Hospitalizations During the COVID-19 Pandemic Among Recently Homeless Individuals: a Retrospective Population-Based Matched Cohort Study.
Hospitalizations fell precipitously among the general population during the COVID-19 pandemic. It remains unclear whether individuals experiencing homelessness experienced similar reductions. To examine how overall and cause-specific hospitalizations changed among individuals with a recent history of homelessness (IRHH) and their housed counterparts during the first wave of the COVID-19 pandemic, using corresponding weeks in 2019 as a historical control. Population-based cohort study conducted in Ontario, Canada, between September 30, 2018, and September 26, 2020. In total, 38,617 IRHH, 15,022,368 housed individuals, and 186,858 low-income housed individuals matched on age, sex, rurality, and comorbidity burden. Primary outcomes included medical-surgical, non-elective (overall and cause-specific), elective surgical, and psychiatric hospital admissions. Average rates of medical-surgical (rate ratio: 3.8, 95% CI: 3.7-3.8), non-elective (10.3, 95% CI: 10.1-10.4), and psychiatric admissions (128.1, 95% CI: 126.1-130.1) between January and September 2020 were substantially higher among IRHH compared to housed individuals. During the peak period (March 17 to June 16, 2020), rates of medical-surgical (0.47, 95% CI: 0.47-0.47), non-elective (0.80, 95% CI: 0.79-0.80), and psychiatric admissions (0.86, 95% CI: 0.84-0.88) were significantly lower among housed individuals relative to equivalent weeks in 2019. No significant changes were observed among IRHH. During the re-opening period (June 17-September 26, 2020), rates of non-elective hospitalizations for liver disease (1.41, 95% CI: 1.23-1.69), kidney disease (1.29, 95% CI: 1.14-1.47), and trauma (1.19, 95% CI: 1.07-1.32) increased substantially among IRHH but not housed individuals. Distinct hospitalization patterns were observed among IRHH even in comparison with more medically and socially vulnerable matched housed individuals. Persistence in overall hospital admissions and increases in non-elective hospitalizations for liver disease, kidney disease, and trauma indicate that the COVID-19 pandemic presented unique challenges for recently homeless individuals. Health systems must better address the needs of this population during public health crises.


Epitope diversity of monoclonal antibodies revealed by cross-species reactivity.
The epitope specificity of two monoclonal antibodies (MAb) which have the same functional activity has been studied. These two independently raised rat IgG2b MAb, NIMP-R10 and M1/70 (Springer et al., 1979), blocked the complement (C) receptor on mouse macrophages. Both MAb showed essentially the same binding pattern with mouse cells, binding to the same extent mouse eosinophils, macrophages, neutrophils, a small proportion of spleen and bone marrow cells, but not thymocytes. That both MAb were apparently recognizing the same epitope was suggested from experiments in which MAb M1/70 inhibited the binding of MAb NIMP-R10. In addition, both MAb showed identity at the molecular level, precipitating the same molecules from the surface of mouse cells. However, NIMP-R10 and M1/70 could be shown to recognize different epitopes when they were tested on human cells. Thus, NIMP-R10 was found to bind to neutrophils and to large granular lymphocytes with natural killer cell activity but not to eosinophils or monocytes, while M1/70 bound to all of these cell types. It is suggested that inter-species testing may have general application in the analysis of antibody specificity.


Juvenile elastoma and osteopoikilosis (the Buschke--Ollendorff syndrome).
Sixteen patients from seven different families with the Buschke-Ollendorff syndrome have been studied. Osteopoikilosis was found in two-thirds of the patients radiologically examined and all but two had skin involvement. The predominant clinical pattern consisted of grouped skin coloured papules and discs that were distributed asymmetrically and which usually had presented at an early age. The skin lesions showed the characteristic histological changes of juvenile elastoma which, it is suggested, is the specific dermatological abnormality of the Buschke-Ollendorff syndrome.


Total saponin extract, ginsenoside Rb1, and compound K alleviate peripheral and central neuropathic pain through estrogen receptors on rats.
In this study, we investigated whether total saponin extract (TSE), ginsenoside Rb1, and Rb1 metabolite compound K, which are isolated from red ginseng, have antinociceptive effects on peripheral and central neuropathic pain (PNP and CNP, respectively). PNP and CNP were induced by tail nerve injury (TNI) at S1 and by contusive spinal cord injury (SCI) at T9 in male Sprague-Dawley rats, respectively. Two weeks after TNI or 4 weeks after SCI, pain-induced rats were orally administered vehicle, TSE (50 mg/kg), Rb1 (12.5 mg/kg), compound K (7 mg/kg), or gabapentin (GBP, 60 mg/kg), and the antinociceptive effects were examined by von Frey filament, cold/warm water, and hot plate analyses. Allodynia and hyperalgesia were significantly alleviated by TSE, Rb1, and GBP 1 hr after drug administration. The immunohistochemistry and real-time RT-PCR results showed that the activation of microglia/astrocytes and the expression of inflammatory mediators such as Il-1β, Il-6, iNOS, and Cox-2 were also significantly inhibited in L4-L5 spinal cord of CNP-induced rats 1 hr after drug administration. Furthermore, the antinociceptive effects of TSE and Rb1 were reversed by treatment with the estrogen receptor (ER) antagonist ICI182780. In particular, compound K also significantly alleviated both PNP and CNP. Therefore, our results indicate that TSE, Rb1, and compound K have potential antinociceptive effects against neuropathic pain that might be mediated through the ER.


Experience with the Portacath.
Fifty Portacaths have been inserted in patients undergoing prolonged outpatient chemotherapy, most for haematological disease. Twenty-one are still working at a median duration of 12 months (range 1-27) and a further 15 were functioning normally at the time of the patients death (median survival 6 months). Four functioning Portacaths have been removed, three suspected of causing septicaemia and one believed erroneously to have occluded. Ten have ceased to function and nine of these have been removed. The causes of these failures are nearly all avoidable and are discussed in detail; many occurred early in our experience. With careful attention to detail and with management by trained and interested staff, the Portacath is a safe and reliable device for intermittent vascular access.


