TNFR1 Contributes to Activation-Induced Cell Death of Pathological CD4+ T Lymphocytes During Ischemic Heart Failure.
CD4+ T cells turn pathological during heart failure (HF). We show that the expression of tumor necrosis factor (TNF)-α and tumor necrosis factor receptor (TNFR1) increases in HF-activated CD4+ T cells. However, the role of the TNF-α/TNFR1 axis in T-cell activation/proliferation is unknown. We show that TNFR1 neutralization during T-cell activation (ex vivo) or the loss of TNFR1 in adoptively transferred HF-activated CD4+ T cells (in vivo) augments their prosurvival and proliferative signaling. Importantly, TNFR1 neutralization does not affect CD69 expression or the pathological activity of HF-activated TNFR1-/- CD4+ T cells. These results show that during HF TNFR1 plays an important role in quelling prosurvival and proliferative signals in CD4+ T cells without altering their pathological activity.


Resistive switching of the HfO x /HfO2 bilayer heterostructure and its transmission characteristics as a synapse.
In this work, HfO x /HfO2 homo-bilayer structure based resistive random access memory devices were fabricated, and the resistive switching characteristics of the devices were investigated. The samples with an Ar/O2 ratio of 12 : 2 exhibited improved switching performance including better uniformity, endurance and retention, which was selected to imitate the "learning" and "forgetting" function of biological synapses. The multilevel conductance of the HfO x /HfO2 homo-bilayer structure under the model of pulse voltage suggests its potential to emulate the nonlinear transmission characteristics of the synapse, and a model of multilevel conductance of the HfO x /HfO2 homo-bilayer structure was proposed. The device conductance continuously increases (decreases) in accordance with the number of positive (negative) voltage pulses during the potentiation (depression) process, which can emulate the change of synaptic weight in a biological synapse.


Breathlessness, chronic bronchitis and reduced pulmonary function as predictors of cardiovascular disease mortality among men in England, Scotland and the United States.
Relationships between cardiovascular disease (CVD) mortality and breathlessness, a definition of chronic bronchitis, and pulmonary function are investigated among men in two employed populations (17,717 London civil servants and 4904 Scottish workers) and in two communities (844 men in Tecumseh, Michigan and 6859 men in Renfrew and Paisley Burghs, Scotland). Men are aged 40-64 years at entry in all studies except Renfrew-Paisley, where they are aged 45-64 years. Length of follow-up ranges from 6 to 16 years. Age and smoking habits were controlled for in all analyses. Chronic phlegm production is not significantly associated with CVD mortality, and 'chronic bronchitis' is significantly associated with mortality only in the employed populations. Low FEV1 is significantly associated with CVD mortality only in the Whitehall study; however, the rate ratios are above one in all studies. Breathlessness is significantly associated with CVD mortality in all studies. These associations between CVD mortality and 'chronic bronchitis', low FEV1, and breathlessness persist after also controlling for employment grade, systolic blood pressure, antihypertensive medication, ECG changes, plasma cholesterol level, body mass index and diabetes. Only the associations between breathlessness and mortality persist after further controlling for low FEV1 and myocardial ischaemia. The rate ratios between breathlessness and mortality are about two for all studies. It is concluded that in these populations, breathlessness is an independent and major predictor of CVD mortality.


Views and experiences of community pharmacists and superintendent pharmacists regarding the New Medicine Service in England prior to implementation.
The New Medicine Service (NMS) was introduced to community pharmacies in England in October 2011. The NMS aims to improve adherence to new medicines in patients with selected long term conditions. The service consists of two follow-up consultations within 1 month in addition to usual care. This study explored community pharmacist and superintendent pharmacist views and experiences of the NMS in the 5 weeks prior to its implementation to identify potential facilitators and barriers to its success. The study also investigated participant experiences of the introduction and provision of existing pharmacy services in order to contrast with the implementation of the NMS. This study consisted of four focus groups with a total of 15 community pharmacists representing locums and employees of small, medium and large chain pharmacies. In addition, 5 semi-structured interviews were conducted with superintendent pharmacists representing independent, small chain, supermarket and large multiple pharmacies. Data were audio-recorded, transcribed verbatim and thematically analyzed. Both pharmacists and superintendent pharmacists were positive about the NMS and identified potential benefits for patients and the pharmacy profession. Awareness of the service was high, however, some confusion between the NMS and changes to Medicine Use Reviews was evident in all focus groups due to their similarity and coincidental implementation. This confusion was not observed in the interviews with superintendent pharmacists. Participants identified pharmacists' positive attitude, the similarity to current practice and the self-accreditation procedure as potential facilitators to service implementation. Potential barriers identified included a perceived lack of interest and awareness by GPs of the service, and the payment structure. Participants were concerned about the speed of implementation, and the absence of some materials needed prior to the start of the service. Participants were enthusiastic about the potential of the NMS to benefit patients and the pharmacy profession. Participants were able to identify several potential barriers and facilitators to the provision of the service. It remains to be seen whether the factors identified affected the early implementation of the service.


Genomic profile of the plants with pharmaceutical value.
There is an ample genetic diversity of plants with medicinal importance around the globe and this pool of genetic variation serves as the base for selection as well as for plant improvement. Thus, identification, characterization and documentation of the gene pool of medicinal plants are essential for this purpose. Genomic information of many a medicinal plant species has increased rapidly since the past decade and genetic resources available for domestication and improvement programs include genome sequencing, expressed sequence tags sequencing, transcript profiling, gene transmit, molecular markers in favor of mapping and breeding. In recent years, multiple endeavors have been undertaken for genomic characterization of medicinal plant species with the aid of molecular markers for sustainable utilization of gene pool, its conservation and future studies. Recent advancement in genomics is so fast that only some researches have been published till date and to a large extent documentation is restricted to electronic resources. Whole genome profiling of the identified medicinal plant species, carried out by several researchers, based on the DNA fingerprinting, is well documented in the present review. This review will facilitate preparing a database of the widely used, economically important medicinal plant species, based on their genomic organization.


Simplified strigolactams as potent analogues of strigolactones for the seed germination induction of Orobanche cumana Wallr.
Strigolactones play an important role in the rhizosphere as signalling molecules stimulating the seed germination of parasitic weed seeds and hyphal branching of arbuscular micorrhiza, and also act as hormones in plant roots and shoots. Strigolactone derivatives, e.g. strigolactams, could be used as suicidal germination inducers in the absence of a host crop for the decontamination of land infested with parasitic weed seeds. We report the stereoselective synthesis of novel strigolactams, together with some of their critical physicochemical properties, such as water solubility, hydrolytic stability, as well as their short soil persistence. In addition, we show that such strigolactams are potent germination stimulants of O. cumana parasitic weed seeds and do not affect the seed germination and the root growth of sunflower. The novel strigolactam derivatives described here compare favourably with the corresponding GR-28 strigolactones in terms of biological activity and physicochemical properties. However, we believe strigolactone and strigolactam derivatives require further structural optimisation to improve their soil persistence to demonstrate a potential for agronomical applications. © 2016 Society of Chemical Industry.


Dual role of IL-12 in the therapeutic efficacy or failure during combined PEG-Interferon-α2A and ribavirin therapy in patients with chronic hepatitis C.
Several efforts have been made to establish novel biomarkers with relevant predictive values to monitor HCV-infected patients under pegilated Interferon-α2A-(PEG-IFN-α2A)/ribavirin therapy. The aim of this study was to monitor the kinetics of HCV viral load, serum levels of pro-inflammatory/regulatory cytokines and leukocyte activation status before and after PEG-IFN-α2A/ribavirin therapy in 52 volunteers, including 12 chronic HCV patients and 40 controls. The HCV viral load, serum levels of cytokines (IL-8/IL-6/TNF-α/IL-12/IFN-γ/IL-4/IL-10) and the phenotype of peripheral blood leukocytes were evaluated before and after 4, 12 and 24 weeks following the PEG-IFN-α2A/ribavirin therapy. Our results demonstrated that sustained virological response-(SVR) is associated with early decrease in the viral load after 4 weeks of treatment. The presence of a modulated pro-inflammatory profile at baseline favors SVR, whereas a strong inflammatory response at baseline predisposes to therapeutic failure. Furthermore, a time-dependent increase on serum IL-12 levels in patients under treatment is critical to support the SVR, while the early predominance of IL-10 correlates to late virological relapse. On the other hand, a broad but unguided "cytokine storm" is observed in the non-responder HCV patients after 12 weeks of treatment. Corroborating these findings, monocyte/lymphocyte activation at baseline is associated with the non-responders to therapy whereas high CD8(+) T-cell numbers associate with SVR. All in all, these data suggest that the baseline pattern of serum pro-inflammatory/regulatory cytokines and the immunological activation status of chronic HCV patients undergoing PEG-IFN-α2A/ribavirin therapy are closely related with the therapeutic response.


Whole genome sequencing of isoniazid monoresistant clinical isolates of Mycobacterium tuberculosis reveals novel genetic polymorphisms.
In an attempt to uncover genotypic indicators for isoniazid (INH) resistance in M. tuberculosis, in addition to the canonical mutations in genes associated with INH resistance, including katG, inhA and fabG promoter; we analyzed, two INH monoresistant isolates, ASTS24/13 (INHR1) and SHR1/14 (INHR2). Targeted Sanger sequencing detected a canonical mutation at katG315 only in INHR2. Infection of THP-1 cells and exposure to antituberculosis drugs led to two-fold increase in the minimum inhibitory concentration of INH in INHR2. Whole genome sequences revealed that INHR1 and INHR2 belonged to Delhi Central Asian Strain and East African Indian lineages, respectively. The sequences were compared with INH susceptible isolates with the same lineage as the INH monoresistant strains. INHR1 had a novel unique mutation STOP420Trp in the efflux pump gene Rv0849, while INHR2 had a novel mutation Arg579Ser in efflux pump gene mmpL5. Comparison of lipid associated genes showed novel mutations in INHR1 in fadE16, fadD3 and fbpD; while INHR2 had mutations in fadE1, Rv0145, Rv1425, fadD9 and mmaA3. Both isolates also demonstrated novel mutations in cell wall associated genes. Our study highlights the importance of searching for alternate mechanisms of INH resistance that may contribute to the development of more comprehensive diagnostic tools.


