but not with cisplatin-etoposide. Survival outcomes were similar among the five most commonly employed platinum-based doublets. We found that patients receiving cisplatin during radiation do not appear to benefit from additional chemotherapy. However, for patients receiving carboplatin, consolidation chemotherapy was associated with improved overall and cancer specific survival.


Recolonisation of translocated metal-contaminated sediments by estuarine macrobenthic assemblages.
A recolonisation experiment was performed using sediments from three locations (Nords Wharf, Cockle Bay and Warners Bay) along a metal contamination gradient (Lake Macquarie, Australia). The study aimed to determine whether the source of the sediments would influence the recolonisation of benthic assemblages, providing additional information regarding the ecological risks associated with the more contaminated sediments. Sediments were translocated to two locations within the lake and retrieved after 22 weeks along with benthic samples from the surrounding sediments (ambient). Total abundance was greater in the reference treatment (Nords Wharf), with this difference being driven by polychaetes, especially capitellids. In general, univariate metrics were similar among the recolonised treatments, although evenness and diversity patterns were complex due to significant location-treatment interactions. PERMANOVA analysis demonstrated that the Nords Wharf treatments were significantly different from the more contaminated treatments (Cockle Bay and Warner's Bay) and the ambient assemblages, with no differences being detected among Cockle Bay and Warners Bay assemblages. Collectively, the findings showed that the source of the sediments influenced the composition of the recolonised assemblages, with the described approach being a powerful tool for examining the effects of location-specific sediments under environmentally relevant conditions.


Fear of exercise and health-related quality of life in patients with an implantable cardioverter defibrillator.
Several studies have reported improved survival rates thanks to the use of an implantable cardioverter defibrillator (ICD) in the treatment of patients with life-threatening arrhythmia. However, the effects of the ICD on health-related quality of life (HR-QoL) of these patients are not clear. The aim of this study is to describe HR-QoL and fear of exercise in ICD patients. Eighty-nine ICD patients from the University Hospital in Groningen, the Netherlands, participated in this study. HR-QoL was measured using the Rand-36 and the Quality of Life After Myocardial Infarction Dutch language version questionnaires. Fear of exercise was measured using the Tampa Scale for Kinesiophobia, Dutch version and the Fear Avoidance Beliefs Questionnaire, Dutch version. Association between outcome variables was analysed by linear regression analyses. Study results show that the HR-QoL of patients with ICDs in our study population is significantly worse than that of normal healthy people. Furthermore, fear of exercise is negatively associated with HR-QoL corrected for sex, age and number of years living with an ICD. After implantation of the ICD, patients with a clear fear of exercise should be identified and interventions should be considered in order to increase their HR-QoL.


Relapsing-remitting central nervous system autoimmunity mediated by GFAP-specific CD8 T cells.
Multiple sclerosis (MS) is an inflammatory disease of the CNS that causes the demyelination of nerve cells and destroys oligodendrocytes, neurons, and axons. Historically, MS has been thought to be a CD4 T cell-mediated autoimmune disease of CNS white matter. However, recent studies identified CD8 T cell infiltrates and gray matter lesions in MS patients. These findings suggest that CD8 T cells and CNS Ags other than myelin proteins may be involved during the MS disease process. In this article, we show that CD8 T cells reactive to glial fibrillary acidic protein (GFAP), a protein expressed in astrocytes, can avoid tolerance mechanisms and, depending upon the T cell-triggering event, drive unique aspects of inflammatory CNS autoimmunity. In GFAP-specific CD8 TCR-transgenic (BG1) mice, tissue resident memory-like CD8 T cells spontaneously infiltrate the gray matter and white matter of the CNS, resulting in a relapsing-remitting CNS autoimmunity. The frequency, severity, and remissions from spontaneous disease are controlled by the presence of polyclonal B cells. In contrast, a viral trigger induces GFAP-specific CD8 T effector cells to exclusively target the meninges and vascular/perivascular space of the gray and white matter of the brain, causing a rapid, acute CNS disease. These findings demonstrate that the type of CD8 T cell-triggering event can determine the presentation of distinct CNS autoimmune disease pathologies.


Fiction-reading for good or ill: eating disorders, interpretation and the case for creative bibliotherapy research.
Compared with self-help bibliotherapy, little is known about the efficacy of creative bibliotherapy or the mechanisms of its possible efficacy for eating disorders or any other mental health condition. It is clear, however, that fiction is widely used informally as a therapeutic or antitherapeutic tool and that it has considerable potential in both directions, with a possibly significant distinction between the effects of reading fiction about eating disorders (which may-contrary to theoretical predictions-be broadly negative in effect) or one's preferred genre of other fiction (which may be broadly positive). Research on creative bibliotherapy, especially systematic experimental research, is lacking and requires a medical humanities approach, drawing on knowledge and methods from psychology and cognitive literary studies as well as clinical disciplines to expand our understanding of how the dynamic processes of interpretation mediate between textual structures and characteristics of mental health and illness.


Auranofin. New oral gold compound for treatment of rheumatoid arthritis.
Eight patients with rheumatoid arthritis were treated with SK & F D-39162 (auranofin), a new oral gold compound which was effective in suppressing adjuvant-induced arthritis in rats. Clinical and humoral parameters were studied during a 3-month period of drug administration followed by a 3-month period under placebo. The drug was absorbed, well tolerated, and its action was manifested by a drop in the mean IgG blood levels in the third week of treatment accompanied by clinical improvement after 5 weeks of oral gold intake. Together with IgG changes, an increase of the albumin ratio was observed, as well as a decrease of alpha2-globulin and rheumatoid factor titres. From a total number of 60 swollen joints found initially in the 8 patients only 17 were swollen at week 12 and 9 at week 15. Although the number of patients treated was too small to allow definite conclusions, a follow-up study under placebo of clinical and laboratory changes in the same patients during another 3-month period showed that IgG serum levels rapidly reverted preceding a flare up of disease activity after withdrawal of the drug. This confirmed a direct role in cause-effect relation played by the new oral gold compound.


Development of a TaqMan Array Card for Acute-Febrile-Illness Outbreak Investigation and Surveillance of Emerging Pathogens, Including Ebola Virus.
Acute febrile illness (AFI) is associated with substantial morbidity and mortality worldwide, yet an etiologic agent is often not identified. Convalescent-phase serology is impractical, blood culture is slow, and many pathogens are fastidious or impossible to cultivate. We developed a real-time PCR-based TaqMan array card (TAC) that can test six to eight samples within 2.5 h from sample to results and can simultaneously detect 26 AFI-associated organisms, including 15 viruses (chikungunya, Crimean-Congo hemorrhagic fever [CCHF] virus, dengue, Ebola virus, Bundibugyo virus, Sudan virus, hantaviruses [Hantaan and Seoul], hepatitis E, Marburg, Nipah virus, o'nyong-nyong virus, Rift Valley fever virus, West Nile virus, and yellow fever virus), 8 bacteria (Bartonella spp., Brucella spp., Coxiella burnetii, Leptospira spp., Rickettsia spp., Salmonella enterica and Salmonella enterica serovar Typhi, and Yersinia pestis), and 3 protozoa (Leishmania spp., Plasmodium spp., and Trypanosoma brucei). Two extrinsic controls (phocine herpesvirus 1 and bacteriophage MS2) were included to ensure extraction and amplification efficiency. Analytical validation was performed on spiked specimens for linearity, intra-assay precision, interassay precision, limit of detection, and specificity. The performance of the card on clinical specimens was evaluated with 1,050 blood samples by comparison to the individual real-time PCR assays, and the TAC exhibited an overall 88% (278/315; 95% confidence interval [CI], 84% to 92%) sensitivity and a 99% (5,261/5,326, 98% to 99%) specificity. This TaqMan array card can be used in field settings as a rapid screen for outbreak investigation or for the surveillance of pathogens, including Ebola virus.