Clinical decision-making by fourth-year pharmacy students: Towards an understanding of their uncertainty.
Clinical decision-making is a critical process underpinning much of a pharmacist's daily activities. While it is known that pharmacists hesitate to make decisions, it remains unclear whether pharmacy students experience similar hesitancy. The objective of this study was to better understand the phenomenon of decision-making in pharmacy students. This study was designed from a social constructivist paradigm using qualitative case study methodology. The purpose was to investigate issues related to hesitancy in clinical decision-making by fourth-year pharmacy students. Data were collected through observation of students engaging in simulations, post-simulation interviews, and written reflections. Data analysis included multiple stages of coding, followed by pattern identification and discovery of interrelationships. The primary themes relating to issues in pharmacy student clinical decision-making were relational factors, teaching and learning, degree of certainty, and personal characteristics. Relational factors include elements of relationships with patients and physicians as well as a sense of autonomy. The theme of teaching and learning included the sub-themes of formal education and learning in the real world. Degree of certainty included patient complexity, weighing risks and benefits, comfort in ambiguity, and a lack of information. Finally, personal characteristics associated with decision-making include personal experiences, leadership skills, and confidence. Pharmacy education needs to focus on ensuring preceptors can help model comfort in ambiguity, that assessments include the reality of practice, and ensuring ample practice of decision-making in a simulated environment.


KRAS Inhibitors- yes but what next? Direct targeting of KRAS- vaccines, adoptive T cell therapy and beyond.
Kirsten rat sarcoma viral oncogene homolog (KRAS) is a proto-oncogene of the RAS-MAPK pathway. KRAS mutations are present in a variety of malignancies including lung, colorectal, and pancreatic cancer. Until the recent approval of sotorasib, a KRAS G12C inhibitor, lack of targeted therapy for KRAS has resulted in poor prognosis of patients with tumors harboring KRAS mutations. While the conditional approval of sotorasib was a major breakthrough for those patients harboring KRAS G12C mutations, G12C only accounts for a fraction of those with KRAS mutations and eventual resistance to G12C inhibitors are unavoidable. This comprehensive review on KRAS inhibitors covers accumulating evidence on not only the G12C inhibitors but also other therapeutic attempts to tackle KRAS including combination therapy as well as direct inhibition with vaccines, adoptive T cell therapy, proteolysis-targeted chimeras (PROTACs) and CRISPR/Cas9.


Relation between egg production and food consumption in species of the genus Pardosa (Lycosidae, Araneae) under experimental conditions of food-abundance and food-shortage.
1. The amount of food intake during the egg ripening period and the conversion of this food into eggs (biomass and number of eggs) in four Pardosa species is described. The amount of food taken in is dependent on the size of the spider species. Basically the process of conversion of food into egg-biomass is the same for all four species. Thus the size of the spider species mainly determines the number of eggs in the egg-sac. There are however minor differences in "efficiency" of the process and in dryweight of the eggs between the species. These differences which are discussed complicated the general process of food conversion into number of eggs. 2. When food shortages are supplied during the egg ripening period two reactions can be observed: a) All species tend to keep the dry weight of the eggs at a constant level. b) Some species produce the same number of eggs under conditions of small food shortages as under conditions of maximum food supply, using reserve material from the body of the female. In this case the female either shows no increase in body weight or a decrease while others immediately adapt the number of eggs to the quantity of food given. Under conditions of strong food shortages, however, both groups of species show the same reaction.


Effect of an Australian community-based caseload midwifery group practice service on maternal and neonatal outcomes for women from a refugee background.
Women from a refugee background who resettle in high-income countries experience poorer perinatal outcomes in comparison to women from host countries. There is a paucity of research on how best to improve these outcomes. To report on the effectiveness of an Australian Refugee Midwifery Group Practice service on perinatal outcomes. We used inverse probability of treatment weighting to balance confounders and calculate treatment effect and compare maternal and neonatal outcomes for women from a refugee background who received Refugee Midwifery Group Practice care (n = 625), to those receiving standard care (n = 634) at a large tertiary hospital (1 January 2016-31 December 2019). Prespecified primary outcomes included: proportion of women attending ≥ 5 antenatal visits, preterm birth (<37 weeks), spontaneous onset of labour, epidural analgesia in the first stage of labour, normal birth (term, spontaneous onset, vertex, spontaneous vaginal birth, no epidural, no episiotomy), and exclusively breast-feeding at discharge. Women who received Refugee Midwifery Group Practice care were more likely to have spontaneous onset of labour (adjusted odds ratio 2·20, 95% CI 1·71-2·82; p < 0·0001), normal birth (1·55, 1·23-1·95; p < 0·0001), and less likely to use epidural analgesia (0·67, 0·50-0·89; p = 0·0067) and have a preterm baby (0·60, 0·36-0·99; p = 0·047). There was no difference between groups in women attending ≥ 5 antenatal visits and exclusive breastfeeding at discharge from hospital. A Refugee Midwifery Group Practice is feasible and clinically effective. Similar services could potentially improve outcomes for women from a refugee background who resettle in high-income countries.