Facilitative orthographic neighborhood effects: the SERIOL model account.
A large orthographic neighborhood (N) facilitates lexical decision for central and left visual field/right hemisphere (LVF/RH) presentation, but not for right visual field/left hemisphere (RVF/LH) presentation. Based on the SERIOL model of letter-position encoding, this asymmetric N effect is explained by differential activation patterns at the orthographic level. This analysis implies that it should be possible to negate the LVF/RH N effect and create an RVF/LH N effect by manipulating contrast levels in specific ways. In Experiment 1, these predictions were confirmed. In Experiment 2, we eliminated the N effect for both LVF/RH and central presentation. These results indicate that the letter level is the primary locus of the N effect under lexical decision, and that the hemispheric specificity of the N effect does not reflect differential processing at the lexical level.


Increased expression of Filaggrin and Claudin-1 in the ocular surface of patients with atopic dermatitis.
Atopic dermatitis (AD) is an itchy, chronic and inflammatory skin condition, with dysfunctional immune response and skin barrier defects. Reduction of filaggrin (FLG) and tight junctions (TJ) proteins, such as claudin-1 (CLDN-1), expression in cutaneous epithelial barrier is remarkable in AD pathogenesis. Ocular involvement occurs in approximately 40% of AD patients leading to changes in the structure of the conjunctiva. We aimed to evaluate the expression of FLG and CLDN-1 in the ocular surface of adults with AD, analysing bulbar conjunctival cells collected by a novel non-invasive cellular imprint. Bulbar conjunctival epithelial cells were collected by cellular imprint technique, and FLG and CLDN-1 expression were assessed by immunofluorescence (IF) and real-time polymerase chain reaction (RT-PCR). We detected increased expression of FLG and CLDN-1, as well as their transcript levels in AD patients compared with healthy controls (HC). There was a positive correlation between tear film break-up time (TBUT) and FLG expression. Fluorescein staining was inversely associated with FLG expression. Our results may reflect a reactive response of the ocular surface to AD-related ocular inflammation and associated dry eye disease. Further investigations focusing on the role of FLG and TJ expression in the ocular surface of AD patients may increment the understanding of the pathophysiology of extracutaneous AD and developing future targeted therapies.


miR-21 synergizes with BMP9 in osteogenic differentiation by activating the BMP9/Smad signaling pathway in murine multilineage cells.
Bone morphogenetic proteins (BMPs), particularly BMP9, have been shown to promote the osteogenic differentiation of murine multilineage cells (MMCs) and to promote bone formation in bone diseases; however, the mechanisms involved remain poorly understood. MicroRNAs (miRNAs or miRs) have been proven to regulate mesenchymal stem cell (MSC) differentiation. In this study, we identified a novel mechanism that unravels the functional axis of a key miRNA (miR-21) which contributes to BMP9‑induced osteogenic differentiation. We screened differentially expressed miRNAs in MMCs during BMP9‑induced osteogenic differentiation and found that miR-21 was significantly upregulated by BMP9 during the osteogenesis of MMCs. Furthermore, miR-21 was confirmed to promote the osteogenic differentiation of the MMCs by suppressing Smad7, which negatively regulates the osteogenic differentiation of MMCs. The upregulation of miR-21 may promote the osteogenic differentiation of MMCs in synergy with BMP9. The findings of our study revealed a novel function of miR-21, and suggest that the overexpression of miR-21 contributes to bone formation by promoting BMP9‑induced osteogenic differentiation. Our data may provide a molecular basis for the development of novel therapeutic strategies to treat bone diseases, such as osteoporosis and other inflammatory bone diseases.


Potential of a new biotreatment: Sphingomonas cloacae S-3T degrades nonylphenol in industrial wastewater.
Sphingomonas cloacae S-3(T), a nonylphenol (NP)-degrading bacterium, was evaluated for its utility in the remediation of NP-contaminated wastewater. In flask-scale experiments, S-3(T) cells immobilized on porous polypropylene carriers (beads) efficiently degraded NP to concentrations routinely measured in aquatic environments [a few parts per billion (ppb), or micrograms per liter). Therefore, we constructed and evaluated a laboratory-scale wastewater treatment system with a 3-l carrier-filled column. The system worked properly and consistently removed several hundred ppb of NP to ecologically safe concentrations of less than 10 ppb in industrial wastewater without the addition of nutrients. The effect of wastewater pH on the system performance was also evaluated; and wastewater samples with pH values of 6 or 8 were treated efficiently without pH adjustment. These results suggest that a biotreatment system using NP-degrading bacteria can efficiently remediate industrial wastewater and contribute to the preservation of aquatic environments.


DNA methylation signatures reveal that distinct combinations of transcription factors specify human immune cell epigenetic identity.
Epigenetic reprogramming underlies specification of immune cell lineages, but patterns that uniquely define immune cell types and the mechanisms by which they are established remain unclear. Here, we identified lineage-specific DNA methylation signatures of six immune cell types from human peripheral blood and determined their relationship to other epigenetic and transcriptomic patterns. Sites of lineage-specific hypomethylation were associated with distinct combinations of transcription factors in each cell type. By contrast, sites of lineage-specific hypermethylation were restricted mostly to adaptive immune cells. PU.1 binding sites were associated with lineage-specific hypo- and hypermethylation in different cell types, suggesting that it regulates DNA methylation in a context-dependent manner. These observations indicate that innate and adaptive immune lineages are specified by distinct epigenetic mechanisms via combinatorial and context-dependent use of key transcription factors. The cell-specific epigenomics and transcriptional patterns identified serve as a foundation for future studies on immune dysregulation in diseases and aging.


Nurse trainees' perception of effective clinical instructor characteristics.
Clinical education and experience in the clinical environment play an important role in shaping the clinical experience. Effective clinical teaching improves the clinical practice of the nursing trainees which in turn improves the quality of patient care. It mandates for the clinical instructor with desired qualities, to have a positive influence in clinical education. This study examined nurse trainees' perceptions of clinical instructor characteristics. The current study was conducted in a multi-cultural tertiary setting using a cross-sectional descriptive design. Using convenience sampling, 302 trainees were chosen as participants for the study, and there were 296 respondents. The data were collected from the participants using the Nursing Clinical Teacher Effectiveness Inventory (NCTEI) tool. The findings of the study revealed that the clinical instructors have scored high in personality (scoring percentage = 84.0%) and relatively low in teaching ability (scoring percentage = 81.3%). Also, the overall perception was almost the same among all the trainees though there was a slight variation in their rating of each dimension. Nursing trainees indicated the instructors as having good personality and relatively low teaching ability. This mandates the clinical instructors in the clinical environment to empower themselves in this area of improvement. This helps the teaching institutions to consider all the domains of effective clinical instructor characteristics while recruitment and also organize programs giving emphasis on building and developing these characteristics to create effective instructors.


Prenatal maternal depression associates with microstructure of right amygdala in neonates at birth.
Antenatal maternal cortisol levels associate with alterations in the amygdala, a structure associated with emotion regulation, in the offspring. However, because offspring brain and behavior are commonly assessed years after birth, the timing of such maternal influences is unclear. This study aimed to examine the association between antenatal maternal depressive symptomatology and neonatal amygdala volume and microstructure and thus establish evidence for the transgenerational transmission of vulnerability for affective disorders during prenatal development. Our study recruited Asian mothers at 10 to 13 weeks pregnancy and assessed maternal depression at 26 weeks gestation using the Edinburgh Postnatal Depression Scale. Structural magnetic resonance imaging and diffusion tensor imaging were performed with 157 nonsedated, 6- to 14-day-old newborns and then analyzed to extract the volume, fractional anisotropy, and axial diffusivity values of the amygdala. Adjusting for household income, maternal age, and smoking exposure, postconceptual age at magnetic resonance imaging, and birth weight, we found significantly lower fractional anisotropy (p = .009) and axial diffusivity (p = .028), but not volume (p = .993), in the right amygdala in the infants of mothers with high compared with those with low-normal Edinburgh Postnatal Depression Scale scores. The results reveal a significant relation between antenatal maternal depression and the neonatal microstructure of the right amygdala, a brain region closely associated with stress reactivity and vulnerability for mood anxiety disorders. These findings suggest the prenatal transmission of vulnerability for depression from mother to child and that interventions targeting maternal depression should begin early in pregnancy.


A phase 1b study of blinatumomab in Japanese children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia.
Novel therapies are needed for children with relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL). Blinatumomab is a bispecific T-cell engager immunotherapy that simultaneously binds to CD3-positive cytotoxic T cells and CD19-positive B cells and redirects the patient's T cells to lyse malignant and normal B cells. We conducted an open-label phase 1b study to determine the safety, pharmacokinetics, efficacy, and recommended dose of blinatumomab in Japanese children with R/R B-cell precursor ALL. Patients received induction blinatumomab for 4 weeks (5 μg/m2/day week 1; 15 μg/m2/day weeks 2-4), followed by a 2-week treatment-free interval (6-week cycle). In subsequent cycles, patients received blinatumomab 15 μg/m2/day. The primary end point was the incidence of dose-limiting toxicities. Nine patients received blinatumomab. Since no dose-limiting toxicities were reported, the maximum tolerated dose was 5 μg/m2/day for week 1, followed by 15 μg/m2/day weeks 2-4 (5-15 μg/m2/day, the global recommended dose of blinatumomab). All patients had ≥ 1 grade ≥ 3 adverse events; 89% had grade ≥ 3 treatment-related adverse events. M1 remission rate within the first two cycles of treatment was 56%; one patient had a minimal residual disease response. Consistent with global studies, blinatumomab appeared to be safe with preliminary evidence of efficacy in Japanese children with R/R B-cell precursor ALL.


Use of secukinumab in a pediatric patient leads to significant improvement in nail psoriasis and psoriatic arthritis.
Many pediatric psoriasis patients suffer from nail involvement and psoriatic arthritis. In adults, biologic agents have demonstrated success in treating refractory nail psoriasis and arthritis, but studies are limited in children. In this report, we present a pediatric patient with severe, recalcitrant nail and joint psoriasis, successfully treated with secukinumab.