Using timed up and go and usual gait speed to predict incident disability in daily activities among community-dwelling adults aged 65 and older.
To compare the ability of Timed Up and Go (TUG) and usual gait speed (UGS) to predict incident disability completing basic activities of daily living (ADL) and instrumental ADL (IADL) in older adults free of disability at baseline, and to provide estimates for the probability of incident disability at different levels of baseline mobility performance. Data from the first 2 waves of The Irish Longitudinal Study on Ageing, a study assessing health, economic, and social aspects of ageing in adults aged ≥50 years. A nationally representative, population-based sample of community-dwelling adults. Participants aged ≥65 years who completed mobility tests during a health assessment, had no reported difficulty in ADL/IADL, and had a Mini-Mental State Examination score ≥24 were re-interviewed after 2 years (n=1664). Not applicable. Participants completed the TUG and UGS at baseline and indicated difficulty in a number of basic ADL and IADL at follow-up. Receiver operating characteristic analysis indicated that TUG and UGS are acceptable tools to predict disability in ADL and IADL (area under the curve [AUC]=.65-.75) with no significant difference between them (P>.05). Both were excellent predictors of difficulty in higher-level functioning tasks such as preparing hot meals, taking medications, and managing money (AUC>.80). Predictive probabilities were obtained across a range of performance levels. TUG and UGS have similar predictive ability in relation to incident disability in basic ADL and IADL. Predictive probabilities can be used to identify those most at risk and in need of particular services. Since improving physical function can prevent or delay dependence in ADL/IADL, TUG and UGS can also provide performance goals and feedback during exercise interventions.


Extracellular processing of peptide antigens that bind class I major histocompatibility molecules.
One problem associated with the use of synthetic peptides as antigens in vivo is their susceptibility to inactivation by proteolytic degradation. A situation is described in which a serum protease, angiotensin-converting enzyme (ACE), is actually responsible for the class I binding activity of a commonly used influenza antigen, nucleoprotein (NP)(147-158R-). This peptide has been reported to be a highly efficient class I antigen. Evidence is presented that demonstrates that the peptide is inactive until cleaved by ACE, which is a normal constituent of serum. The enzyme removes a COOH-terminal dipeptide resulting in the sequence NP(147-155), which is identical to the naturally processed peptide. Such extracellular processing of peptides and proteins may occur for a variety of antigens both in vitro and in vivo, and could have important implications for the design of proteolytically resistant vaccines.


Comparing Trauma Exposure, Mental Health Needs, and Service Utilization Across Clinical Samples of Refugee, Immigrant, and U.S.-Origin Children.
Most mental health services for trauma-exposed children and adolescents were not originally developed for refugees. Information is needed to help clinicians design services to address the consequences of trauma in refugee populations. We compared trauma exposure, psychological distress, and mental health service utilization among children and adolescents of refugee-origin, immigrant-origin, and U.S.-origin referred for assessment and treatment by U.S. providers in the National Child Traumatic Stress Network (NCTSN). We used propensity score matching to compare trauma profiles, mental health needs, and service use across three groups. Our sample comprised refugee-origin youth (n = 60, 48.3% female, mean age = 13.07 years) and propensity-matched samples of immigrant-origin youth (n = 143, 60.8% female, mean age = 13.26 years), and U.S.-origin youth (n = 140, 56.1% female, mean age = 12.11 years). On average, there were significantly more types of trauma exposure among refugee youth than either U.S.-origin youth (p < .001) or immigrant youth (p ≤ .001). Compared with U.S.-origin youth, refugee youth had higher rates of community violence exposure, dissociative symptoms, traumatic grief, somatization, and phobic disorder. In contrast, the refugee group had comparably lower rates of substance abuse and oppositional defiant disorder (ps ranging from .030 to < .001).This clinic-referred sample of refugee-origin youth presented with distinct patterns of trauma exposure, distress symptoms, and service needs that merit consideration in services planning.


Cardiotoxins: Functional Role of Local Conformational Changes.
Cardiotoxins (CTs) from snake venoms are a family of homologous highly basic proteins that have extended hydrophobic patterns on their molecular surfaces. CTs are folded into three β-structured loops stabilized by four disulfide bridges. Being well-structured in aqueous solution, most of these proteins are membrane-active, although the exact molecular mechanisms of CT-induced cell damage are still poorly understood. To elucidate the structure-function relationships in CTs, a detailed knowledge of their spatial organization and local conformational dynamics is required. Protein domain motions can be either derived from a set of experimental structures or generated via molecular dynamics (MD). At the same time, traditional clustering algorithms in the Cartesian coordinate space often fail to properly take into account the local large-scale dihedral angle transitions that occur in MD simulations. This is because such perturbations are usually offset by changes in the neighboring dihedrals, thus preserving the overall protein fold. States with a "locally perturbed" backbone were found in experimental 3D models of some globular proteins and have been shown to be functionally meaningful. In this work, the possibility of large-scale dihedral angle transitions in the course of long-term MD in explicit water was explored for three CTs with different membrane activities: CT 1, 2 (Naja oxiana) and CT A3 (Naja atra). Analysis of the MD-derived distributions of backbone torsion angles revealed several important common and specific features in the structural/dynamic behavior of these proteins. First, large-amplitude transitions were detected in some residues located in the functionally important loop I region. The K5/L6 pair of residues was found to induce a perturbation of the hydrophobic patterns on the molecular surface of CTs-reversible breaking of a large nonpolar zone ("bottom") into two smaller ones and their subsequent association. Second, the characteristic sizes of these patterns perfectly coincided with the dimensions of the nonpolar zones on the surfaces of model two-component (zwitterionic/anionic) membranes. Taken together with experimental data on the CT-induced leakage of fluorescent dye from such membranes, these results allowed us to formulate a two-stage mechanism of CT-membrane binding. The principal finding of this study is that even local conformational dynamics of CTs can seriously affect their functional activity via a tuning of the membrane binding site - specific "hot spots" (like the K5/L6 pair) in the protein structure.


Mannose inhibits hyaluronan synthesis by down-regulation of the cellular pool of UDP-N-acetylhexosamines.
We found that d-mannose dose-dependently decreases hyaluronan synthesis in cultured epidermal keratinocytes to approximately 50%, whereas glucose, galactose, and fructose up to 20 mm concentration had no effect. The full inhibition occurred within 3 h following introduction of mannose and did not involve down-regulation of hyaluronan synthase (Has1-3) mRNA. Following introduction of mannose, there was an approximately 50% reduction in the cellular concentration of UDP-N-acetylhexosamines (UDP-HexNAc, i.e. UDP-N-acetylglucosamine and UDP-N-acetylgalactosamine). On the other hand, 2 mm glucosamine in the culture medium increased UDP-HexNAc content, stimulated hyaluronan secretion, and negated the effect of mannose, supporting the notion that the inhibition by mannose on hyaluronan synthesis was because of down-regulated UDP-HexNAc content. The content of UDP-glucuronic acid, the other building block for hyaluronan synthesis, was not reduced by mannose but declined from 39 to 14% of controls by 0.2-1.0 mm 4-methylumbelliferone, another compound that inhibits hyaluronan synthesis. Applying 4-methylumbelliferone and mannose together produced the expected reductions in both UDP sugars but no additive reduction in hyaluronan production, indicating that the concentration of each substrate alone can limit hyaluronan synthesis. Mannose is a potentially useful tool in studies on hyaluronan-dependent cell functions, as demonstrated by reduced rates of keratinocyte proliferation and migration, functions known to depend on hyaluronan synthesis.