A randomized controlled study of single-agent cisplatin and radiotherapy versus docetaxel/cisplatin and radiotherapy in high-risk early-stage cervical cancer after radical surgery.
This study explored whether docetaxel/cisplatin and radiotherapy (TP-R) increases overall survival (OS) and recurrence-free survival (RFS) compared to single-agent cisplatin and radiotherapy (C-R) in patients with high-risk early-stage cervical cancer post surgery. Patients with clinical stage IB and IIA carcinoma of the cervix, initially treated with radical hysterectomy and pelvic lymphadenectomy, and who had positive pelvic lymph nodes and/or positive margins and/or the diameter of the primary tumor ≥4 cm and/or depth of interstitial infiltration ≥1/2 and/or lymphovascular space invasion were eligible for this study. Patients were randomized to receive C-R or TP-R. Radiotherapy in both groups was external radiation (46-54 Gy) followed by high-dose rate brachytherapy (12-24 Gy). Patients were given cisplatin (40 mg/m(2)) every week for five cycles (C-R group) or docetaxel (30 mg/m(2)) and cisplatin (30 mg/m(2)) every week for five cycles (TP-R group). Between 2003 and 2008, 320 patients were entered onto the study. Final analyses included 285 patients. One hundred and forty patients comprised the C-R group and 145 were in the TP-R group. The 5-year OS were 74.3 % in the C-R group and 82.8 % in the TP-R group. The hazard ratio (HR) for death was 0.65 in the TP-R group (95 % CI: 0.39-1.09, P = 0.098). The RFS were 69.3 % in the C-R group and 79.3 % in the TP-R group, and the HR for recurrence was 0.64 in the TP-R group (95 % CI: 0.40-1.03, P = 0.061). Recurrence rates were similar in both groups (27 in the C-R group and 18 in the TP-R group, P = 0.112). The seriousness of late side effects was similar in the two groups, with a higher rate of reversible hematological effects in the TP-R group. Compared with single-agent cisplatin and radiotherapy, docetaxel/cisplatin in combination with radiotherapy does not increase OS but has the trend of increasing RFS in patients with high-risk early-stage cervical cancer. However, docetaxel/cisplatin in combination with radiotherapy is associated with a higher incidence of side effects, this effect was reversible, and the incidence of late side effects was similar in the two treatment groups.


Structural-mechanical and antibacterial properties of a soft elastic polyurethane surface after plasma immersion N2(+) implantation.
The surface of elastic polyurethane treated by plasma immersion N2(+) ion implantation at different fluences has been investigated. A folded surface structure is observed in all cases. Analysis has been performed to study the structural (roughness, steepness and fraction of folds, fractal characteristics), mechanical (stiffness, adhesion force between the AFM probe and the material) and wetting properties of surfaces. Under uniaxial stretching the cracks orthogonal to the axis of deformation and longitudinal folds are formed on the examined surfaces. After unloading the initial structure of the surface of deformed materials exposed to low fluences becomes smoother and does not recover, i.e. it has plastic properties. By contrast, the structure of the surfaces of materials subjected to high-fluence treatment recovers without visible changes and the cracks are fully closed. The study of Staphylococcus colonies grown on these materials has demonstrated significant reduction (from 3 to 5 times) in the vitality of bacteria on treated surfaces. This result was repeated on samples after 11 months of storage. Such antibacterial properties are primarily related to the structural changes of the surfaces accompanied by the increased hydrophilicity.


LC-MS/MS determination of HY072808, a novel candidate for treating atopic dermatitis, and its active metabolite: Application to a first-in-human pharmacokinetic study.
HY072808 is a novel phosphodiesterase 4 inhibitor currently under clinical development to treat atopic dermatitis. The first step is to address the pharmacokinetics and safety after topical administration of HY072808 ointments in healthy humans. In this study, we developed a highly sensitive liquid chromatography-tandem mass spectrometry method to determine plasma HY072808 and its active metabolite, ZZ24, in tiny amounts. The plasma samples were prepared using a simple liquid-liquid extraction method. Liquid chromatographic separation was achieved by gradient elution. The MS/MS quantification was performed in positive ion mode via multiple reaction monitoring. The method showed satisfactory linearity from 10 to 4,000 pg/ml for HY072808 and ZZ24. There was no significant interference from blank plasma. The method was validated for accuracy and precision, matrix effect and extraction recovery, dilution integrity, injection carryover and stability according to the related guidelines of the regulatory authorities. The HY072808 and ZZ24 concentrations in human plasma from a clinical trial were determined using this method. In conclusion, the validated method was robust and could be utilized to support the clinical development of HY072808.


Kinetic constants for the inhibition of camel retinal acetylcholinesterase by the carbamate insecticide lannate.
We have designed this study to determine various kinetic parameters of camel retinal membrane-bound acetylcholinesterase (AChE; EC 18.104.22.168) inhibition by carbamate insecticide lannate [methyl N-[[(methylamino)carbonyl]oxy] ethanimidothioate]. All these kinetic constants were derived by simple graphical methods. The value of kinetic parameters was estimated as follows: 0.061 microM)(-1), 1.14 (microM)(-1), 0.216 microM, 0.016 min(-1), 0.0741 (gammaM min)(-1) 0.746 microM, and 4.42 microM for velocity constant (Kv), new inhibition constant (Knic), dissociation constant (Kd), carbamylation rate constant (k2c), overall carbamylation rate constant (k'2), 50% inhibition constant (K150), and 99% inhibition constant (K199), respectively. These unique methods may be used to estimate such kinetic parameters for time-dependent inhibition of enzymes by variety of chemicals, insecticides, herbicides, and drugs.


Chitosan microparticles for delivery of proteins to the retina.
Chitosan microparticles (CMPs) have previously been developed for topical applications to the eye, but their safety and efficacy in delivering proteins to the retina have not been adequately evaluated. This study examines the release kinetics of CMPs in vitro, and assesses their biocompatibility and cytotoxicity on retinal cells in vitro and in vivo. Two proteins were used in the encapsulation and release studies: BSA (bovine serum albumin) and tat-EGFP (enhanced green fluorescent protein fused to the transactivator of transcription peptide). Not surprisingly, the in vitro release kinetics were dependent on the protein encapsulated, with BSA showing higher release than tat-EGFP. CMPs containing encapsulated tat-EGFP were tested for cellular toxicity in photoreceptor-derived 661W cells. They showed no signs of in vitro cell toxicity at a low concentration (up to 1mgml(-1)), but at a higher concentration of 10mgml(-1) they were associated with cytotoxic effects. In vivo, CMPs injected into the subretinal space were found beneath the photoreceptor layer of the retina, and persisted for at least 8weeks. Similar to the in vitro studies, the lower concentration of CMPs was generally well tolerated, but the higher concentration resulted in cytotoxic effects and in reduced retinal function, as assessed by electroretinogram amplitudes. Overall, this study suggests that CMPs are effective long-term delivery agents to the retina, but the concentration of chitosan may affect cytotoxicity.