Efficacy of SPI-1865, a novel gamma-secretase modulator, in multiple rodent models.
Modulation of the gamma-secretase enzyme, which reduces the production of the amyloidogenic Aβ42 peptide while sparing the production of other Aβ species, is a promising therapeutic approach for the treatment of Alzheimer's disease. Satori has identified a unique class of small molecule gamma-secretase modulators (GSMs) capable of decreasing Aβ42 levels in cellular and rodent model systems. The compound class exhibits potency in the nM range in vitro and is selective for lowering Aβ42 and Aβ38 while sparing Aβ40 and total Aβ levels. In vivo, a compound from the series, SPI-1865, demonstrates similar pharmacology in wild-type CD1 mice, Tg2576 mice and Sprague Dawley rats. Animals were orally administered either a single dose of SPI-1865 or dosed for multiple days. Aβ levels were measured using a sensitive plate-based ELISA system (MSD) and brain and plasma exposure of drug were assessed by LC/MS/MS. In wild-type mice using either dosing regimen, brain Aβ42 and Aβ38 levels were decreased upon treatment with SPI-1865 and little to no statistically meaningful effect on Aβ40 was observed, reflecting the changes observed in vitro. In rats, brain Aβ levels were examined and similar to the mouse studies, brain Aβ42 and Aβ38 were lowered. Comparable changes were also observed in the Tg2576 mice, where Aβ levels were measured in brain as well as plasma and CSF. Taken together, these data indicate that SPI-1865 is orally bioavailable, brain penetrant, and effective at lowering Aβ42 in a dose responsive manner. With this unique profile, the class of compounds represented by SPI-1865 may be a promising new therapy for Alzheimer's disease.


Nonstructural protein (NS1) of human parvovirus B19 stimulates host innate immunity and blunts the exogenous type I interferon signaling in vitro.
B19 virus is a non-enveloped DNA virus and belongs to the family of parvoviridae. There are two large open reading frames (ORFs), nonstructural protein (NS1) and two capsid proteins (VP1 and VP2). Host innate immune responses form the first line of defense against many pathogen invasion. How B19 virus, especially its encoded viral proteins interacts with host innate immune system remains unknown. In this study we aim to investigate the effect of NS1 on the host innate immune response and exogenous type I IFN signaling. Here we found that the type I IFN can be stimulated by NS1. Interestingly, NS1 also plays an important role in inhibiting the exogenous type I IFN signaling at p-STAT1, ISRE and ISGs levels. We concluded that NS1 may play pivotal role in evading the host immune surveillance. Our data shed novel light on the pathogenesis of B19 viral infection and virus evasion strategies.


Implementation of totally robotic right hemicolectomy: lessons learned from a prospective cohort.
Robotics facilitates the realization of intra-corporeal anastomosis during right hemicolectomy and allows extracting the operative specimen through a C-section, offering potential benefits in terms of post-operative recovery and incidence of incisional hernia. Therefore, we progressively implemented robotic right hemicolectomy (robRHC) in our centre, and would like to report our initial experience with the technique. Consecutive patients who underwent robRHC within a single centre were prospectively included. Variables related to patients' demographics, surgical procedures, post-operative recovery and pathological outcomes were collected. Sixty patients underwent robRHC in our centre. Indications for robRHC were colon cancer in 58 patients (96.7%) and polyps not amenable to endoscopic resection in 2 patients (3.3%). Fifty-eight patients underwent robRHC with D2 lymphadenectomy and central vessel ligation (96.7%), and two patients (3.3%) had robRHC associated with another procedure. All patients had intra-corporeal anastomosis. The mean ± operative time was of 200.4 ± 114.9 min. Two conversions (3.3%) to open surgery were performed. The mean ± SD length of stay was of 5.4 ± 3.8 days. Seven patients (11.7%) experienced a post-operative complication with a Clavien-Dindo score ≥ 2. Two patients (3.5%) had an anastomotic leak. The mean ± SD number of harvested lymph nodes was of 22.4 ± 7.6. All patients had negative pathological margins (R0 resection). To conclude, robotic RHC is a safe procedure, which can be implemented with satisfying peri- and post-operative outcomes. The potential benefits of the technique remain to be demonstrated by randomized controlled trials.


Clioquinol-zinc chelate: a candidate causative agent of subacute myelo-optic neuropathy.
5-chloro-7-iodo-8-hydroxyquinoline (clioquinol) was used clinically three decades ago as an oral antiparasitic agent and to increase intestinal absorption of zinc in patients with acrodermatitis enteropathica, a genetic disorder of zinc absorption. Use of clioquinol was epidemiologically linked to subacute myelo-optic neuropathy (SMON), characterized by peripheral neuropathy and blindness, which affected 10,000 patients in Japan. Discontinuation of oral clioquinol use led to elimination of SMON, however, the mechanism of how clioquinol induces neurotoxicity is unclear. We tested the effect of clioquinol-metal chelates on neural crest-derived melanoma cells. The effect of clioquinol chelates on cells was further studied by electron microscopy and by a mitochondrial potential-sensitive fluorescent dye. Of the ions tested, only clioquinol-zinc chelate demonstrated cytotoxicity. The cytotoxicity of clioquinol-zinc chelate was extremely rapid, suggesting that its primary effect was on the mitochondria. Electron microscopic analysis demonstrated that clioquinol-zinc chelate caused mitochondrial damage. This finding was further confirmed by the observation that clioquinol-zinc chelate caused a decrease in mitochondrial membrane potential. We demonstrate that clioquinol, in the presence of zinc, is converted to a potent mitochondrial toxin. The phenomenon of clioquinol mediated toxicity appears to be specific to zinc and is not seen with other metals tested. Since clioquinol has been shown to cause increased systemic absorption of zinc in humans, it is likely that clioquinol-zinc chelate was present in appreciable levels in patients with SMON and may be the ultimate causative toxin of SMON.


Clinical and Neurologic Outcomes in Acetaminophen-Induced Acute Liver Failure: A 21-Year Multicenter Cohort Study.
Acetaminophen (APAP)-induced acute liver failure (ALF) is a rare disease associated with high mortality rates. This study aimed to evaluate changes in interventions, psychosocial profile, and clinical outcomes over a 21-year period using data from the ALF Study Group registry. A retrospective review of this prospective, multicenter cohort study of all APAP-ALF patients enrolled during the study period (1998-2018) was completed. Primary outcomes evaluated were the 21-day transplant-free survival (TFS) and neurologic complications. Covariates evaluated included enrollment cohort (early, 1998-2007; recent, 2008-2018), intentionality, psychiatric comorbidity, and use of organ support including continuous renal replacement therapy (CRRT). Of 1190 APAP-ALF patients, recent cohort patients (n = 608) had significantly improved TFS (recent, 69.8% vs early, 61.7%; P = .005). Recent cohort patients were more likely to receive CRRT (22.2% vs 7.6%; P < .001), and less likely to develop intracranial hypertension (29.9% vs 51.5%; P < .001) or die by day 21 from cerebral edema (4.5% vs 11.6%; P < .001). Grouped by TFS status (non-TFS, n = 365 vs TFS, n = 704), there were no differences in psychiatric comorbidity (51.5% vs 55.0%; P = .28) or intentionality (intentional, 39.7% vs 41.6%; P = .58). On multivariable logistic regression adjusting for vasopressor support, development of grade 3/4 hepatic encephalopathy, King's College criteria, and MELD score, the use of CRRT (odds ratio, 1.62; P = .023) was associated with significantly increased TFS (c-statistic, 0.86). In a second model adjusting for the same covariates, recent enrollment was associated significantly with TFS (odds ratio, 1.42; P = .034; c-statistic, 0.86). TFS in APAP-ALF has improved in recent years and rates of intracranial hypertension/cerebral edema have decreased, possibly related to increased CRRT use.


A brief, peer-led HIV prevention program for college students in Bangkok, Thailand.
To test the effectiveness of a brief theory-based HIV prevention program led by peers among college students. A quasi-experimental research using a pretest-posttest nonequivalent control group design with 2-mo follow-up. A university in Bangkok. For peer leaders, 70 undergrad students taking health sexuality course were invited to participate in the study. Then, a convenience sample of undergraduate students was recruited through peer leaders, 226 for experimental group and 209 for control group. Information, motivation, behavioral skills, and AIDS/STIs preventive behaviors. The study revealed that a Brief, Peer-Led HIV Prevention Program significantly increased knowledge of preventive behaviors (β = 2.67, P < .000), motivated participants to have a better attitude toward preventive behaviors (β = -5.26, P < .000), better subjective norms (β = -1.54, P < .000), and greater intentions to practice preventive behavior (β = -1.38, P < .000). The program also significantly decreased perceived difficulty of AIDS/STIs preventive behaviors (β = 2.38, P < .000) and increased perceived effectiveness at AIDS/STIs preventive behavior (β = -3.03, P < .000). However, it did not significantly increase AIDS/STIs preventive behaviors (β = 2.13, P > .05). Findings of this study provide initial evidence as to how theoretical variables were operated to effectively increase knowledge, change motivation, and behavioral skills of AIDS/STIs preventive behavior among Thai college students. More research is needed to further test the effectiveness of the program on AIDS/STIs preventive behaviors among college students.


Microbial processing of autochthonous organic matter controls the biodegradation of 17α-ethinylestradiol in lake sediments under anoxic conditions.
The decay of algal biomass and aquatic plants in freshwater lakes leads to the overproduction of autochthonous organic matter (OM) and the exhaustion of dissolved oxygen, impacting the microbial community and subsequent biodegradation of emerging contaminants in sediment. This study explored how the microbial processing of aquatic plant- and algal-derived OM (POM and AOM) mediates 17α-ethinylestradiol (EE2) biodegradation in the anoxic sediments of Lake Taihu in China. In four months of microcosm incubations, the increased concentrations of protein-like substances in AOM and POM exhibited temporary activation on microbial metabolic enzyme activity (fluorescein diacetate hydrolase and dehydrogenase) and significantly promoted the carbon mineralization with iron reduction (P < 0.001). These in turn increased the EE2 biodegradation efficiency to 77-90 ng g-1 in the anoxic sediment. However, a higher EE2 biodegradation of 109 ng g-1 was achieved with the humic acid augmentation containing more quinone-like compounds, showing a weaker substrate-priming effect but accelerated redox cycling of iron and organic substrates in the later period of incubation. The microbial analysis further revealed that the quinone-like compounds in OM were more closely associated with microbial electron transfer and strengthened their interspecies syntrophic cooperation favorable to contaminant biodegradation, even though the connective members exposed to protein-like components upregulated more functional genes related to organic carbon and xenobiotics metabolism and biodegradation. Our findings will help predict the fate of estrogens in various sedimentary environments under increasing eutrophication and further climate change scenarios.