Epithelial Ca(2+) channel expression and Ca(2+) uptake in developing zebrafish.
The purpose of the present work was to study the possible role of the epithelial Ca(2+) channel (ECaC) in the Ca(2+) uptake mechanism in developing zebrafish (Danio rerio). With rapid amplification of cDNA ends, full-length cDNA encoding the ECaC of zebrafish (zECaC) was cloned and sequenced. The cloned zECaC was 2,578 bp in length and encoded a protein of 709 amino acids that showed up to 73% identity with previously described vertebrate ECaCs. The zECaC was found to be expressed in all tissues examined and began to be expressed in the skin covering the yolk sac of embryos at 24 h postfertilization (hpf). zECaC-expressing cells expanded to cover the skin of the entire yolk sac after embryonic development and began to occur in the gill filaments at 96 hpf, and thereafter zECaC-expressing cells rapidly increased in both gills and yolk sac skin. Corresponding to ECaC expression profile, the Ca(2+) influx and content began to increase at 36-72 hpf. Incubating zebrafish embryos in low-Ca(2+) (0.02 mM) freshwater caused upregulation of the whole body Ca(2+) influx and zECaC expression in both gills and skin. Colocalization of zECaC mRNA and the Na(+)-K(+)-ATPase alpha-subunit (a marker for mitochondria-rich cells) indicated that only a portion of the mitochondria-rich cells expressed zECaC mRNA. These results suggest that the zECaC plays a key role in Ca(2+) absorption in developing zebrafish.


Partial purification and characterization of an endo-alpha-N-acetylgalactosaminidase from the culture medium of Streptomyces sp. OH-11242.
For the purification of a new type of endo-alpha-N-acetylgalactosaminidase from the culture medium of Streptomyces sp. OH-11242 (endo-GalNAc-ase-S) [Iwase, Ishii, Ishihara, Tanaka, Omura & Hotta (1988) Biochem. Biophys. Res. Commun. 151, 422-428], a method for assaying enzyme activity was established. Using purified pig gastric mucus glycoprotein (PGM) as the substrate, oligosaccharides liberated from PGM were pyridylaminated, and the reducing terminal sugars of oligosaccharides larger than Gal beta 1-3GalNAc were analysed by h.p.1.c. The crude enzyme of endo-GalNAc-ase-S was prepared as an 80% (w/v) ammonium sulphate precipitate from the concentrated culture medium. The enzyme was partially purified by gel chromatofocusing and subsequent DEAE-Toyopearl chromatography. Endo-enzyme activity eluted around pI 4.8 on a gel chromatofocusing column and eluted with 0.19-0.25 M-NaCl on a DEAE-Toyopearl column. In the enzyme fraction obtained, no exo-glycosidases or proteases could be detected. The molecular mass of the enzyme was estimated as 105 kDa by gel filtration, and the optimum pH was 5.5. Endo-GalNAc-ase-S hydrolysed the O-glycosidic linkage between GalNAc and Ser (Thr) in 3H-labelled and unlabelled asialofetuin, liberating both the disaccharide (Gal beta 1-3GalNAc) and the tetrasaccharide [Gal beta 1-3 (Gal beta 1-4GlcNAc beta 1-6)GalNAc]. When endo-alpha-N-acetylgalactosaminidase from Alcaligenes sp. (endo-GalNac-ase-A) was incubated with 3H-labelled and unlabelled asialofetuin, only the disaccharide (Gal beta 1-3GalNAc) was liberated.


Rangeland dynamics: investigating vegetation composition and structure of urban and exurban prairie dog habitat.
Rapid human population growth and habitat modification in the western United States has led to the formation of urban and exurban rangelands. Many of these rangelands are also home to populations of black-tailed prairie dogs (Cynomys ludovicianus). Our study aimed to compare the vegetation composition of an urban and exurban rangeland, and explore the role that prairie dogs play in these systems. The percent absolute canopy cover of graminoids (grasses and grass-likes), forbs, shrubs, litter, and bare ground were estimated at sampling areas located on and off prairie dog colonies at an urban and an exurban site. Herbaceous forage quality and quantity were determined on plant material collected from exclosure cages located on the colony during the entire growing season, while a relative estimate of prairie dog density was calculated using maximum counts. The exurban site had more litter and plant cover and less bare ground than the urban site. Graminoids were the dominant vegetation at the exurban plots. In contrast, mostly introduced forbs were found on the urban prairie dog colony. However, the forage quality and quantity tests demonstrated no difference between the two colonies. The relative prairie dog density was greater at the urban colony, which has the potential to drive greater vegetation utilization and reduced cover. Exurban rangeland showed lower levels of impact and retained all of the plant functional groups both on- and off-colony. These results suggest that activities of prairie dogs might further exacerbate the impacts of humans in fragmented urban rangeland habitats. Greater understanding of the drivers of these impacts and the spatial scales at which they occur are likely to prove valuable in the management and conservation of rangelands in and around urban areas.


Practical approach to paediatric enteral nutrition: a comment by the ESPGHAN committee on nutrition.
Enteral nutrition support (ENS) involves both the delivery of nutrients via feeding tubes and the provision of specialised oral nutritional supplements. ENS is indicated in a patient with at least a partially functioning digestive tract when oral intake is inadequate or intake of normal food is inappropriate to meet the patients' needs. The aim of this comment by the Committee on Nutrition of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition is to provide a clinical practice guide to ENS, based on the available evidence and the clinical expertise of the authors. Statements and recommendations are presented, and future research needs highlighted, with a particular emphasis placed on a practical approach to ENS.Among the wide array of enteral formulations, standard polymeric feeds based on cow's-milk protein with fibre and age adapted for energy and nutrient content are suitable for most paediatric patients. Whenever possible, intragastric is preferred to postpyloric delivery of nutrients, and intermittent feeding is preferred to continuous feeding because it is more physiological. An anticipated duration of enteral nutrition (EN) exceeding 4 to 6 weeks is an indication for gastrostomy or enterostomy. Among the various gastrostomy techniques available, percutaneous endoscopic gastrostomy is currently the first option. In general, both patients and caregivers express satisfaction with this procedure, although it is associated with a number of well-recognised complications. We strongly recommend the development and application of procedural protocols that include scrupulous attention to hygiene, as well as regular monitoring by a multidisciplinary nutrition support team to minimise the risk of EN-associated complications.