HOX cluster-embedded lncRNAs and epithelial-mesenchymal transition in cancer: Molecular mechanisms and therapeutic opportunities.
Although there has been substantial improvement in the treatment modalities, cancer remains the major cause of fatality worldwide. Metastasis, recurrence, and resistance to oncological therapies are the leading causes of cancer mortality. Epithelial-mesenchymal transition (EMT) is a complex biological process that allows cancer cells to undergo morphological transformation into a mesenchymal phenotype to acquire invasive potential. It encompasses reversible and dynamic ontogenesis by neoplastic cells during metastatic dissemination. Hence, understanding the molecular landscape of EMT is imperative to identify a reliable clinical biomarker to combat metastatic spread. Accumulating evidence reveals the role of HOX (homeobox) cluster-embedded long non-coding RNAs (lncRNAs) in EMT and cancer metastasis. They play a crucial role in the induction of EMT, modulating diverse biological targets. The present review emphasizes the involvement of HOX cluster-embedded lncRNAs in EMT as a molecular sponge, chromatin remodeler, signaling regulator, and immune system modulator. Furthermore, the molecular mechanisms behind therapy resistance and the potential use of novel drugs targeting HOX cluster-embedded lncRNAs in the clinical management of distant metastasis will be discussed.


Possible mechanism of adverse reaction following levodopa plus benserazide treatment.
1 Rats treated for seven days with seryl-trihydroxybenzylhydrazine (benserazide), and inhibitor of peripheral aromatic L-amino acid decarboxylase (500 mg/kg, daily, i.p.) alone or in combination with L-DOPA methylester (500 mg/kg, daily, i.p.) for seven days showed a moderate but significant decrease of liver aldehyde dehydrogenase (ALDH), without accompanying change in alcohol dehydrogenase (ADH) activity, compared with saline-treated controls. 2 Administration of L-DOPA methylester (500 mg/kg, daily, i.p.) alone for seven days had little effect on liver ADH or ALDH. 3. The combined treatment might be conducive to the in vivo formation of L-DOPA-derived tetrahydroisoquinoline derivatives which might be implicated in L-DOPA produced adverse effects.


A new scoring system for malignant astrocytomas.
Currently there are a few scoring systems for malignant astrocytoma, but they are not widely accepted. The aim of this study was to create a scoring system for supratentorial malignant astrocytoma, which could be used in both developed and developing societies. This study was performed in 128 patients who had supratentorial malignant astrocytoma (grade III or IV). They were operated, and after the operation patients were irradiated with 50-60 Gy. The mean age was 55.1 years. The mean Karnofsky performance status (KPS) was 51. The tumour removal >90% was achieved in 57.8%. A biopsy was never exclusively performed. The mean survival was 8.2 months and 12-month survival was 25%. Thirteen out of 35 data that we tested had a prognostic value for survival time. By using the most appropriate four parameters (age, KPS, initial seizure and histopathological grade) we created a scoring system - MAS (Malignant Astrocytoma Score). The scores range from 0-16. The area under the ROC (Receiver Operating Characteristic) curve showed that the AUC for the prediction of 6-, 12- and 18-month survival was 0.729, 0.755, and 0.927. We compared MAS with two of the most commonly used scoring systems. The AUC for the same prediction, using the MRC (Medical Research Council) was 0.673, 0.637, and 0.888. For the RTOG (Radiation Therapy Oncology Group) score the AUC was 0.672, 0.700, and 0.854. We are of the opinion that MAS represents a useful scoring system to determine the severity of the illness and make a prognosis for both individuals and groups of patients with malignant supratentorial astrocytoma. MAS is more accurate than predictions made by other systems currently in use; it includes prognostic factors that are widely accepted; it can be done at the patient's bedside and in clinics in developing societies.


Comparison of the hypoglycemic effect of acarbose monotherapy in patients with type 2 diabetes mellitus consuming an Eastern or Western diet: a systematic meta-analysis.
Because of its mechanism of action, the starch content of a diet might alter the hypoglycemic effect of acarbose. We aimed to determine whether differences in this hypoglycemic effect existed between individuals consuming Eastern and Western diets with significantly different starch contents, a systematic meta-analysis of studies comparing acarbose with placebo or other hypoglycemic agents in patients with type 2 diabetes mellitus (T2DM) was performed. Records were retrieved from the Cochrane clinical controlled trials, MEDLINE, EMBASE, Wanfang, Chinese Technical Periodicals, and ongoing trials databases, and full texts and reference lists were screened. Because no study has directly compared patients consuming different types of diet, fixed- and random-effect models were used to indirectly compare the hypoglycemic effect of acarbose monotherapy with that of placebo and/or comparator drugs in patients with T2DM consuming an Eastern (Eastern Asia) or Western (including Europe and North America) diet. A total of 46 studies were included in the meta-analysis. The results revealed that, compared with placebo, hemoglobin A1c (HbA1c) levels were reduced to a significantly greater extent (1.02%) in the Eastern diet (mean [SD], 1.54% [2.00%]) than in the Western diet (mean [SD], 0.52% [1.20%]) P < 0.00001). The ability of acarbose to reduce HbA1c levels in the Eastern (P = 0.20) and Western (P = 0.10) diet groups was similar to that of sulfonylureas, and HbA1c levels were reduced significantly more (0.39%; P < 0.00001) in the Eastern than in the Western diet group. The ability of acarbose to reduce HbA1c levels was similar to those of metformin and nateglinide/repaglinide, but a comparison of its efficacy with different diets was difficult because of the inclusion of few studies in these categories. Analysis of all included studies revealed that acarbose achieved a greater absolute reduction of HbA1c levels in the Eastern diet (mean [SD], 1.26% [1.20%]) than in the Western diet (mean [SD], 0.62% [1.28%]; P < 0.00001) group. However, the poor quality of Eastern diet trials may have affected the outcomes of the meta-analysis. The hypoglycemic effect of acarbose is superior in patients with T2DM consuming an Eastern diet than in those consuming a Western diet and is similar to that of sulfonylureas, metformin, and glinide drugs.