Open versus laparoscopic incisional hernia repair: something different from a meta-analysis.
Incisional hernias after laparotomy are a large financial burden for society as well as for the patients suffering from pain and limitations of activity over time. The introduction of alloplastic materials such as polypropylene seems to improve the results. The question of whether to apply open or laparoscopic implantation of the mesh is of ongoing interest. We compare the available alloplastic materials and try to clarify the question of whether the laparoscopic procedure is superior to the conventional (open) technique based on the available randomized studies. All available meshes for intraperitoneal and extraperitoneal implantation were described regarding their handling and their pros and cons. A database search (PubMed, Medline, Ovid, and in the secondary literature) was carried out to retrieve all randomized studies comparing laparoscopic and open hernia repair. Data were reviewed by two independent scientists for surgical and statistical design. The ideal mesh for a laparoscopic maintenance of abdominal wall hernias as well as the optimal fixation of the mesh has not been found yet. Recent available literature shows no evidence demonstrating the superiority of one of these meshes. The available studies found a lower infection rate, but higher occurrence of seroma for the laparoscopic procedure. The value of the different studies is reduced due to deficiency in study design and power. Guidelines for further studies are discussed to avoid surgical and statistical pitfalls. Laparoscopic incisional hernia repair shows, in some (randomized) studies as well as a large number of retrospective analyses and in case control studies, superiority compared to conventional hernia repair. Long-term results with a high level of evidence are not available. Additional well-designed randomized trials including long-term observation of patients are required in order to clarify a number of interesting questions.


Erratum: Author Correction: Clinical validation of smartphone-based activity tracking in peripheral artery disease patients.
[This corrects the article DOI: 10.1038/s41746-018-0073-x.].


Integrating Palliative Care in Hematopoietic Stem Cell Transplantation: A Qualitative Study Exploring Patient, Caregiver, and Clinician Perspectives.
To explore patient, caregiver, and clinician perspectives on palliative care for patients undergoing hematopoietic stem cell transplantation (HSCT). 8 patients who had undergone or would undergo HSCT, 4 caregivers, and 16 HSCT clinicians. This qualitative, interpretive descriptive study used semistructured interviews conducted via telephone or videoconference. Responses were categorized into the following two themes: concerns and challenges during and after HSCT, and tensions with integrating palliative care into HSCT. The findings from this study highlight the unique and varied needs of patients and their caregivers during and after HSCT. More research is required to determine how to best integrate palliative care in this setting.


Cradle to grave environmental impact evaluation of the consumption of potato and tomato products.
This study discusses the environmental life cycle impacts of potato and tomato supply chains in a "cradle-to-grave" perspective. The principal focus is to evaluate the processed products, while fresh products are also briefly discussed. Processed products included are potato-chips, frozen fries and dehydrated flakes, and tomato-pasta sauce. The functional unit (FU) is 1 kg product(s), eaten at the consumer stage. Life cycle assessment (LCA) modeling has utilized multiple mechanistic crop models to estimate the crop yields, crop nutrient uptakes and irrigation water requirements. The farming systems represent the primary crop reporting districts where the selected crops are produced on a commercial scale in the United States. The post-harvest system was constructed utilizing the data collected from a processing plant and from other available studies. LCA modeling also constituted handling of co-products (e.g. starch in potatoes) and biowaste. A wide range of environmental impact categories were selected for the evaluation, which showed environmental differences between fresh and processed products. For instance, global warming potential for potato-fresh, chips, fries and dehydrated was 0.97, 0.85, 1.21 and 0.65 kg CO2-eq/FU respectively. For fresh tomato and tomato sauce, it was 0.74 and 1.5 kg CO2-eq/FU respectively. Likewise, fossil resource scarcity for fresh potatoes was higher than chips and dehydrated flakes, but lower than fries. Water consumption was slightly higher in fresh potatoes compared to the processed products. Similar impact patterns were found in fresh and processed tomato products. For most of the impact categories, processing and the agriculture systems were the major contributors. The contribution from the consumer stage varied with the ways the product is prepared, e.g. whether fries are oven heated or deep-fried in oil. Environmental mitigation measures include, the use of drip irrigation (for potatoes), and reducing: food miles, food waste and the use of secondary packaging materials.


Spermiogenesis in the cattle egret (Bubulcus ibis).
Avian species comprise more than half of all vertebrates yet there is a dearth of information regarding spermatid development in this class of animals. This report of spermiogenesis in the cattle egret, Bubulcus ibis, is the first in the order Pelecaniformes. Five sexually mature and reproductively active male cattle egrets were captured in the wild, humanely euthanized, the reproductive organs dissected out, and tissues from the testes routinely prepared for transmission electron microscopy. Twelve steps of spermatid development, using the step-wise system, were determined. Acrosomogenesis in the egret results in a relatively short, solid, bullet-shaped acrosome that ends bluntly anteriorly and flat posteriorly or basally. The nucleus displays remarkable morphological changes, with the anterior end of the mature spermatid becoming flat, lacking a rostrum and an endonuclear canal. A perforatorium does not develop. It is noteworthy that a longitudinal, but not a circular, manchette develops during spermiogenesis in this bird. The proximal centriole is attached to the nucleus, at the implantation fossa, by means of well-formed, electron dense struts of material. An amorphous fibrous sheath develops in the principal piece. The interesting development and peculiar features of the acrosome and nucleus, as well as the absence of the perforatorium and circular manchette in the spermatozoon of the cattle egret, may be of phylogenetic significance.


Invited review: integration of technologies and systems for precision animal agriculture-a case study on precision dairy farming.
Precision livestock farming (PLF) offers a strategic solution to enhance the management capacity of large animal groups, while simultaneously improving profitability, efficiency, and minimizing environmental impacts associated with livestock production systems. Additionally, PLF contributes to optimizing the ability to manage and monitor animal welfare while providing solutions to global grand challenges posed by the growing demand for animal products and ensuring global food security. By enabling a return to the "per animal" approach by harnessing technological advancements, PLF enables cost-effective, individualized care for animals through enhanced monitoring and control capabilities within complex farming systems. Meeting the nutritional requirements of a global population exponentially approaching ten billion people will likely require the density of animal proteins for decades to come. The development and application of digital technologies are critical to facilitate the responsible and sustainable intensification of livestock production over the next several decades to maximize the potential benefits of PLF. Real-time continuous monitoring of each animal is expected to enable more precise and accurate tracking and management of health and well-being. Importantly, the digitalization of agriculture is expected to provide collateral benefits of ensuring auditability in value chains while assuaging concerns associated with labor shortages. Despite notable advances in PLF technology adoption, a number of critical concerns currently limit the viability of these state-of-the-art technologies. The potential benefits of PLF for livestock management systems which are enabled by autonomous continuous monitoring and environmental control can be rapidly enhanced through an Internet of Things approach to monitoring and (where appropriate) closed-loop management. In this paper, we analyze the multilayered network of sensors, actuators, communication, networking, and analytics currently used in PLF, focusing on dairy farming as an illustrative example. We explore the current state-of-the-art, identify key shortcomings, and propose potential solutions to bridge the gap between technology and animal agriculture. Additionally, we examine the potential implications of advancements in communication, robotics, and artificial intelligence on the health, security, and welfare of animals.


Dopamine-induced endocytosis of Na+,K+-ATPase is initiated by phosphorylation of Ser-18 in the rat alpha subunit and Is responsible for the decreased activity in epithelial cells.
Dopamine inhibits Na+,K+-ATPase activity in renal tubule cells. This inhibition is associated with phosphorylation and internalization of the alpha subunit, both events being protein kinase C-dependent. Studies of purified preparations, fusion proteins with site-directed mutagenesis, and heterologous expression systems have identified two major protein kinase C phosphorylation residues (Ser-11 and Ser-18) in the rat alpha1 subunit isoform. To identify the phosphorylation site(s) that mediates endocytosis of the subunit in response to dopamine, we have performed site-directed mutagenesis of these residues in the rat alpha1 subunit and expressed the mutated forms in a renal epithelial cell line. Dopamine inhibited Na+,K+-ATPase activity and increased alpha subunit phosphorylation and clathrin-dependent endocytosis into endosomes in cells expressing the wild type alpha1 subunit or the S11A alpha1 mutant, and both effects were blocked by protein kinase C inhibition. In contrast, dopamine did not elicit any of these effects in cells expressing the S18A alpha1 mutant. While Ser-18 phosphorylation is necessary for endocytosis, it does not affect per se the enzymatic activity: preventing endocytosis with wortmannin or LY294009 blocked the inhibitory effect of dopamine on Na+,K+-ATPase activity, although it did not alter the increased alpha subunit phosphorylation induced by this agonist. We conclude that dopamine-induced inhibition of Na+, K+-ATPase activity in rat renal tubule cells requires endocytosis of the alpha subunit into defined intracellular compartments and that phosphorylation of Ser-18 is essential for this process.


Local radiofrequency (RF) hyperthermia in the treatment of cancer: Edmonton experience.
We have treated 16 patients suffering from recurrent malignancies who were unsuitable for any other form of treatment with local radiofrequency (RF) hyperthermia. Relief of pain as a major symptom occurred in six patients and reduction in size of tumor occurred in 13 instances.


Increase in Cape Verde hurricanes during Atlantic Niño.
At seasonal-to-interannual timescales, Atlantic hurricane activity is greatly modulated by El Niño-Southern Oscillation and the Atlantic Meridional Mode. However, those climate modes develop predominantly in boreal winter or spring and are weaker during the Atlantic hurricane season (June-November). The leading mode of tropical Atlantic sea surface temperature (SST) variability during the Atlantic hurricane season is Atlantic Niño/Niña, which is characterized by warm/cold SST anomalies in the eastern equatorial Atlantic. However, the linkage between Atlantic Niño/Niña and hurricane activity has not been examined. Here, we use observations to show that Atlantic Niño, by strengthening the Atlantic inter-tropical convergence zone rainband, enhances African easterly wave activity and low-level cyclonic vorticity across the deep tropical eastern North Atlantic. We show that such conditions increase the likelihood of powerful hurricanes developing in the deep tropics near the Cape Verde islands, elevating the risk of major hurricanes impacting the Caribbean islands and the U.S.