The Association between Serum Serine and Glycine and Related-Metabolites with Pancreatic Cancer in a Prospective Cohort Study.
Background. Serine and glycine play an important role in the folate-dependent one-carbon metabolism. The metabolism of serine and glycine has been shown to be associated with cancer cell proliferation. No prior epidemiologic study has investigated the associations for serum levels of serine and glycine with pancreatic cancer risk. Methods. We conducted a nested case-control study involved 129 incident pancreatic cancer cases and 258 individually matched controls within a prospective cohort study of 18,244 male residents in Shanghai, China. Glycine and serine and related metabolites in pre-diagnostic serum were quantified using gas chromatography-tandem mass spectrometry. A conditional logistic regression method was used to evaluate the associations for serine, glycine, and related metabolites with pancreatic cancer risk with adjustment for potential confounders. Results: Odds ratios (95% confidence intervals) of pancreatic cancer for the highest quartile of serine and glycine were 0.33 (0.14−0.75) and 0.25 (0.11−0.58), respectively, compared with their respective lowest quartiles (both p's < 0.01). No significant association with risk of pancreatic cancer was observed for other serine- or glycine related metabolites including cystathionine, cysteine, and sarcosine. Conclusion. The risk of pancreatic cancer was reduced by more than 70% in individuals with elevated levels of glycine and serine in serum collected, on average, more than 10 years prior to cancer diagnosis in a prospectively designed case-control study. These novel findings support a protective role of serine and glycine against the development of pancreatic cancer in humans that might have an implication for cancer prevention.


Protective role of murine β-defensins 3 and 4 and cathelin-related antimicrobial peptide in Fusarium solani keratitis.
Antimicrobial peptides (AMPs), such as β-defensins and cathelicidins, are essential components of innate and adaptive immunity owing to their extensive multifunctional activities. However, their role in fungal infection in vivo remains elusive. In this study, we investigated the protective effect of murine β-defensin 3 (mBD3), mBD4, and the cathelicidin cathelin-related antimicrobial peptide (CRAMP) in a murine model of Fusarium solani keratitis. C57BL/6 mice showed significant corneal disease 1 and 3 days after infection, which was accompanied by enhanced expression of β-defensins and CRAMP. Disease severity was significantly improved 7 days after infection, at which time AMP expression was returning to baseline. Mice deficient in mBD3 (genetic knockout), mBD4 (short interfering RNA knockdown), or CRAMP (genetic knockout) exhibited enhanced disease severity and progression, increased neutrophil recruitment, and delayed pathogen elimination compared to controls. Taken together, these data suggest a vital role for AMPs in defense against F. solani keratitis, a potentially blinding corneal disease.


Viral modulation of cell death by inhibition of caspases.
Caspases are key effectors of the apoptotic process. Some of them play important roles in the immune system, being involved in the proteolytic maturation of the key cytokines, including interleukin 1beta (IL-1beta) and IL-18. The latter directs the production of interferon gamma (IFN-gamma). Among pathogens, particularly viruses express various modulators of caspases that inhibit their activity by direct binding. By evading the apoptotic process, viruses can better control their production in the infected cell and avoid the attack of the immune system. Targeting the maturation of the key cytokines involved in the initiation of (antiviral) immune response helps to avoid recognition and eradication by the immune system. The three main classes of caspase inhibitors frequently found among viruses include serine proteinase inhibitors (serpins: CrmA/SPI-2), viral IAPs (vIAPs) and p35. Their molecular mechanisms of action, structures and overall influence on cellular physiology are discussed in the review below.


Model-based cost-effectiveness analyses for prostate cancer chemoprevention : a review and summary of challenges.
Decision-analytic modelling is often used to examine the economics associated with using a specific treatment. As a result, it is important to understand structural and methodological approaches used in published decision-analytic models for examining the cost effectiveness of 5α-reductase inhibitors (5ARIs) for prostate cancer (PCa) chemoprevention. This understanding allows us to provide recommendations for using decision modelling in future economic evaluations of chemoprevention for PCa. A review of the published literature was performed using MEDLINE and the Cochrane Library to identify studies involving mathematical decision models that evaluated 5ARIs for PCa chemoprevention. Published articles were reviewed and key modelling components were extracted and summarized. Recommendations for developing future decision models to examine the economic consequences of PCa chemoprevention were presented. We identified seven published models of PCa chemoprevention. All the models identified used a Markov framework with time horizons ranging from 4 years to lifetime. Due to the wide range of patient risk groups examined, PCa risk data were taken from the Surveillance, Epidemiology, and End Results (SEER) and other databases or estimates published in relevant clinical trials. Treatment effects included change in the incidence of high- and low-grade PCa and impacts on benign prostate hyperplasia. Adverse events were considered to affect compliance, discontinuation and quality of life. Quality-of-life impacts were similar among studies. Examination of modelling parameter sensitivities was comprehensive. Published models have examined the cost effectiveness of PCa chemoprevention; however, limitations exist. Decision models should take into account the full PCa clinical pathway when compiling health states. The time horizon should be long enough to consider the full benefit of chemoprevention while allowing actual time receiving the drug to occur from the start of the model until a man's life expectancy is less than 10 years. Baseline PCa risk should be specific to the population of concern. Models should examine the impact on both low- and high-grade tumours and account for the impact of 5ARIs on benign prostatic hyperplasia. Because chemoprevention has an upfront effect, the structure of the model should be constructed so that the downstream effect of avoiding or delaying recurrence can be considered. Adverse events due to chemoprevention should be considered through compliance, discontinuation or quality-of-life impact, and understanding the impact of avoiding PCa and benign prostatic hyperplasia events are important model properties.


Did send-down experience benefit youth? A reevaluation of the social consequences of forced urban-rural migration during China's Cultural Revolution.
During China's Cultural Revolution, a large proportion of urban youth were forced to go to the countryside as a result of the state's "send-down" policy. Past research has been ambivalent about the long-term social consequences for the Chinese youth who experienced send-down. Some scholars have suggested that the send-down experience may have yielded beneficial effects. To test this claim, we analyze data from the Survey of Family Life in Urban China, which we conducted in three large cities in 1999. Questions available in this data set allow us to ascertain the send-down experience of both the respondent and a sibling and educational attainment at the times of send-down and return. Our analyses of the new data show that the send-down experience does not seem to have benefited the affected Chinese youth. Differences in social outcomes between those who experienced send-down and those who did not are either non-existent or spurious due to other social processes.


High-throughput screening and analysis of genes of Xanthomonas citri subsp. citri involved in citrus canker symptom development.
Citrus canker is caused by Xanthomonas citri subsp. citri and is one of the most devastating diseases on citrus plants. To investigate the virulence mechanism of this pathogen, a mutant library of strain 306 containing approximately 22,000 mutants was screened for virulence-deficient mutants in grapefruit (Citrus paradise). Eighty-two genes were identified that contribute to citrus canker symptom development caused by X. citri subsp. citri. Among the 82 identified genes, 23 genes were classified as essential genes, as mutation of these genes caused severe reduction of bacterial growth in M9 medium. The remaining 59 genes were classified as putative virulence-related genes that include 32 previously reported virulence-related genes and 27 novel genes. The 32 known virulence-related genes include genes that are involved in the type III secretion system (T3SS) and T3SS effectors, the quorum-sensing system, extracellular polysaccharide and lipopolysaccharide synthesis, and general metabolic pathways. The contribution to pathogenesis by nine genes (pthA4, trpG, trpC, purD, hrpM, peh-1, XAC1230, XAC1548, and XAC3049) was confirmed by complementation assays. We further validated the mutated genes and their phenotypes by analyzing the EZ-Tn5 insertion copy number using Southern blot analysis. In conclusion, we have significantly advanced our understanding of the putative genetic determinants of the virulence mechanism of X. citri subsp. citri by identifying 59 putative virulence-related genes, including 27 novel genes.