A proteolytic fragment of Trypanosoma cruzi trans-sialidase lacking the carboxyl-terminal domain is active, monomeric, and generates antibodies that inhibit enzymatic activity.
trans-Sialidase isolated from trypomastigote forms of Trypanosoma cruzi, the protozoan parasite that causes Chagas' disease, is multimeric and heterogeneous in size. We show here that limited proteolysis of tans-sialidase with papain yields a single monomeric polypeptide chain of 70 kDa that conserves full enzymatic activity on soluble and membrane-bound substrates. The papain fragment lacks most of the 12-amino acid repeats of the carboxyl-terminal domain that comprises about 50% of the native trans-sialidase. When injected into rabbits, the papain-generated fragment induces antibodies that inhibit trans-sialidase activity and trypomastigote sialylation. The repeats are also not required for the stability of the enzyme or for the correct folding during the biosynthesis in Escherichia coli, but seem essential for trans-sialidase oligomerization. We conclude that trans-sialidase is composed of two structurally and functionally independent domains.


18 F-flortaucipir tau positron emission tomography distinguishes established progressive supranuclear palsy from controls and Parkinson disease: A multicenter study.
18 F-flortaucipir (formerly 18 F-AV1451 or 18 F-T807) binds to neurofibrillary tangles in Alzheimer disease, but tissue studies assessing binding to tau aggregates in progressive supranuclear palsy (PSP) have yielded mixed results. We compared in vivo 18 F-flortaucipir uptake in patients meeting clinical research criteria for PSP (n = 33) to normal controls (n = 46) and patients meeting criteria for Parkinson disease (PD; n = 26). Participants underwent magnetic resonance imaging and positron emission tomography for amyloid-β (11 C-PiB or 18 F-florbetapir) and tau (18 F-flortaucipir). 18 F-flortaucipir standardized uptake value ratios were calculated (t = 80-100 minutes, cerebellum gray matter reference). Voxelwise and region-of-interest group comparisons were performed in template space, with receiver operating characteristic curve analyses to assess single-subject discrimination. Qualitative comparisons with postmortem tau are reported in 1 patient who died 9 months after 18 F-flortaucipir. Clinical PSP patients showed bilaterally elevated 18 F-flortaucipir uptake in globus pallidus, putamen, subthalamic nucleus, midbrain, and dentate nucleus relative to controls and PD patients (voxelwise p < 0.05 family wise error corrected). Globus pallidus binding best distinguished PSP patients from controls and PD (area under the curve [AUC] = 0.872 vs controls, AUC = 0.893 vs PD). PSP clinical severity did not correlate with 18 F-flortaucipir in any region. A patient with clinical PSP and pathological diagnosis of corticobasal degeneration had severe tau pathology in PSP-related brain structures with good correspondence between in vivo 18 F-flortaucipir and postmortem tau neuropathology. 18 F-flortaucipir uptake was elevated in PSP versus controls and PD patients in a pattern consistent with the expected distribution of tau pathology. Ann Neurol 2017;82:622-634.


Extracellular cysteine (Cys)/cystine (CySS) redox regulates metabotropic glutamate receptor 5 activity.
Extracellular cysteine (Cys)/cystine (CySS) redox potential (E(h)) has been shown to regulate diverse biological processes, including enzyme catalysis, gene expression, and signaling pathways for cell proliferation and apoptosis, and is sensitive to aging, smoking, and other host factors. However, the effects of extracellular Cys/CySS redox on the nervous system remain unknown. In this study, we explored the role of extracellular Cys/CySS E(h) in metabotropic glutamate receptor 5 (mGlu5) activation to understand the mechanism of its regulation of nerve cell growth and activation. We showed that the oxidized Cys/CySS redox state (0 mV) in C6 glial cells induced a significant increase in mGlu5-mediated phosphorylation of extracellular signal-regulated kinase (ERK), blocked by an inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (MEK), U0126, a nonpermeant alkylating agent, 4-acetamide-4'-maleimidylstilbene-2,2'-disulfonic acid (AMS), and a specific mGlu5 antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP), respectively. ERK phosphorylation under oxidized extracellular Cys/CySS E(h) was confirmed in mGlu5-overexpressed human embryonic kidney 293 (HEK293) cells. Oxidized extracellular Cys/CySS E(h) also stimulated the generation of intracellular reactive oxygen species (ROS) involved in the phosphorylation of ERK by mGlu5. Moreover, activation of mGlu5 by oxidized extracellular Cys/CySS E(h) was found to affect expression of NF-κB and inducible nitric oxide synthase (iNOS). The results also showed that extracellular Cys/CySS E(h) involved in the activation of mGlu5 controlled cell death and cell activation in neurotoxicity. In addition, plasma Cys/CySS E(h) was found to be associated with the process of Parkinson's disease (PD) in a rotenone-induced rat model of PD together with dietary deficiency and supplementation of sulfur amino acid (SAA). The effects of extracellular Cys/CySS E(h) on SAA dietary deficiency in the rotenone-induced rat model of PD was almost blocked by MPEP pretreatment, further indicating that oxidized extracellular Cys/CySS E(h) plays a role in mGlu5 activity. Taken together, the results indicate that mGlu5 can be activated by extracellular Cys/CySS redox in nerve cells, which possibly contributes to the process of PD. These in vitro and in vivo findings may aid in the development of potential new nutritional strategies that could assist in slowing the degeneration of PD.