The crucial roles of m6A RNA modifications in cutaneous cancers: Implications in pathogenesis, metastasis, drug resistance, and targeted therapies.
N6-methyladenosine (m6A) is the most abundant internal modification on RNA. It is a dynamical and reversible process, which is regulated by m6A methyltransferase and m6A demethylase. The m6A modified RNA can be specifically recognized by the m6A reader, leading to RNA splicing, maturation, degradation or translation. The abnormality of m6A RNA modification is closely related to a variety of biological processes, especially the occurrence and development of tumors. Recent studies have shown that m6A RNA modification is involved in the pathogenesis of skin cancers. However, the precise molecular mechanisms of m6A-mediated cutaneous tumorigenesis have not been fully elucidated. Therefore, this review will summarize the biological characteristics of m6A modification, its regulatory role and mechanism in skin cancers, and the recent research progress of m6A-related molecular drugs, aiming to provide new ideas for clinical diagnosis and targeted therapy of cutaneous cancers.


Adult rhabdomyoma of the larynx.
A case of rhabdomyoma of the larynx in a 76-year-old woman patient is reported. The tumor was localized on the left vocal cord. This case is, so far described, the seventh one of adult rhadbomyoma of the larynx. The differential histological and histochemical diagnosis with granular cell myoblastoma is discussed and tabulated. Both tumors can easily be confused. In accordance with previously reported cases no evidence of recurrence after more than two years could be observed.


Giardia muris: correlation between oral dosage, course of infection, and trophozoite distribution in the mouse small intestine.
Oral inoculations of Giardia muris cysts to CD-1 Swiss mice resulted in a reproducible pattern of infection measured by cyst excretion and the number of trophozoites in the small intestine. Housing of animals together or individually did not alter the pattern of cyst release for the first 30 days of infection. Administration of 10 to 10(5) cysts/mouse resulted in a similar rate of cyst excretion from Day 10 to the end of the infection period. There was a direct correlation between the size of inoculum and the length of the latent period. Mice which received larger doses (10(3), 10(4), 10(5] had significantly higher numbers of cysts in feces during the first week of infection, compared to those which received lower doses (10 or 100). The extent of trophozoite colonization and their distribution in the small intestine was not related to the size of inoculum. The location of trophozoites in the small intestine varied during the infection. In the first 3 to 8 days of infection the trophozoites were situated in the upper 25% of the small intestine, but moved posteriorly (upper 40%) during the period of peak cyst output. The number of trophozoites in the small intestine and cyst excretion were found to be proportional at all stages of infection.


Mesenchymal stromal cell therapy reduces lung inflammation and vascular remodeling and improves hemodynamics in experimental pulmonary arterial hypertension.
Experimental research has reported beneficial effects of mesenchymal stromal cell (MSC) therapy in pulmonary arterial hypertension (PAH). However, these studies either were based on prophylactic protocols or assessed basic remodeling features without evaluating possible mechanisms. We analyzed the effects of MSC therapy on lung vascular remodeling and hemodynamics and its possible mechanisms of action in monocrotaline (MCT)-induced PAH. Twenty-eight Wistar rats were randomly divided into two groups. In the PAH group, animals received MCT 60 mg/kg intraperitoneally, while a control group received saline (SAL) instead. On day 14, both groups were further randomized to receive 105 adipose-derived MSCs or SAL intravenously (n = 7/group). On day 28, right ventricular systolic pressure (RVSP) and the gene expression of mediators associated with apoptosis, inflammation, fibrosis, Smad-1 levels, cell proliferation, and endothelial-mesenchymal transition were determined. In addition, lung histology (smooth muscle cell proliferation and plexiform-like injuries), CD68+ and CD163+ macrophages, and plasma levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) were evaluated. In the PAH group, adipose-derived MSCs, compared to SAL, reduced mean RVSP (29 ± 1 vs 39 ± 2 mmHg, p < 0.001), lung tissue collagen fiber content, smooth muscle cell proliferation, CD68+ macrophages, interleukin-6 expression, and the antiapoptotic mediators Bcl-2 and survivin. Conversely, expression of the proapoptotic mediator procaspase-3 and plasma VEGF increased, with no changes in PDGF. In the pulmonary artery, MSCs dampened the endothelial-mesenchymal transition. In MCT-induced PAH, MSC therapy reduced lung vascular remodeling, thus improving hemodynamics. These beneficial effects were associated with increased levels of proapoptotic markers, mesenchymal-to-endothelial transition, reduced cell proliferation markers, and inflammation due to a shift away from the M1 phenotype.


No effect of age and estrogen on aromatic L- amino acid decarboxylase activity in rhesus monkey brain.
A variety of studies have shown an effect of estrogen on dopamine function and suggest that estrogen may modulate central dopaminergic activity. Positron emission tomography (PET) and the dopamine metabolism tracer, [18F]6-fluoro-L-m-tyrosine (FMT) were used to evaluate dopaminergic function in the frontal cortex and striatum in six aged, but pre-menopausal, female monkeys before and after ovariectomy (OVX). Dynamic PET brain uptake data and metabolite-corrected blood input functions were fit to a three-compartment model for FMT uptake. Prior to OVX, all animals showed preferential accumulation of the tracer bilaterally in the striatum and less but measurable activity in the frontal cortex. Paired comparisons showed that there were no significant differences in FMT uptake (K(i)) in either brain region before and after OVX. In addition, FMT uptake did not differ from a group of young adult female monkeys at either time point. These findings may represent a compensatory up-regulation of aromatic L- amino acid decarboxylase (AADC) activity.


Social network and genomic analysis of an OXA-48 carbapenemase-producing Enterobacterales hospital ward outbreak in Ireland, 2018-2019.
Nosocomial transmission and outbreaks of carbapenemase-producing Enterobacterales (CPE) represent a challenge to healthcare systems. In July 2018, a CPE hospital ward outbreak was declared. Our aim was to investigate transmission patterns, using social network analysis and genomics in a nosocomial CPE outbreak. A retrospective descriptive analysis of all patients (cases and contacts) admitted to a ward experiencing a CPE outbreak (2018-2019) was undertaken. A case had a negative CPE admission screen, and subsequent positive test. A contact shared a multi-bed area and/or facility with a case (>4 hours). Social networks, including genomics data and ward locations, were constructed. Network metrics were analysed. Forty-five cases and 844 contacts were analysed. The median age of cases was 78 years (IQR 67-83), 58% (n=26) were male and 100% had co-morbidities. The median outbreak ward length-of-stay (LOS) was 17 days (IQR 10-34). OXA-48 CPE was confirmed in all cases and from 26 environmental samples. Social networks identified clusters by time, gender and species/sequence type/plasmid. Network metrics indicated potential superspreading involving a subset of patients with behavioural issues. Social networks elucidated high resolution transmission patterns involving two related OXA-48 plasmids, multiple species/genotypes and potential super-spreading. Interventions prevented intra-hospital spread. An older patient cohort, extended hospital LOS and frequent intra-ward bed transfers, coupled with suboptimal ward infrastructure, likely prolonged this outbreak. We recommend social network analysis contemporaneously with genomics (on case and environmental samples) for complex nosocomial outbreaks and bespoke care plans for patients with behavioural issues on outbreak wards.


The lymphogram in abdominal tuberculosis.
Lymphograms of 11 patients with histologically proven abdominal tuberculosis have been assessed in an attempt to define a typical pattern of appearance in retroperitoneal lymph glands. Glandular enlargement, poor glandular filling and lymphovascular obstruction were present. A gradient of abnormality with more marked adenopathy in the upper para-aortic chain extending to a lesser involvement below in the iliac chain was demonstrated in keeping with a retrograde spread of the tuberculosis process from the abdominal lymphatics cauded along the retroperitoneal chain. Lymphography may be valuable in cases where data from clinical observations and routine radiological studies is inconclusive in cases of vague abdominal disease.


Uptake of the core outcome set on polycystic ovary syndrome before and after its publication.
Does the core outcome set (COS) on polycystic ovary syndrome (PCOS) impact the selection of research outcomes? Following the publication of the COS on PCOS, an increasing number of trials are reporting both the generic domain and body mass index; however, the uptake of this COS has not been as extensive as expected. The COS on PCOS included 33 core outcomes in the following seven domains: the generic (3), metabolic (8), reproductive (7), pregnancy (10), psychological (3), oncological (1), and long-term (1). This was done to improve consistency in outcome selection and definition. However, thus far, no studies have investigated the effectiveness of this COS in the above-mentioned tasks. A methodological study based on the trial registries, including 395 eligible clinical trials registered between 1 January 2018 and 21 September 2022. A total of 1258 registered clinical studies on PCOS were retrieved from the World Health Organization International Clinical Trials Registry Platform. Of those, 395 were selected according to the inclusion and exclusion criteria, and divided into two groups based on the publication date of the COS on PCOS (4 February 2020): pre-publication and post-publication. The practical uptake of this COS was explored after data collation, assessment, comparison of the uptake of core outcomes or domains before and after the publication of this COS, and correlation analysis between the domains. There were 26 out of 33 core outcomes and five out of seven domains reported in the 395 trials. The highest uptake was observed for the reproductive domain and the reproductive hormonal profile (63.0% and 38.7%, respectively). After the publication of the COS on PCOS, the uptake of the generic domain and body mass index increased from 24.1% to 35.8% (P = 0.011) and 17.8% to 26.5% (P = 0.039), respectively. The total number of reported core outcomes in the generic domain met statistical significance (P = 0.012). Moreover, multivariable analyses still supported the above finding in the generic domain. Correlation analysis showed that most of the domains were positively correlated with each other. However, the pregnancy domain was negatively correlated with the metabolic domain. Reasons responsible for the unsatisfactory uptake may be the absence of specific definitions of core outcomes, as well as the lack of awareness among researchers regarding this COS. Due to the lack of standardized definition of outcomes, it was difficult to avoid some subjectivity in the process of consistency assessment. Two years after its publication, there was no substantial improvement in the uptake of the COS on PCOS. This suggests that this COS may require further revision, refinement, and promotion to improve the comparability of PCOS studies. This work was funded by Beijing Municipal Health Science and Technology Achievements and Appropriate Technology Promotion Project (BHTPP2022069), and the special fund of Beijing Key Clinical Specialty Construction Project. The authors do not have conflicts of interest to declare. N/A.