Nickel hydroxide nanosheet membranes with fast water and organics transport for molecular separation.
Two-dimensional nanosheets of late show great promise as novel materials for size-selective separation membranes of high efficiency. Herein, we demonstrate a novel laminated nanofiltration membrane for fast water purification and organic solvent nanofiltration using the 1 nm-thick and 50 nm-wide nickel hydroxide nanosheets that are facilely prepared by a green chemistry method. The resulting membranes exhibit uniform and flectional two-dimensional laminated structure. With about 1 nm high laminated channels, they allow super-fast transport of water and organic solvents. The water and organic fluxes are three orders of magnitude higher than commercially available polymeric nanofiltration membranes. In addition, the membranes have high retention for organic dyes in aqueous and organic solutions. Typically, the 3.18 μm-thick membrane with the molecular weight cut-off of 328 g mol-1 has an outstanding pure water flux of 99 L m-2 h-1 bar-1 and up to 97% rejection for direct yellow dye molecules. The newly developed nickel hydroxide nanosheets and the subsequent membranes have great potential application in water purification, organic solvent filtration and electronic devices.


Indian family systems, collectivistic society and psychotherapy.
Indian society is collectivistic and promotes social cohesion and interdependence. The traditional Indian joint family, which follows the same principles of collectivism, has proved itself to be an excellent resource for the care of the mentally ill. However, the society is changing with one of the most significant alterations being the disintegration of the joint family and the rise of nuclear and extended family system. Although even in today's changed scenario, the family forms a resource for mental health that the country cannot neglect, yet utilization of family in management of mental disorders is minimal. Family focused psychotherapeutic interventions might be the right tool for greater involvement of families in management of their mentally ill and it may pave the path for a deeper community focused treatment in mental disorders. This paper elaborates the features of Indian family systems in the light of the Asian collectivistic culture that are pertinent in psychotherapy. Authors evaluate the scope and effectiveness of family focused psychotherapy for mental disorders in India, and debate the issues and concerns faced in the practice of family therapy in India.


Oxygen-dependent generation of a graded polydopamine coating on nanofibrous materials for controlling stem cell functions.
Substrates modified with gradient surface chemistry are of fundamental importance for designing a new bio-interface in biomaterial research and tissue engineering. However, current gradient fabrication strategies are not easily accessible to most laboratories due to complex, expensive, and expertise-requiring procedures. In this study, we generated a gradient of polydopamine (PD) coating on a PLLA nanofiber surface using a spatially restricted supply of oxygen in the reaction solution. Analysis of the oxygen distribution revealed that oxygen availability varied along different reaction solution depths during dopamine polymerization. We then extensively investigated the effects of different parameters, such as tilting angle, reaction time, pH of the reaction solution, and concentration of dopamine, on PD gradient formation, which should be appropriately modulated for PD gradient on nanofibers. Further, culturing of human mesenchymal stem cells (hMSCs) on the PD gradient nanofiber resulted in a gradient of adhesion and spreading from high to low PD coating. However, the proliferation rate was not affected by the PD gradient, with an approximately 3-fold change after 5 days of culture. Maintenance of the stem cell density gradient on the PD gradient nanofiber resulted in controlled osteogenic differentiation, which was greater in the higher PD-coated area. Interestingly, stemness analysis showed a reverse trend relative to osteogenic differentiation of hMSCs. In summary, the spatially controlled polymerization of dopamine can be a versatile tool to generate substrates with gradient surface chemistry, which holds promise to direct stem cell behavior.


Factors influencing the implementation of screening and brief interventions for alcohol use in primary care practices: a systematic review using the COM-B system and Theoretical Domains Framework.
Alcohol is a leading risk factor contributing to the global burden of disease. Several national and international agencies recommend that screening and brief interventions (SBI) should be routinely delivered in primary care settings to reducing patients' alcohol consumption. However, evidence shows that such activities are seldom implemented in practice. A review of the barriers and facilitators mediating implementation, and how they fit with theoretical understandings of behaviour change, to inform the design of implementation interventions is lacking. This study aimed to conduct a theory-informed review of the factors influencing general practitioners' and primary care nurses' routine delivery of alcohol SBI in adults. A systematic literature search was carried out in four electronic databases (Medline, CINAHL, CENTRAL, PsycINFO) using comprehensive search strategies. Both qualitative and quantitative studies were included. Two authors independently abstracted and thematically grouped the data extracted. The barriers and facilitators identified were mapped to the domains of the Capability-Opportunity-Motivation-Behaviour system/Theoretical Domains Framework (TDF). Eighty-four out of the 258 studies identified met the selection criteria. The majority of the studies reported data on the views of general practitioners (n = 60) and used a quantitative design (n = 49). A total of 660 data items pertaining to barriers and 253 data items pertaining to facilitators were extracted and thematically grouped into 46 themes. The themes mapped to at least one of the 14 domains of the TDF. The three TDF domains with the highest number of data units coded were 'Environmental Context and Resources' (n = 158, e.g. lack of time), 'Beliefs about Capabilities' (n = 134, e.g. beliefs about the ability to deliver screening and brief advice and in helping patients to cut down) and 'Skills' (n = 99, e.g. lack of training). This study identified a range of potential barriers and facilitators to the implementation of alcohol SBI delivery in primary care and adds to the scarce body of literature that identifies the barriers and facilitators from a theoretical perspective. Given that alcohol SBI is seldom implemented, this review provides researchers with a tool for designing novel theory-oriented interventions to support the implementation of such activity. PROSPERO CRD42016052681.


The Munich MIDY Pig Biobank - A unique resource for studying organ crosstalk in diabetes.
The prevalence of diabetes mellitus and associated complications is steadily increasing. As a resource for studying systemic consequences of chronic insulin insufficiency and hyperglycemia, we established a comprehensive biobank of long-term diabetic INSC94Y transgenic pigs, a model of mutant INS gene-induced diabetes of youth (MIDY), and of wild-type (WT) littermates. Female MIDY pigs (n = 4) were maintained with suboptimal insulin treatment for 2 years, together with female WT littermates (n = 5). Plasma insulin, C-peptide and glucagon levels were regularly determined using specific immunoassays. In addition, clinical chemical, targeted metabolomics, and lipidomics analyses were performed. At age 2 years, all pigs were euthanized, necropsied, and a broad spectrum of tissues was taken by systematic uniform random sampling procedures. Total beta cell volume was determined by stereological methods. A pilot proteome analysis of pancreas, liver, and kidney cortex was performed by label free proteomics. MIDY pigs had elevated fasting plasma glucose and fructosamine concentrations, C-peptide levels that decreased with age and were undetectable at 2 years, and an 82% reduced total beta cell volume compared to WT. Plasma glucagon and beta hydroxybutyrate levels of MIDY pigs were chronically elevated, reflecting hallmarks of poorly controlled diabetes in humans. In total, ∼1900 samples of different body fluids (blood, serum, plasma, urine, cerebrospinal fluid, and synovial fluid) as well as ∼17,000 samples from ∼50 different tissues and organs were preserved to facilitate a plethora of morphological and molecular analyses. Principal component analyses of plasma targeted metabolomics and lipidomics data and of proteome profiles from pancreas, liver, and kidney cortex clearly separated MIDY and WT samples. The broad spectrum of well-defined biosamples in the Munich MIDY Pig Biobank that will be available to the scientific community provides a unique resource for systematic studies of organ crosstalk in diabetes in a multi-organ, multi-omics dimension.