Mechanobiology of Bone Metastatic Cancer.
In this review, we provide an overview of what is currently known about the impacts of mechanical stimuli on metastatic tumor-induced bone disease (TIBD). Further, we focus on the role of the osteocyte, the skeleton's primary mechanosensory cell, which is central to the skeleton's mechanoresponse, sensing and integrating local mechanical stimuli, and then controlling the downstream remodeling balance as appropriate. Exercise and controlled mechanical loading have anabolic effects on bone tissue in models of bone metastasis. They also have anti-tumorigenic properties, in part due to offsetting the vicious cycle of osteolytic bone loss as well as regulating inflammatory signals. The impacts of metastatic cancer on the mechanosensory function of osteocytes remains unclear. Increased mechanical stimuli are a potential method for mitigating TIBD.


Initial Report of a Prospective Dosimetric and Clinical Feasibility Trial Demonstrates the Potential of Protons to Increase the Therapeutic Ratio in Breast Cancer Compared With Photons.
To compare dosimetric endpoints between proton therapy (PT) and conventional radiation and determine the feasibility of PT for regional nodal irradiation (RNI) in women with breast cancer. From 2012 to 2014, 18 women (stage IIA-IIIB) requiring RNI prospectively enrolled on a pilot study. Median age was 51.8 years (range, 42-73 years). The cohort included breast-conserving therapy (BCT) and mastectomy patients and right- and left-sided cancers. Treatment targets and organs at risk were delineated on computed tomography scans, and PT and conventional plans were developed. Toxicity was prospectively recorded using Common Terminology Criteria for Adverse Events version 4.0. A Wilcoxon signed-rank sum test compared the dose-volume parameters. The primary endpoint was a reduction in cardiac V5. Median follow-up was 20 months (range, 2-31 months). For all patients, the PT plan better met the dosimetric goals and was used for treatment. Proton therapy alone was used for 10 patients (9 postmastectomy, 1 after BCT) and combined proton-photon in 8 (6 BCT, 2 postmastectomy with immediate expander reconstruction). Proton therapy improved coverage of level 2 axilla (P=.0005). Adequate coverage of internal mammary nodes was consistently achieved with PT (median D95, 50.3 Gy; range, 46.6-52.1 Gy) but not with conventional radiation therapy (median D95, 48.2 Gy; range, 40.8-55 Gy; P=.0005). Median cardiac V5 was 0.6% with PT and 16.3% with conventional radiation (P<.0001). Median ipsilateral lung V5 and V20 were improved with PT (median V5 35.3% vs 60.5% [P<.0001]; and median V20, 21.6% vs 35.5% [P<.0001]). Grade 3 dermatitis developed in 4 patients (22%), which was the only grade 3 toxicity. No grade 4+ toxicities developed. Proton therapy for RNI after mastectomy or BCT significantly improves cardiac dose, especially for left-sided patients, and lung V5 and V20 in all patients without excessive acute toxicity. Proton therapy simultaneously improves target coverage for the internal mammary nodes and level 2 axilla, which may positively impact long-term survival in breast cancer patients.


Impact of COVID-19 on the gastrointestinal surgical oncology patient population.
The onset of the COVID-19 pandemic led to substantial alterations in healthcare delivery and access. In this study, we aimed to evaluate the impact of COVID-19 on the presentation and surgical care of patients with gastrointestinal (GI) cancers. All patients who underwent GI cancer surgery at a large, tertiary referral center between March 15, 2019 and March 15, 2021 were included. March 15, 2020 was considered the start of the COVID-19 pandemic. Changes in patient, tumor, and treatment characteristics before the pandemic compared to during the pandemic were evaluated. Of 522 patients that met study criteria, 252 (48.3%) were treated before the COVID-19 pandemic. During the first COVID-19 wave, weekly volume of GI cancer cases was one-third lower than baseline (p = 0.041); during the second wave, case volume remained at baseline levels (p = 0.519). There were no demographic or tumor characteristic differences between patients receiving GI cancer surgery before versus during COVID-19 (p > 0.05 for all), and no difference in rate of emergency surgery (p > 0.9). Patients were more likely to receive preoperative chemotherapy during the first six months of the pandemic compared to the subsequent six months (35.6% vs. 15.5%, p < 0.001). Telemedicine was rapidly adopted at the start of the pandemic, rising from 0% to 47% of GI surgical oncology visits within two months. The COVID-19 pandemic caused an initial disruption to the surgical care of GI cancers, but did not compromise stage at presentation. Preoperative chemotherapy and telemedicine were utilized to mitigate the impact of a high COVID-19 burden on cancer care.


Molecular docking and structure-activity relationship studies on benzothiazole based non-peptidic BACE-1 inhibitors.
A similarity search on the structural analogs of an inhibitor of BACE-1 with IC(50) 2.8μM, which contained a P1 benzothiazole group together with a triazine ring linked by a secondary amine group, was described in this Letter and some more potent inhibitors against BACE-1 were identified. The most potent compound 5 (IC(50)=0.12μM) increases the inhibitory potency by 24 folds. Our results suggest that a pyrrolidinyl side group at the P3' and P4' of the inhibitors are favored for strong inhibition and a small aromatic group at the P4 position is also essential to the potency.


Childhood obesity and the metabolic syndrome in developing countries.
Rapidly changing dietary practices accompanied by an increasingly sedentary lifestyle predispose to nutrition-related non-communicable diseases, including childhood obesity. Over the last 5 y, reports from several developing countries indicate prevalence rates of obesity (inclusive of overweight) >15 % in children and adolescents aged 5-19 y; Mexico 41.8 %, Brazil 22.1 %, India 22.0 % and Argentina 19.3 %. Moreover, secular trends also indicate an alarming increase in obesity in developing countries; in Brazil from 4.1 % to 13.9 % between 1974 and 1997; in China from 6.4 % to 7.7 % between 1991 and 1997; and in India from 4.9 % to 6.6 % between 2003-04 to 2005-06. Other contributory factors to childhood obesity include: high socio-economic status, residence in metropolitan cities and female gender. Childhood obesity tracks into adulthood, thus increasing the risk for conditions like the metabolic syndrome, type 2 diabetes mellitus (T2DM), polycystic ovarian syndrome, hypertension, dyslipidemia and coronary artery disease later in life. Interestingly, prevalence of the metabolic syndrome was 35.2 % among overweight Chinese adolescents. Presence of central obesity (high waist-to-hip circumference ratio) along with hypertriglyceridemia and family history of T2DM increase the odds of T2DM by 112.1 in young Asian Indians (< 40 y). Therapeutic lifestyle changes and maintenance of regular physical activity are most important strategies for preventing childhood obesity. Effective health awareness educational programs for children should be immediately initiated in developing countries, following the successful model program in India (project 'MARG').