Unraveling the link between metabolic syndrome and abdominal aortic calcification.
Over the last few decades, the prevalence of metabolic syndrome (MetS) has gradually increased. As we know, many prior studies have connected MetS with diabetes, coronary heart disease, and cardiovascular disease. Abdominal aortic calcification (AAC) is a good marker of morbidity and mortality of vascular disease, as its degree may be associated with the severity of coronary artery calcification and disease. The aim of this article is to investigate the connection between MetS and AAC. This retrospective observational study included 2731 participants aged 58 years from the National Health and Nutrition Examination Survey (NHANES) (2013-2014). We used Dual-Energy X-ray Absorptiometry to define the degree of AAC. We defined MetS according to the National Cholesterol Education Program Adult Treatment Panel III definition. A total of 2731 participants with complete data were included for data analysis. In the fully adjusted model, an increase in the severity of AAC with the number of MetS components was still significant with βvalues of AAC Total 24 Score 0.498 (95% confidence interval (CI): 0.018,0.978), 1.016 (95% CI: 0.514,1.519) and 1.426 (95% CI: 0.916,1.937) respectively in 2, 3 and ≧ 4 components. Additionally, associations were observed between MetS components, including blood pressure, HDL and glucose with βvalues of AAC Total 24 Score 0.332(95% CI: 0.069, 0.595), 0.652(95% CI: 0.380, 0.925) and 0.534 (95% CI: 0.285, 0.783) after fully adjusted, respectively. The results indicated that, in the US adult population, a greater number of components of MetS were significantly associated with AAC. Among the components of metabolic syndrome, the blood pressure, HDL and blood sugar were observed apparent association with AAC.


The baseline neutrophil lymphocyte ratio predicts survival in soft-tissue sarcoma: A 17-year cohort study.
Abnormal ratios of peripheral blood cells, e.g. neutrophil-lymphocyte ratio (NLR), are strongly associated with poor outcomes in numerous cancers. In soft-tissue sarcoma (STS), the NLR has been studied in populations outside the UK although many have major methodological flaws, which represents the rationale for this study. Over 17 years old (2002-2019) adults with extremity STS were included. The baseline NLR (at the time of diagnosis) was calculated. The association between NLR, disease recurrence and survival was explored using cubic splines and a threshold of 3 selected, which is in keeping with the literature. Multivariable Cox regression was used to estimate overall survival, disease-free survival and recurrence with Hazard Ratios (HR) and 95% confidence intervals (CI). Overall, 401 patients were included. The median follow-up was 3 years 8 months (interquartile range 1 years 7 months to 5 years 2 months). During surveillance 148 died (37%), of which 123 (76%) were attributable to sarcoma. At the time of diagnosis, an NLR≥3 was independently associated with worse overall survival (adjusted HR 1.44 [95% 1.01, 2.03]). However, the baseline NLR was not associated with the risk of recurrence (adjusted HR 0.98 [95% CI 0.62, 1.57]) or disease-free survival (adjusted HR 1.11 [95% CI 0.79, 1.56]). At the time of diagnosis of STS, the NLR is strongly associated with survival and may serve as a cheap and readily available biomarker to personalise treatment plans for patients.


Possibilities of regulating disorders in functional activity of the retina with antioxidants under conditions of high-intensity light exposure.
We studied the effects of natural (α-tocopherol and SOD) and synthetic (potassium phenosane and hydroxypyridine) antioxidants on the recovery of disordered parameters of the electroretinogram under conditions of high-intensity light exposure. Potassium phenosane and tocopherol acetate more effectively normalized parameters of electroretinogram in monotherapy. The use of a complex of antioxidants completely prevented the disorders in the electroretinogram parameters in retinopathy after exposure to intense light.


Data-driven assessment of eQTL mapping methods.
The analysis of expression quantitative trait loci (eQTL) is a potentially powerful way to detect transcriptional regulatory relationships at the genomic scale. However, eQTL data sets often go underexploited because legacy QTL methods are used to map the relationship between the expression trait and genotype. Often these methods are inappropriate for complex traits such as gene expression, particularly in the case of epistasis. Here we compare legacy QTL mapping methods with several modern multi-locus methods and evaluate their ability to produce eQTL that agree with independent external data in a systematic way. We found that the modern multi-locus methods (Random Forests, sparse partial least squares, lasso, and elastic net) clearly outperformed the legacy QTL methods (Haley-Knott regression and composite interval mapping) in terms of biological relevance of the mapped eQTL. In particular, we found that our new approach, based on Random Forests, showed superior performance among the multi-locus methods. Benchmarks based on the recapitulation of experimental findings provide valuable insight when selecting the appropriate eQTL mapping method. Our battery of tests suggests that Random Forests map eQTL that are more likely to be validated by independent data, when compared to competing multi-locus and legacy eQTL mapping methods.


A case of foreign accent syndrome.
Foreign accent syndrome is a rare but potentially devastating clinical condition associated with altered speech rhythm and prosody, often occurring after a cerebral vascular accident. Missing this diagnosis can lead to delayed stroke work-up and treatment. We report a case of foreign accent syndrome in a 60-year-old woman who presented to the Emergency Department (ED) with 3 weeks of altered speech pattern, widened gait, bilateral leg heaviness, and mild headache. The patient had a history of Type 2 diabetes, malignant hypertension, toxic nodular goiter, and hyperlipidemia. She initially presented to the ED at the onset of symptoms, was thought to have had speech change secondary to a goiter impinging on the recurrent laryngeal nerve, and was discharged. She returned to the ED 3 weeks later when outpatient imaging revealed subacute infarction of the left hemi-pons and absent flow within the left vertebral artery. On examination, the patient was alert and conversational. She spoke fluently with an accent that had components of Jamaican and the accent of an Italian speaking English. Neurology was consulted and the patient was admitted. The patient was treated medically, and was discharged home with primary care follow-up. She developed a second, more significant stroke 1 month later, with unilateral weakness and slurred speech in the middle cerebral artery distribution. Clinicians should be aware that some stroke patients present with various atypical symptoms, and should suspect stroke in any patient with acute-onset neurological symptoms, including speech change.


Drug Hepatotoxicity: Causality Assessment.
Drug induced liver injury is a diagnosis that relies on the patterns of injury associated with specific medications and toxins. The process by which a clinician determines which agent is the likely culprit of the liver injury is called causality assessment. The Roussel Uclaf Causality Assessment Method (RUCAM) and additional causality assessment methods have been developed with the goal of providing a more standardized, less subjective approach to causality assessment. RUCAM remains the most used standardized method, however many physicians continue to rely on their experience for causality assessment.


Development of the European Health Interview Survey - Physical Activity Questionnaire (EHIS-PAQ) to monitor physical activity in the European Union.
A domain-specific physical activity questionnaire (EHIS-PAQ) was developed in the framework of the second wave of the European Health Interview Survey (EHIS). This article presents the EHIS-PAQ and describes its development and evaluation processes. Research institutes from Belgium, Estonia and Germany participated in the Improvement of the EHIS (ImpEHIS) Grant project issued by Eurostat. The instrument development process comprised a non-systematic literature review and a systematic HIS/HES database search for physical activity survey questions. The developed EHIS-PAQ proposal was reviewed by survey experts. Cognitive testing of the EHIS-PAQ was conducted in Estonia and Germany. The EHIS-PAQ was further tested in a pilot survey in Belgium, Estonia and Germany in different modes of data collection, face-to-face paper and pencil interview (PAPI) and computer assisted telephone interview (CATI). The EHIS-PAQ is a rather pragmatic tool aiming to evaluate how far the population is physically active in specific public health relevant settings. It assesses work-related, transport-related and leisure-time physical activity in a typical week. Cognitive testing revealed that the EHIS-PAQ worked as intended. The pilot testing showed the feasibility of using the EHIS-PAQ in an international health interview survey setting in Europe. It will be implemented in all 28 European Union Member States via European Union implementing regulation in the period between 2013 and 2015. This will be a first opportunity to get comparable data on domain-specific physical activity in all 28 EU MS and to publish indicators at the EU level. The EHIS-PAQ is a short, domain-specific PA questionnaire based on PA questions which have been used in large-scale health interview surveys before. It was designed by considering the respondents' perspective in answering PA questions.


The profile of glaucoma in a Tertiary Ophthalmic University Center in Riyadh, Saudi Arabia.
To report the pattern of glaucoma among Saudi patients who were presented to King Abdul Aziz University Hospital (KAUH). All glaucoma or glaucoma suspect patients who were presented to KAUH from 2006 to 2008 were included; medical files of all patients were retrieved and evaluated through standardized international guidelines. Collected data included: age, sex, laterality, intraocular pressure, and cup/disk ratio. Prevalence of different glaucoma types (including 95% CI) was calculated, ANOVA and post hoc tests were applied to evaluate the difference in indices across different types. A total of 2296 eyes of 1236 patients were included. Primary angle closure glaucoma (PACG) was the predominant type (46.6%) followed by primary angle closure (PAC) (17.2%), then primary open angle glaucoma (POAG) (12.8%), and secondary glaucoma (13%). Other types including (normal tension glaucoma (5.9%), childhood glaucoma (2.6%), and juvenile glaucoma (1.9%)) were also present but of lower prevalence. Primary angle closure glaucoma was the predominant form of glaucoma followed by PAC, and POAG suggesting that the pattern in Saudi Arabia could be quite different from that reported for primary glaucomas in the Western literature. In addition, pseudoexfoliation was the most common form of secondary open and closed angle glaucoma. These results indicate the need for a national intervention program for early detection and referral of glaucoma cases in order to prevent significant visual loss. There is also a need for a community based assessment to determine the prevalence of glaucoma as a baseline for future intervention.


Cell and molecular biology of septins.
Septins are a family of GTP-binding proteins that assemble into cytoskeletal filaments. Unlike other cytoskeletal components, septins form ordered arrays of defined stoichiometry that can polymerize into long filaments and bundle laterally. Septins associate directly with membranes and have been implicated in providing membrane stability and serving as diffusion barriers for membrane proteins. In addition, septins bind other proteins and have been shown to function as multimolecular scaffolds by recruiting components of signaling pathways. Remarkably, septins participate in a spectrum of cellular processes including cytokinesis, ciliogenesis, cell migration, polarity, and cell-pathogen interactions. Given their breadth of functions, it is not surprising that septin abnormalities have also been linked to human diseases. In this review, we discuss the current knowledge of septin structure, assembly and function, and discuss these in the context of human disease.