A nationwide prospective multicenter study of external ventricular drainage: accuracy, safety, and related complications.
External ventricular drainage (EVD) catheters are associated with complications such as EVD catheter infection (ECI), intracranial hemorrhage (ICH), and suboptimal placement. The aim of this study was to investigate the rates of EVD catheter complications and their associated risk factor profiles in order to optimize the safety and accuracy of catheter insertion. A total of 348 patients with urgently placed EVD catheters were included as a part of a prospective multicenter observational cohort. Strict definitions were applied for each complication category. The rates of misplacement, ECI/ventriculitis, and ICH were 38.6%, 12.2%, and 9.2%, respectively. Catheter misplacement was associated with midline shift (p = 0.002), operator experience (p = 0.031), and intracranial length (p < 0.001). Although mostly asymptomatic, ICH occurred more often in patients receiving prophylactic low-molecular-weight heparin (LMWH) (p = 0.002) and those who required catheter replacement (p = 0.026). Infectious complications (ECI/ventriculitis and suspected ECI) occurred more commonly in patients whose catheters were inserted at the bedside (p = 0.004) and those with smaller incisions (≤ 1 cm) (p < 0.001). ECI/ventriculitis was not associated with preinsertion antibiotic prophylaxis (p = 0.421), catheter replacement (p = 0.118), and catheter tunneling length (p = 0.782). EVD-associated complications are common. These results suggest that the operating room setting can help reduce the risk of infection, but not the use of preoperative antibiotic prophylaxis. Although EVD-related ICH was associated with LMWH prophylaxis for deep vein thrombosis, there were no significant clinical manifestations in the majority of patients. Catheter misplacement was associated with operator level of training and midline shift. Information from this multicenter prospective cohort can be utilized to increase the safety profile of this common neurosurgical procedure.


Two-photon graphene oxide/aptamer nanosensing conjugate for in vitro or in vivo molecular probing.
Two-photon excitation (TPE) with near-infrared (NIR) photons as the excitation source have the unique properties of lower tissue autofluorescence and self-absorption, reduced photodamage and photobleaching, higher spatial resolution, and deeper penetration depth (>500 μm). Carbon nanomaterials, for example, graphene oxide (GO), have the advantages of good biocompatibility, efficient transporters into cells, protecting the carried DNA or peptides from enzymatic cleavage, and super fluorescence quenching efficiency. By combination of the nanostructured carbon materials with the TPE technique, herein we have designed an aptamer-two-photon dye (TPdye)/GO TPE fluorescent nanosensing conjugate for molecular probing in biological fluids, living cells, and zebrafish. This approach takes advantage of the exceptional quenching capability of GO for the proximate TP dyes and the higher affinity of single-stranded DNA on GO than the aptamer-target complex. Successful in vitro and in vivo detection of ATP was demonstrated with this sensing strategy. Our results reveal that the GO/Aptamer-TPdye system not only is a robust, sensitive, and selective sensor for quantitative detection of ATP in the complex biological environment but also can be efficiently delivered into live cells or tissues and act as a "signal-on" in vivo sensor for specific, high-contrast imaging of target biomolecules. Our design provides a methodology model scheme for development of future carbon nanomaterial-based two-photon fluorescent probes for in vitro or in vivo determination of biological or biologically relevant species.


Mapping the Bibliometrics Landscape of AI in Medicine: Methodological Study.
Artificial intelligence (AI), conceived in the 1950s, has permeated numerous industries, intensifying in tandem with advancements in computing power. Despite the widespread adoption of AI, its integration into medicine trails other sectors. However, medical AI research has experienced substantial growth, attracting considerable attention from researchers and practitioners. In the absence of an existing framework, this study aims to outline the current landscape of medical AI research and provide insights into its future developments by examining all AI-related studies within PubMed over the past 2 decades. We also propose potential data acquisition and analysis methods, developed using Python (version 3.11) and to be executed in Spyder IDE (version 5.4.3), for future analogous research. Our dual-pronged approach involved (1) retrieving publication metadata related to AI from PubMed (spanning 2000-2022) via Python, including titles, abstracts, authors, journals, country, and publishing years, followed by keyword frequency analysis and (2) classifying relevant topics using latent Dirichlet allocation, an unsupervised machine learning approach, and defining the research scope of AI in medicine. In the absence of a universal medical AI taxonomy, we used an AI dictionary based on the European Commission Joint Research Centre AI Watch report, which emphasizes 8 domains: reasoning, planning, learning, perception, communication, integration and interaction, service, and AI ethics and philosophy. From 2000 to 2022, a comprehensive analysis of 307,701 AI-related publications from PubMed highlighted a 36-fold increase. The United States emerged as a clear frontrunner, producing 68,502 of these articles. Despite its substantial contribution in terms of volume, China lagged in terms of citation impact. Diving into specific AI domains, as the Joint Research Centre AI Watch report categorized, the learning domain emerged dominant. Our classification analysis meticulously traced the nuanced research trajectories across each domain, revealing the multifaceted and evolving nature of AI's application in the realm of medicine. The research topics have evolved as the volume of AI studies increases annually. Machine learning remains central to medical AI research, with deep learning expected to maintain its fundamental role. Empowered by predictive algorithms, pattern recognition, and imaging analysis capabilities, the future of AI research in medicine is anticipated to concentrate on medical diagnosis, robotic intervention, and disease management. Our topic modeling outcomes provide a clear insight into the focus of AI research in medicine over the past decades and lay the groundwork for predicting future directions. The domains that have attracted considerable research attention, primarily the learning domain, will continue to shape the trajectory of AI in medicine. Given the observed growing interest, the domain of AI ethics and philosophy also stands out as a prospective area of increased focus.


Photodynamic therapy of cervical cancer by eradication of cervical cancer cells and cervical cancer stem cells.
The heterogeneous nature of cancer puts cancer stem cells (CSCs) at the beating heart of the tumour. Because of their inherent characteristics of stemness, CSCs evade putative cancer therapies, resulting in treatment resistance or tumour recurrence after a seemingly successful treatment. To prevent treatment resistance and cancer recurrence, killing the beating heart of the tumour is of utmost importance. This study therefore, sought to determine the effect of Photodynamic Therapy (PDT) in eradicating cervical cancer and cervical CSCs. Cervical CSCs were isolated from a cervical adenocarcinoma cell line, HeLa cells, and grown in liquid medium incubated at 37° C, 5% CO2 and 85% humidity. Increasing doses of AlPcSmix photosensitizer were administered to both the total cell population and the isolated CSCs, and irradiated using 673.2 nm diode laser. Post-irradiation cellular changes were observed using biochemical assays and microscopy to determine the response of both the total cell population and the CSCs. Results showed a dose-dependent response of both cell populations to treatment, by demonstration of significant morphologic changes, increased cytotoxicity, and decreased cell viability and proliferation. The study suggested that PDT using AlPcSmix is a very effective treatment method for the eradication of cervical cancer cells and cervical CSCs, in vitro.