Different activities of the conserved lysine residues in the double-stranded RNA binding domains of RNA helicase A in vitro and in the cell.
RNA helicase A regulates a variety of RNA metabolism processes including HIV-1 replication and contains two double-stranded RNA binding domains (dsRBD1 and dsRBD2) at the N-terminus. Each dsRBD contains two invariant lysine residues critical for the binding of isolated dsRBDs to RNA. However, the role of these conserved lysine residues was not tested in the context of enzymatically active full-length RNA helicase A either in vitro or in the cells. The conserved lysine residues in each or both of dsRBDs were substituted by alanine in the context of full-length RNA helicase A. The mutant RNA helicase A was purified from mammalian cells. The effects of these mutations were assessed either in vitro upon RNA binding and unwinding or in the cell during HIV-1 production upon RNA helicase A-RNA interaction and RNA helicase A-stimulated viral RNA processes. Unexpectedly, the substitution of the lysine residues by alanine in either or both of dsRBDs does not prevent purified full-length RNA helicase A from binding and unwinding duplex RNA in vitro. However, these mutations efficiently inhibit RNA helicase A-stimulated HIV-1 RNA metabolism including the accumulation of viral mRNA and tRNA(Lys3) annealing to viral RNA. Furthermore, these mutations do not prevent RNA helicase A from binding to HIV-1 RNA in vitro as well, but dramatically reduce RNA helicase A-HIV-1 RNA interaction in the cells. The conserved lysine residues of dsRBDs play critical roles in the promotion of HIV-1 production by RNA helicase A. The conserved lysine residues of dsRBDs are key to the interaction of RNA helicase A with substrate RNA in the cell, but not in vitro.


Comments on design and analysis of multiple-choice feeding-preference experiments.
An approach to the analysis of multiple-choice food selection experiments proposed recently is criticised on three grounds and modified methods are suggested.


Determination of miRNAs from Cancer Stem Cells Using a Low Density Array Platform.
A microarray approach has been extensively used for global gene expression profiles in many biological research fields such as understanding of pathological mechanism in malignancies and defining of molecular biomarkers to monitor disease status. The most attractive advantage of microarray technology is its application to simultaneous analysis of miRNA expression pattern with a large amount of assessments. In this chapter, we provide a facile and universal protocol for divergent miRNA expression profiles in prostate cancer stem cells with a low density array-based microarray analysis.


Dibenamine blockade on gastric acid secretion in vitro and its protection by histamine antagonists.
Experiments to protect the histamine receptor against dibenamine blockade were carried out to elucidate the pharmacological characteristics of the H2-histamine receptor system for gastric acid secretion in isolated bullfrog gastric mucosa. Dibenamine alone (5 times 10-minus 5 g/ml) irreversibly blocked both basal and histamine-stimulated acid secretion. However, when the preparation was treated with dibenamine in combination with histamine (1 times 10-minus 5 g/ml) irreversibly blocked both basal and histamine-stimulated acid secretion. However, when the preparation was treated with dibenamine in combination with histamine (1 times 10-minus 5 g/ml), the acid secretory response to histamine was restored after washing out dibenamine. Burimamide, an H2-receptor antagonist, also protected the histamine sensitivity against dibenamine blockade in the concentration of 1 times 10-minus 4 g/ml. Diphenhydramine and pyribenzamine were also protected with histamine receptor against dibenamine blockade. The acid secretion induced by the action of histamine on the diphenhydramine-protected receptor was antagonized by diphenhydramine as well as burimamide.


Risk assessment and the credibility of federal regulatory policy: an FDA perspective.
FDA's fundamental goals are to protect and promote the public health, using the best possible science and the law. The evolution of food safety policy toward potential carcinogens reflects a conscious decision by the agency and Administration to use risk assessment in carrying out these goals. Examples include FDA policies toward assessing the safety of animal drug residues, setting specifications for constituents of food and color additives, and most recently, a common sense de minimis interpretation of the "Delaney clause." While committed to risk assessment as a useful tool, FDA acknowledges that judgments must be made on less than perfect data. In addition, recent history shows that there may be a serious "credibility gap" in public acceptance of regulatory toxicology. To ensure that there is an adequate science base for regulatory decisions, the challenge is twofold: First, the data necessary for sound safety evaluations in individual cases must be developed, based on current knowledge; and, second, the validity of assumptions underlying risk assessment should be tested and refined and scientific consensus achieved. Otherwise, risk management policy will rely on assessments based on extremely conservative assumptions, tending to overestimate risk. Risk assessment assumptions must also be better communicated to policymakers and the public. If these challenges are successfully addressed, public confidence in marketed products, and in science-based regulatory policy, will be enhanced.


Gram-negative bacillary endocarditis. Interpretation of the serum bactericial test.
Although the serum bactericidal test is commonly used in the management of infective endocarditis, little has been written about its validity or limitations. We report three cases of gram-negative bacillary endocarditis (Pseudomonas aeruginosa, Vibrio fetus and Serratia marcescens) encountered in 1 year at a Veterans Administration hospital. Serum bactericidal titers were considered necessary to identify inadequate antibiotic regimens or to avoid unnecessary drug toxicity. The limitations of the test, particularly those pertaining to gram-negative infections, are reviewed. Misleading results during treatment with aminoglycoside antibiotics could be due to the tendency of serum to become alkaline on standing. A detailed study of the interaction of the complement-dependent bactericidal system of serum with eight antibiotics is presented. In the context of the serum bactericidal test, the interaction was additive or synergistic in 15 of 16 determinations, indicating the need to include a control study of serum sensitivity of the infecting microorganism in each case.