Acyl homoserine lactone-based quorum sensing in a methanogenic archaeon.
Acyl homoserine lactone (AHL)-based quorum sensing commonly refers to cell density-dependent regulatory mechanisms found in bacteria. However, beyond bacteria, this cell-to-cell communication mechanism is poorly understood. Here we show that a methanogenic archaeon, Methanosaeta harundinacea 6Ac, encodes an active quorum sensing system that is used to regulate cell assembly and carbon metabolic flux. The methanogen 6Ac showed a cell density-dependent physiology transition, which was related to the AHL present in the spent culture and the filI gene-encoded AHL synthase. Through extensive chemical analyses, a new class of carboxylated AHLs synthesized by FilI protein was identified. These carboxylated AHLs facilitated the transition from a short cell to filamentous growth, with an altered carbon metabolic flux that favoured the conversion of acetate to methane and a reduced yield in cellular biomass. The transcriptomes of the filaments and the short cell forms differed with gene expression profiles consistent with the physiology. In the filaments, genes encoding the initial enzymes in the methanogenesis pathway were upregulated, whereas those for cellular carbon assimilation were downregulated. A luxI-luxR ortholog filI-filR was present in the genome of strain 6Ac. The carboxylated AHLs were also detected in other methanogen cultures and putative filI orthologs were identified in other methanogenic genomes as well. This discovery of AHL-based quorum sensing systems in methanogenic archaea implies that quorum sensing mechanisms are universal among prokaryotes.


Two quantitative trait loci influence whipworm (Trichuris trichiura) infection in a Nepalese population.
Whipworm (Trichuris trichiura) infection is a soil-transmitted helminth infection that affects >1 billion people. It is a serious public health problem in many developing countries and can result in deficits in growth and cognitive development. In a follow-up study of significant heritability for whipworm infection, we conducted the first genome scan for quantitative trait loci (QTL) influencing the heritability of susceptibility to this important parasitic disease. Whipworm egg counts were determined for 1,253 members of the Jirel population of eastern Nepal. All individuals in the study sample belonged to a single pedigree including >26,000 pairs of relatives that are informative for genetic analysis. Linkage analysis of genome scan data generated for the pedigree provided unambiguous evidence for 2 QTL influencing susceptibility to whipworm infection, one located on chromosome 9 (logarithm of the odds ratio [LOD] score, 3.35; genomewide P = .0138) and the other located on chromosome 18 (LOD score, 3.29; genomewide P = .0159). There was also suggestive evidence that 2 loci located on chromosomes 12 and 13 influenced whipworm infection. The results of this first genome scan for T. trichiura egg counts provides new information on the determinants of genetic predisposition to whipworm infection.


Laparo-endoscopic versus open recurrent inguinal hernia repair: should we follow the guidelines?
On the basis of six meta-analyses, the guidelines of the European Hernia Society (EHS) recommend laparo-endoscopic recurrent repair following previous open inguinal hernia operation and, likewise, open repair following previous laparo-endoscopic operation. So far no data are available on implementation of the guidelines or for comparison of outcomes. Besides, there are no studies for comparison of outcomes for compliance versus non-compliance with the guidelines. In total, 4812 patients with elective unilateral recurrent inguinal hernia repair in men were enrolled between September 1, 2009, and September 17, 2014, in the Herniamed Registry. Only patients with 1-year follow-up were included. Out of the 2482 laparo-endoscopic recurrent repair operations 90.5% of patients, and out of the 2330 open recurrent repair procedures only 38.5% of patients, were operated on in accordance with the guidelines of the EHS. Besides, on compliance with the guidelines multivariable analysis demonstrated for laparo-endoscopic recurrent repair a significantly lower risk of pain at rest (OR 0.643 [0.476; 0.868]; p = 0.004) and pain on exertion (OR 0.679 [0.537; 0.857]; p = 0.001). Comparison of laparo-endoscopic and open recurrent repair in settings of compliance versus non-compliance with the guidelines showed a higher incidence of perioperative complications and re-recurrences for recurrent repairs that did not comply with the guidelines. The EHS guidelines for recurrent inguinal hernia repair are not yet being observed to the extent required. Non-compliance with the guidelines is associated with higher perioperative complication rates and higher risk of re-recurrence. Even on compliance with the guidelines, the risk of pain at rest and pain on exertion is higher after open recurrent repair than after laparo-endoscopic repair.


Macroalgae for biomonitoring of trace elements in relation to environmental parameters and seasonality in a sub-tropical mangrove estuary.
Being a resourceful ecosystem, mangrove estuaries have always been subjected to trace elements (TEs) contamination, and therefore, the biomonitoring approach holds immense potential for surveilling the aquatic environment. To investigate the potentiality of mangrove macroalgae as biomonitors, estuarine water, intertidal-sediment, and macroalgal samples were collected from the Pasur River estuary of Sundarbans mangrove ecosystem, Bangladesh, and afterward studied through Atomic Absorption Spectrometer to quantify the levels of six concerned TEs (Fe, Mn, Zn, Cu, Pb, and Cd). This study utilized the geo-environmental and ecological indices and sediment characterization approaches (sediment quality guidelines-SQGs) for assessing the contamination scenario of the adjacent environment to macroalgae whereas the performance of studied algal groups was evaluated using Bio-contamination factor, Comprehensive bio-concentration index, and Metal accumulation index. Metal occurrence scheme in the water followed the order of Fe > Zn > Mn > Pb > Cd while Fe > Mn > Zn > Cu > Pb > Cd for both sediment and macroalgae. Both Pb and Cd exceeded the guideline limit in estuarine water and the indices approach manifested low to moderate contamination with enrichment from anthropogenic origin of Mn, Zn, and Cu in sediment. Moreover, the SQGs revealed rare biological effects of Cu on an aquatic community. Within algal samples, Chlorophyta contributed the highest biomass production, followed by Phaeophyta and Rhodophyta. Statistical relationship disclosed the influence of environmental variables on TE's accumulation in Chlorophyta. By contrast, hydrochemical's association showed prevalence over the TEs accumulation process for Phaeophyta and Rhodophyta. Bioaccumulation performance analysis revealed that the ability to accumulate TEs in macroalgal groups varied with seasons. Therefore, biomonitoring with macroalgae for the region of interest might require further temporal considerations.


Toxoplasma gondii and mucosal immunity.
Toxoplasma gondii, an intracellular parasite infects the host through the oral route. Infection induces a cascade of immunological events that involve both the components of the innate and adaptative immune responses. Alteration of the homeostatic balance of infected intestine results in an acute inflammatory ileitis in certain strains of inbred mice. Both the infected enterocytes as well as the CD4 T cells from the lamina propria produce chemokines and cytokines that are necessary to clear the parasite whereas CD8 intraepithelial lymphocytes secrete transforming growth factor beta that reduces the inflammation. In this review, we describe the salient features of this complex network of interactions among the different components of the gut-associated lymphoid tissue cell population that are induced after oral infection with T. gondii.


Global mechanical consequences of reduced cement/bone coupling rigidity in proximal femoral arthroplasty: a three-dimensional finite element analysis.
Component loosening in total hip arthroplasty is often accompanied by substantial bony remodelling, associated initially with reduced stiffness of the cancellous bone bordering the cement, and eventually with the formation and proliferation of a compliant fibrous membrane at the bone/cement interface. An anatomically based three-dimensional finite element model has been developed to explore the salient stress changes occurring with progressive degradation of the stiffness of the cancellous bone in a thin zone bordering the cement. This border zone, modelled as a distinct linearly elastic and isotropic material layer, assumed a geometry and a range of mechanical properties inferred from eventual membrane thickness apparent in recent animal studies of component loosening. The major variables considered were: stiffness (elastic modulus) and compressibility (Poisson ratio) of the border zone, stiffness changes in the outlying cancellous bone, resultant hip contact force, and trochanteric muscle loadings. The results for the limiting case of a non-degraded border zone compared reasonably with previous studies of femoral reconstructions having rigid bone-to-cement attachment. Progressive decay of border zone stiffness produced complex changes in load transmission. Foremost among these were a generalized increase in stress levels (especially of transverse-plane tension) in the proximo-lateral cancellous bone, and a corresponding generalized decrease in stress levels in the proximo-medial cancellous bone. There were also large bending moment increases in the prosthesis and its cement mantle, especially at mid-stem. At almost all sites, the critical stress levels were those developed for peak stance-phase loading, rather than for the lower loads (and different resultant contact force directions) occurring elsewhere in the gait cycle. The elevated proximo-lateral cancellous bone stresses occurring with eventual membrane development, consistent with localized bony hypertrophy seen in recent animal studies, may be a response to hoop stresses occurring during pistoning of the tapered cement mantle.


Stress imaging. Current clinical options for the diagnosis, localization, and evaluation of coronary artery disease.
As technology advances, new methods evolve. In this article, the methods of stress testing and related imaging in coronary disease are addressed, and dynamic and pharmacologic stress, direct and indirect methods, are defined and evaluated. The stress imaging methods related to the modalities of scintigraphy and ultrasound are reviewed and their advantages and disadvantages assessed in view of scientific and economic factors.


Sooner or later: age at onset of generalized anxiety disorder in older adults.
Generalized anxiety disorder (GAD) is a common disorder in older adults, with widespread and long-lasting consequences. In this study, we assessed the characteristics associated with lifetime GAD in community-dwelling adults according to their age at onset of the disorder. Study sample was extracted from the 2007 National Survey of Mental Health and Well Being, a nationally representative cross-sectional survey that interviewed 8,841 Australians aged between 16 and 85 years using the Composite International Diagnostic Interview. Of the 3,178 participants aged 55-85 years, there were 227 (M = 63.7 years; 65% female) with a lifetime diagnosis of GAD who were the focus of our analyses. Age at onset was defined as early (<26 years) or late (≥ 26 years), based on the median age at onset for the entire sample. The weighted prevalence estimates for 12-month and lifetime GAD were 2.8% (95% CI: 2.0, 3.7) and 7.0% (95% CI: 5.7, 8.3), respectively, with less than one-tenth of the participants being diagnosed after the age of 60 years. Having the first GAD episode earlier in life was significantly associated with physical abuse during childhood (OR = 0.34, 95% CI: 0.16, 0.75), lifetime diagnosis of dysthymia (OR = 0.34, 95% CI: 0.18, 0.67), and number of GAD episodes (OR = 0.29, 95% CI: 0.14, 0.58), after adjusting for current age and 12-month GAD. In older adults, an earlier age at onset of GAD was associated with childhood physical abuse and worse clinical outcomes, thus appearing to be a marker for increased vulnerability to GAD.