[Vertical transmission of HIV, syphilis and hepatitis B in the municipality with the highest incidence of AIDS in Brazil: a population-based study from 2002 to 2007].
The objective of this study was to verify the prevalence and vertical transmission rate of HIV, syphilis and hepatitis B in pregnant women in the municipality of Itajaí, state of Santa Catarina, Brazil, during the 2002-2007 period. Data were collected in a retrospective population-based longitudinal study using computerized medical records of the state and local health authorities during the 2002-2007 period for HIV, and 2004-2007 for syphilis and hepatitis B. The prevalence of HIV, acute hepatitis B, chronic hepatitis B and syphilis in pregnant women was 1.7%, 0.41%, 0.46%, and 0.43%, respectively. Overall, vertical transmission of HIV was 6.28%, although it was less than 5% among women diagnosed with HIV before or during pregnancy, compared to 20% and 55% among women first diagnosed with HIV during and after delivery, respectively. Vertical transmission of syphilis was 68.89%. No trend was confirmed for the transmission rate either regarding the year of diagnosis or age group of pregnant women. Almost 44% of HIV infected pregnant women knew their HIV status before becoming pregnant; the HIV transmission rate for these women was less than 5%. No case of vertical transmission was observed for hepatitis B. The vertical transmission rate for HIV was within the target of the Ministry of Health when HIV diagnosis was made during pregnancy, but increased sharply when the diagnosis was made only at delivery. Vertical transmission of syphilis was much higher than expected, showing the importance of reinforcing the procedures recommended for its reduction.


The effect of olfactory exposure to non-insecticidal agrochemicals on bumblebee foraging behavior.
Declines in bumblebee populations have led to investigations into potential causes - including agrochemical effects on bumblebee physiology. The indirect effects of agrochemicals (i.e. behavior modulation) have been postulated, but rarely directly tested. Olfactory information is critical in mediating bumblebee-floral interactions. As agrochemicals emit volatiles, they may indirectly modify foraging behavior. We tested the effects of olfactory contamination of floral odor by agrochemical scent on foraging activity of Bombus impatiens using two behavioral paradigms: localization of food within a maze and forced-choice preference. The presence of a fungicide decreased bumblebees' ability to locate food within a maze. Additionally, bumblebees preferred to forage in non-contaminated feeding chambers when offered a choice between control and either fertilizer- or fungicide-scented chambers.


Cash transfers for HIV prevention: A systematic review.
Given the success of cash programs in improving health outcomes and addressing upstream drivers of HIV risk such as poverty and education, there has been an increasing interest in their potential to improve HIV prevention and care outcomes. Recent reviews have documented the impacts of structural interventions on HIV prevention, but evidence about the effects of cash transfer programs on HIV prevention has not been systematically reviewed for several years. We did a systematic review of published and unpublished literature to update and summarize the evidence around cash programs for HIV prevention from January 2000 to December 17, 2020. We included studies with either a cash transfer intervention, savings program, or program to reduce school costs. Included studies measured the program's impact on HIV infection, other sexually transmitted infections (STIs), or sexual behaviors. We screened 1,565 studies and examined 78 in full-text review to identify a total of 45 peer-reviewed publications and reports from 27 different interventions or populations. We did not do a meta-analysis given the range of outcomes and types of cash transfer interventions assessed. Most studies were conducted in sub-Saharan Africa (N = 23; South Africa, Tanzania, Malawi, Lesotho, Kenya, Uganda, Zimbabwe, Zambia, and eSwatini) followed by Mexico (N = 2), the United States (N = 1), and Mongolia (N = 1)). Of the 27 studies, 20 (72%) were randomized trials, 5 (20%) were observational studies, 1 (4%) was a case-control study, and 1 (4%) was quasi-experimental. Most studies did not identify a strong association between the program and sexual behaviors, except sexual debut (10/18 finding an association; 56%). Eight of the 27 studies included HIV biomarkers, but only 3 found a large reduction in HIV incidence or prevalence, and the rest found no statistically significant association. Of the studies that identified a statistically significant association with other STIs (N = 4/8), 2 involved incentives for staying free of the STI, and the other 2 were cash transfer programs for adolescent girls that had conditionalities related to secondary schooling. Study limitations include the small number of studies in key populations and examining interventions to reduce school costs and matched saving programs. The evidence base for large-scale impacts of cash transfers reducing HIV risk is limited; however, government social protection cash transfer programs and programs that incentivize school attendance among adolescent girls and young women show the greatest promise for HIV prevention.


Brief report: psychological symptoms in healthy female siblings of adolescents with and without chronic conditions.
To examine the psychological impact of having a sibling with a chronic condition on healthy adolescent females and to explore the potential moderating role of birth order on this relationship. We compared selected Brief Symptom Index subscales (anxiety, depression, interpersonal sensitivity, hostility) and global severity scores (GSI) in two groups of healthy, inner-city female adolescents matched for sibling age, gender, birth order, and age spacing: 34 sisters of males and females ages 13-19 years with chronic health conditions (ILLSIBS) and 34 sisters of males and females in the same age range without conditions (WELLSIBS). ILLSIBS generally had more symptoms than WELLSIBS. MANOVA yielded significant three-way interactions of sibling illness status, birth order, and gender for the anxiety, hostility, and GSI. A similar pattern was nonsignificant for the two other subscales. Among younger sisters in general and among older sisters of males only, ILLSIBS had higher scores; however, ILLSIBS who were older sisters of females did not differ significantly in symptom levels from the comparable group of WELLSIBS. Psychological symptoms in sisters of inner-city, male and female adolescents are related to sibling health status. However, the combination of sibling gender and birth order may modify this relationship and should be considered when evaluating psychological risk or designing interventions.


Multi-day perfusion of transplant organs: The how and the why.
In a recent paper, Clavien et al. demonstrate the successful transplant of a sub-optimal donor liver using multi-day normothermic machine perfusion. This technological milestone opens up exciting new avenues for liver transplantation with the potential to ameliorate donor organ shortages and permit targeted therapeutic interventions.


Maternal and perinatal outcomes of pregnancies delivered at 23 weeks' gestation.
To evaluate the maternal and perinatal outcomes of pregnancies delivered at 23+0 to 23+6 weeks' gestation. This prospective cohort study included women in the Canadian Perinatal Network who were admitted to one of 16 Canadian tertiary perinatal units between August 1, 2005, and March 31, 2011, and who delivered at 23+0 to 23+6 weeks' gestation. Women were included in the network if they were admitted with spontaneous preterm labour with contractions, a short cervix without contractions, prolapsing membranes with membranes at or beyond the external os or a dilated cervix, preterm premature rupture of membranes, intrauterine growth restriction, gestational hypertension, or antepartum hemorrhage. Maternal outcomes included Caesarean section, placental abruption, and serious complication. Perinatal outcomes were mortality and serious morbidity. A total of 248 women and 287 infants were included in the study. The rate of Caesarean section was 10.5% (26/248) and 40.3% of women (100/248) had a serious complication, the most common being chorioamnionitis (38.6%), followed by blood transfusion (4.5%). Of infants with known outcomes, perinatal mortality was 89.9% (223/248) (stillbirth 23.3% [67/287] and neonatal death 62.9% [156/248]). Of live born neonates with known outcomes (n = 181), 38.1% (69/181) were admitted to NICU. Of those admitted to NICU, neonatal death occurred in 63.8% (44/69). Among survivors at discharge, the rate of severe brain injury was 44.0% (11/25), of retinopathy of prematurity 58.3% (14/24), and of any serious neonatal morbidity 100% (25/25). Two subgroup analyses were performed: in one, antepartum stillbirths were excluded, and in the other only centres that indicated they offered fetal monitoring at 23 weeks' gestation were included and antepartum stillbirths were excluded. In each of these, perinatal outcomes similar to the overall group were found. Pregnant women delivering at 23 weeks' gestation are at risk of morbidity. Their infants have high rates of serious morbidity and mortality. Further research is needed to identify strategies and forms of management that not only increase perinatal survival but also reduce morbidities in these extremely low gestational age infants and reduce maternal morbidity.


Vaginoplasty with a Pudendal-groin Flap in Male-to-female Transsexuals.
Many vaginoplasty techniques have been introduced to improve the outcomes of sex reassignment surgery for male-to-female transsexuals. Some vaginoplasty patients still require additional skin grafts, making dilation mandatory to overcome shrinkage. We developed a new vaginoplasty method (called the "pudendal-groin flap") that uses pudendal-groin flaps. One of this procedure's advantages is that skin grafts are unnecessary, even for patients with small penises and scrotums. We introduce the procedure here and describe our evaluation of its utility. We retrospectively analyzed the cases of the 15 patients who underwent vaginoplasty using pudendal-groin flaps from May 2010 to January 2016 at our institution. We compared the complications as well as the functional and aesthetic outcomes with those of previous studies. The most common complication was bleeding, which occurred at the corpus spongiosum or while creating a new vaginal cavity. Bleeding can be reduced with more careful hemostasis and dissection. Aside from inadequate vaginal depth in one patient, the incidence of other complications, sexual intercourse, and aesthetic outcomes were acceptable. The pudendal- groin flap is thin and pliable and can create sufficient vaginal depth without skin grafts. The resulting scar is inconspicuous. Our findings suggest that vaginoplasty using the pudendal-groin flap method is feasible.


The CarO rhodopsin of the fungus Fusarium fujikuroi is a light-driven proton pump that retards spore germination.
Rhodopsins are membrane-embedded photoreceptors found in all major taxonomic kingdoms using retinal as their chromophore. They play well-known functions in different biological systems, but their roles in fungi remain unknown. The filamentous fungus Fusarium fujikuroi contains two putative rhodopsins, CarO and OpsA. The gene carO is light-regulated, and the predicted polypeptide contains all conserved residues required for proton pumping. We aimed to elucidate the expression and cellular location of the fungal rhodopsin CarO, its presumed proton-pumping activity and the possible effect of such function on F. fujikuroi growth. In electrophysiology experiments we confirmed that CarO is a green-light driven proton pump. Visualization of fluorescent CarO-YFP expressed in F. fujikuroi under control of its native promoter revealed higher accumulation in spores (conidia) produced by light-exposed mycelia. Germination analyses of conidia from carO(-) mutant and carO(+) control strains showed a faster development of light-exposed carO(-) germlings. In conclusion, CarO is an active proton pump, abundant in light-formed conidia, whose activity slows down early hyphal development under light. Interestingly, CarO-related rhodopsins are typically found in plant-associated fungi, where green light dominates the phyllosphere. Our data provide the first reliable clue on a possible biological role of a fungal rhodopsin.


Landscape dynamics in northwestern Amazonia: an assessment of pastures, fire and illicit crops as drivers of tropical deforestation.
Many studies have identified drivers of deforestation throughout the tropics and, in most cases, have recognised differences in the level of threat. However, only a few have also looked at the temporal and spatial dynamics by which those drivers act, which is critical for assessing the conservation of biodiversity as well as for landscape planning. In this study, we analyse land cover change between 2000 and 2009 in north-western Colombian Amazonia to identify the interactions between the use of fire, cultivation of illicit crops and establishment of pastures, and their impacts on the loss of forest in the region. Yearly analyses were undertaken at randomly selected sample areas to quantify the average areas of transition of land cover types under different landscape compositions: forest-dominated mosaics, pasture mosaics, fire mosaics, and illicit crop mosaics. Our results indicate that despite the fact that forest areas were well-preserved, deforestation occurred at a low annual rate (0.06%). Conversion to pasture was the main factor responsible for forest loss (the area of pastures tripled within forest mosaics over 8 years), and this process was independent of the landscape matrix in which the forests were located. In fire mosaics, burning is a common tool for forest clearing and conversion to pasture. Thus, forests in fire mosaics were highly disturbed and frequently transformed from primary to secondary forests. The use of fire for illicit cropping was not detected, partly due to the small size of common illicit crops. Forest regeneration from pastures and secondary vegetation was observed in areas with large amounts of natural forest. Overall, assuming the continuation of the observed pasture conversion trend and the use of forest fire, we suggest that our results should be incorporated into a spatially explicit and integrated decision support tool to target and focus land-planning activities and policies.


Reduction of human-to-pig cellular response by alteration of porcine MHC with human HLA DPW0401 exogenes.
In pig-to-human discordant xenotransplantation, the xenograft can be rejected by a formidable human xenogenic T-cell response, even if the graft has gone through hyperacute rejection or delayed xenograft rejection (acute vascular rejection). We therefore examined, in this study, whether the human-to-pig cellular response could be attenuated through the generation of a transgenic pig for human HLA II. With the technique of microinjection, we produced the HLA DPw0401 transgenic pig. The expression of the HLA DPw0401 gene on peripheral blood mononuclear cells (PBMCs) of the transgenic pig was examined by reverse transcriptase-polymerase chain reaction and flow cytometry. The antigenicity of the transgenic HLA DPw0401 molecule was tested by the HLA DPw0401-primed lymphocyte test reagent. The cellular response was analyzed by xenogenic mixed lymphocyte culture. The mRNA and protein of HLA DPw0401 were expressed in the PBMCs of the transgenic pig. The PBMCs of the HLA transgenic pig induced a stronger cellular reaction to HLA DPw0401-primed lymphocyte test reagents than the nontransgenic littermate pig (n=7, P<0.01). In direct xenogenic mixed lymphocyte culture with responders from HLA DPw0401(+) humans, the PBMCs from the HLA DPw0401 transgenic pig, as compared with those from the normal pig, induced a lower degree of xenogenic cellular response to human PBMCs (n=4, P=0.08). Our preliminary data demonstrated the possibility that the human HLA DPw0401 phenotype can be transferred onto porcine cells through the generation of HLA transgenic pigs and make the PBMCs of humans more tolerant to porcine cells.


Cesarean delivery and hematopoietic stem cell epigenetics in the newborn infant: implications for future health?
Cesarean section (CS) has been associated with a greater risk for asthma, diabetes, and cancer later in life. Although elective CS continues to rise, it is unclear whether and how it may contribute to compromised future health. Our aim was to investigate the influence of mode of delivery on the epigenetic state in neonatal hematopoietic stem cells. This was an observational study of 64 healthy, singleton, newborn infants (33 boys) born at term. Cord blood was sampled after elective CS (n = 27) and vaginal delivery. Global deoxyribonucleic acid (DNA) methylation in hematopoietic stem cells (CD34+) was determined by luminometric methylation assay, and genome-wide, locus-specific DNA methylation analysis was performed by Illumina Infinium 450K (Illumina, San Diego, CA), validated by bisulfite-pyrosequencing. CD34+ cells from infants delivered by CS were globally more DNA methylated (+2%) than DNA from infants delivered vaginally (P = .02). In relation to mode of delivery, a locus-specific analysis identified 343 loci with a difference in DNA methylation of 10% or greater (P < .01). A majority of the differentially methylated loci in neonatal CD34+ cells (76%) were found to be hypermethylated after vaginal delivery. In these infants, the degree of DNA methylation in 3 loci correlated to the duration of labor. The functional relevance of differentially methylated loci involved processes such as immunoglobulin biosynthetic process, regulation of glycolysis and ketone metabolism, and regulation of the response to food. A possible interpretation is that mode of delivery affects the epigenetic state of neonatal hematopoietic stem cells. Given the functional relevance indicated, our findings may have important implications for health and disease in later life.