A new microsample grinding technique for quantitative determination of calcium and phosphorus in dental enamel.
A new microsampling method is described for measuring variations in calcium and phosphorus distribution in dental enamel. Ten successive layers, 10 micron thick, from five human enamel posts with previously abraded flat upper surfaces were ground and analyzed. Mean Ca and P values were, respectively, 1116 +/- 110 and 527 +/- 47 micrograms/mm3, and mean Ca/P w/w and molar ratios, 2.11 +/- 0.10 and 1.63 +/- 0.08, respectively. Despite its limitations, the present method allows for accurate investigation of the mineral content in sound, experimentally-treated enamel.


The Role of the Glucosinolate-Myrosinase System in Mediating Greater Resistance of Barbarea verna than B. vulgaris to Mamestra brassicae Larvae.
We investigated the influences of two structurally similar glucosinolates, phenethylglucosinolate (gluconasturtiin, NAS) and its (S)-2-hydroxyl derivative glucobarbarin (BAR), as well as their hydrolysis products on larvae of the generalist Mamestra brassicae (Lepidoptera: Noctuidae). Previous results suggested a higher defensive activity of BAR than NAS based on resistance toward M. brassicae larvae of natural plant genotypes of Barbarea vulgaris R. Br. (Brassicaceae) dominated by BAR. In the present study, the hypothesis of a higher defensive activity of BAR than NAS was tested by comparing two Barbarea species similarly dominated either by BAR or by NAS and by testing effects of isolated BAR and NAS on larval survival and feeding preferences. Larvae reared on leaf disks of B. verna (Mill.) Asch. had a lower survival than those reared on B. vulgaris P- and G-chemotypes. Leaves of B. verna were dominated by NAS, whereas B. vulgaris chemotypes were dominated by BAR or its epimer. In addition, B. verna leaves showed a threefold higher activity of the glucosinolate-activating myrosinase enzymes. The main product of NAS from breakdown by endogenous enzymes including myrosinases ("autolysis") in B. verna leaves was phenethyl isothiocyanate, while the main products of BAR in autolyzed B. vulgaris leaves were a cyclized isothiocyanate product, namely an oxazolidine-2-thione, and a downstream metabolite, an oxazolidin-2-one. The glucosinolates BAR and NAS were isolated and offered to larvae on disks of cabbage. Both glucosinolates exerted similar negative effects on larval survival but effects of NAS tended to be more detrimental. Low concentrations of BAR, but not of NAS, stimulated larval feeding, whereas high BAR concentrations acted deterrent. NAS only tended to be deterrent at the highest concentration, but the difference was not significant. Recoveries of NAS and BAR on cabbage leaf disks were similar, and when hydrolyzed by mechanical leaf damage, the same isothiocyanate-type products as in Barbarea plants were formed with further conversion of BAR to cyclic products, (R)-5-phenyloxazolidine-2-thione [(R)-barbarin] and (R)-5-phenyloxazolidin-2-one [(R)-resedine]. We conclude that a previously proposed generally higher defensive activity of BAR than NAS to M. brassicae larvae could not be confirmed. Indeed, the higher resistance of NAS-containing B. verna plants may be due to a combined effect of rather high concentrations of NAS and a relatively high myrosinase activity or other plant traits not investigated yet.


Comparison between condensation and overall chain elongation of arachidoyl-CoA and arachidonoyl-CoA in swine cerebral microsomes.
The condensation and overall elongation products of exogenous arachidoyl-CoA (20:0-CoA) and endogenous fatty acids in swine cerebral microsomes were detected by radio gas chromatography. In addition, the condensation products with malonyl-CoA as substrate were analyzed by radio high-performance liquid chromatography. Three main condensation products were detected; the overall elongation products of exogenous 20:0-CoA were 22:0 and 24:0, and those of endogenous substrates were 18:0, 22:4, and 24:4. The yield was estimated for the conversion of 3-ketoacyl-CoAs to the corresponding saponification products (methyl ketones or R-2-one; e.g., 2-heptadecanone = 17:0-2-one); these products were identified in the preceding paper (S. Yoshida and M. Takeshita (1987) Arch. Biochem. Biophys. 254, 170-179). The extraction of R-2-one by hexane depended on the acyl chain length. The yield of 2-heneicosanone (21:0-2-one) detected by radio gas chromatography was 80% whereas the yields of 17:0-2-one and 2-heneicosatetraenone (21:4-2-one) from the corresponding 3-ketoacyl-CoAs were 56 and 48%, respectively. A quantitative comparison was performed for the condensation and overall elongation activity; it was noticed that the condensation activity for the system which simultaneously produced two elongation products was nearly the same as that of the corresponding overall elongation activity. This result suggests that the condensation step may be at least one of the rate-limiting steps in the overall elongation of very-long-chain fatty acyl-CoA.


Anti-PD1 rechallenge in combination with anti-angiogenesis or anti-EGFR treatment beyond progression in recurrent/metastatic nasopharyngeal carcinoma patients.
We aim to evaluate the efficacy and safety of anti-PD1 rechallenge in combination with anti-angiogenesis or anti-EGFR treatment in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC) patients who progressed to previous anti-PD1 therapy. Enrolled patients were divided into a combination group and a chemotherapy only group. A total of 145 patients were enrolled. The median progress-free survival (mPFS) was 7.9 months and 4.4 months, respectively for the two groups. The combination group exhibited significantly longer PFS (HR=0.363, p < 0.001), and better disease control ratio (DCR, p = 0.022) compared with the chemotherapy group. Among the combination group, longer PFS was found in those patients who received different PD1 inhibitor from prior therapy, reached object response rate (ORR) from prior anti-PD1 therapy, and EBV DNA ≤ 1500 copy/ml before therapy, comparing to the corresponding other patients. R/M NPC patients who progressed from prior anti-PD1 therapy could benefit from the anti-PD1 rechallenge in combination with anti-angiogenesis or anti-EGFR agents.


Outcomes of eight cats with oral neoplasia treated with radical mandibulectomy.
To report outcomes after radical mandibulectomy in cats. Multi-institutional retrospective study. Eight cats were included. Medical records were searched for cats with confirmed oral neoplasia treated with radical mandibulectomy. Data collected included demographics, surgical procedure, histopathological diagnosis, postoperative management, and outcomes. Ages ranged from 8 to 17 years. All cats had 75% to 90% of the mandible removed and feeding tubes placed. Seven cats had squamous cell carcinoma, and one cat had a giant cell tumor. Six cats ate on their own postoperatively. Three cats had local recurrence and tumor-related died at 136 and 291 days. Six cats had no recurrence, with survival times of 156, 465, 608, and 1023 days, and two cats were still alive at 316 and 461 days after surgery. The three long-term survivors died of causes unrelated to oral neoplasia. One cat died at 156 days due to aspiration of food material. The overall estimated mean survival time was 712 days. After radical mandibulectomy, independent food intake was achieved in 6 of eight cats, and four cats lived longer than one year. Radical mandibulectomy should be considered for the treatment of extensive oral neoplasia in cats. Successful long-term outcomes are possible with aggressive supportive care perioperatively.


Plaque formation and removal assessed in vivo in a novel repeated measures imaging methodology.
A repeated measures digital imaging technique (Digital Plaque Image Analysis) was used to assess variations in plaque formation, including levels of plaque developed following evening and morning tooth brushing with a standard dentifrice, to establish a baseline for future assessments of antimicrobial formulations. Following a rigorous oral hygiene period, subjects were provided with a standard commercial (non-antibacterial) dentifrice and manual toothbrush and instructed to brush b.i.d., as normal. On six separate days over two weeks, subjects reported at three times for a daily plaque assessment: in the morning before oral hygiene, post-brushing, and in the afternoon post-brushing. Morning plaque levels covered approximately 10% of the measured dentition, and plaque was removed by 75% with morning tooth brushing. Plaque underwent rapid regrowth during the day, and averaged approximately 7% coverage by the afternoon. These results support the value of Digital Plaque Image Analysis in recording diurnal plaque variations and treatment effects, and suggest that assessment of oral hygiene efficacy (either mechanical or chemopreventive) accounts for diurnal variations in plaque formation. In addition, the results suggest that plaque regrowth and virulence activity overnight is a significant target for oral hygiene interventions.


Home range - body mass relations: a field study on African browsing ruminants.
Home range data were collected concurrently from four syntopic browsing ruminant species in a conserved savanna ecosystem. Mean home range areas were: giraffe (Giraffa camelopardalis) 282 km2; kudu (Tragelaphus strepsiceros) 21.9 km2; impala (Aepyceros melampus) 5.82 km2; steenbok (Raphicerus campestris) 0.62 km2. Home range area (A hr) scaled on body mass (M) as: A hr=0.024 M 1.38 (r 2=0.99).


Carbon-ion radiotherapy (CIRT) as treatment of pancreatic cancer at HIT: initial radiation plan analysis of the prospective phase II PACK-study.
To analyze the dose objectives and constraints applied at the prospective phase II PACK-study at Heidelberg ion therapy center (HIT) for different radiobiological models. Treatment plans of 14 patients from the PACK-study were analyzed and recomputed in terms of physical, biological dose and dose-averaged linear energy transfer (LETd). Both LEM-I (local effect model 1) and the adapted NIRS-MKM (microdosimetric kinetic model), were used for relative biological effectiveness (RBE)-weighted dose calculations (DBio|HIT and DBio|NIRS). A new constraint to the gastrointestinal (GI) tract was derived from the National Institute of Radiological Science (NIRS) clinical experience and considered for plan reoptimization (DBio|NIRS-const_48Gy and DBio|NIRS-const_50.4Gy). The Lyman-Kutcher-Burman (LKB) model of Normal Tissue Complication Probability (NTCP) for GI toxicity endpoints was computed. Furthermore, the computed LETd distribution was evaluated and correlated with Local Control (LC). Only two patients showed a LETd98% in the GTV greater than 44 keV/μm. A HIT-dose constraint to the GI of [Formula: see text] was derived from the NIRS experience, in alternative to the standard at HIT Dmax = 45.6 GyRBEHIT. In comparison with the original DBio|HIT,DBio|NIRS-const_48GyandDBio|NIRS-const_50.4Gy resulted in an increase in the ITV's D98% of 8.7% and 11.3%. The NTCP calculation resulted in a probability for gastrointestinal bleeding of 4.5%, 12.3% and 13.0%, for DBio|NIRS, DBio|NIRS-const_48Gy and DBio|NIRS-const_50.4Gy, respectively. The results indicate that the current standards applied at HIT for CIRT closely align with the Japanese experience. However, to enhance tumor coverage, a more relaxed constraint on the GI tract may be considered. As the PACK-trial progresses, further analyses of various clinical endpoints are anticipated.