Influence of the Surface Chemistry of Metal-Organic Polyhedra in Their Assembly into Ultrathin Films for Gas Separation.
The formation of ultrathin films of Rh-based porous metal-organic polyhedra (Rh-MOPs) by the Langmuir-Blodgett method has been explored. Homogeneous and dense monolayer films were formed at the air-water interface either using two different coordinatively alkyl-functionalized Rh-MOPs (HRhMOP(diz)12 and HRhMOP(oiz)12) or by in situ incorporation of aliphatic chains to the axial sites of dirhodium paddlewheels of another Rh-MOP (OHRhMOP) at the air-liquid interface. All these Rh-MOP monolayers were successively deposited onto different substrates in order to obtain multilayer films with controllable thicknesses. Aliphatic chains were partially removed from HRhMOP(diz)12 films post-synthetically by a simple acid treatment, resulting in a relevant modification of the film hydrophobicity. Moreover, the CO2/N2 separation performance of Rh-MOP-supported membranes was also evaluated, proving that they can be used as selective layers for efficient CO2 separation.


Pathway-based association analysis of genome-wide screening data suggest that genes associated with the gamma-aminobutyric acid receptor signaling pathway are involved in neuroleptic-induced, treatment-resistant tardive dyskinesia.
Neuroleptic-induced tardive dyskinesia (TD) is an involuntary movement disorder that develops in patients who have undergone long-term treatment with antipsychotic medications, and its etiology is unclear. In this study, a genome-wide association screening was done to identify the pathway(s) in which genetic variations influence susceptibility to neuroleptic-induced TD. Screening with Sentrix Human-1 Genotyping BeadChip (Illumina, San Diego, California, USA) was done for 50 Japanese schizophrenia patients with treatment-resistant TD and 50 Japanese schizophrenia patients without TD. A total of 40 573 single nucleotide polymorphisms that were not in linkage disequilibrium with each other and were located in the exonic and intronic regions of 13 307 genes were analyzed. After gene-based corrections, P values for allelic associations were subjected to canonical pathway-based analyses with Ingenuity Pathway Analysis software (Ingenuity Systems, Inc., Redwood City, California, USA). Eight genes (ABAT, ALDH9A1, GABRA3, GABRA4, GABRB2, GABRAG3, GPHN, and SLC6A11) contained polymorphisms with gene-based corrected allelic P values of less than 0.05. They were aggregated significantly in 33 genes belonging to the gamma-aminobutyric acid (GABA) receptor signaling pathway (P=0.00007, corrected P=0.01). Associations were replicated in an independent sample of 36 patients with TD and 136 patients without TD for polymorphisms in SLC6A11 (GABA transporter 3) (P=0.0004 in the total sample), GABRB2 (beta-2 subunit of GABA-A receptor) (P=0.00007 in the total sample), and GABRG3 (gamma-3 subunit of GABA-A receptor) (P=0.0006 in the total sample). The results suggest that the GABA receptor signaling pathway may be involved in genetic susceptibility to treatment-resistant TD, at least in a subgroup of Japanese patients with schizophrenia. The present results suggest that benzodiazepines may be considered as possible treatment option for TD.


Dissecting aneurysm of a right-sided descending aorta with a left-sided aortic arch.
A 66-year-old man presented with myocardial infarction. Chest X-ray showed a large mediastinal mass. Aortic dissection was suggested by a past history of chest trauma, but the mass was in a very atypical site. Dissection of an abnormally placed right-sided descending aorta was confirmed by computed tomography. The aortic arch lay on the left side. This rare combination of congenital and acquired heart disease led to diagnostic difficulty.


Effect of Indian monsoon on the glacial airborne bacteria over the Tibetan Plateau.
The glacier of the Tibetan Plateau (TP) is influenced by the Indian monsoon and continental westerlies. Wind flow can carry a variety of bacteria and disperse across the TP. Once these bacteria are colonized to the glacier surface, they could affect the biogeochemical cycle of the glacial ecosystems. However, very few studies have focused on the relationships between these airborne bacteria and atmospheric circulation over glaciers of the TP. Here we studied the diversity, taxonomic composition, and community structure of airborne bacteria on six TP glaciers using 16S rRNA gene sequencing. The results revealed an increase in the airborne bacterial diversity over the glaciers under the effect of the Indian monsoon. Airborne bacteria were dominated by Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria, while relative abundances of Bacteroidetes and Firmicutes were significantly higher under the influence of the Indian monsoon in the southern and central of the TP, respectively. Moreover, significantly different airborne bacterial community structures were observed over glaciers under the influence of the Indian monsoon, which could be explained by the increased community stochasticity. In addition, the Indian monsoon increases the diversity and relative abundance of potential pathogens, which includes the most notorious bacteria such as Pseudomonas fluorescens, Staphylococcus aureus, and Clostridium butyricum. Our results revealed for the first time that atmospheric circulation influences the composition of airborne bacteria over the glaciers on the TP, this may provide critical insights into the distinct microbial community structure and function in glaciers across the TP.


Electrostatic theory of rectangular waveguides filled with anisotropic media.
The electrostatic (or, in a better word, quasi-electrostatic) theory of waves propagation in a long, rectangular waveguide having perfect electric conductor walls that filled with an anisotropic medium (here, a medium of nanowire-based hyperbolic metamaterials) is presented. Some data on characteristics of these waves are prepared. The presented results include electrostatic field configurations (modes) that can be supported by such structures and their corresponding cutoff frequencies, group velocities, power flows and storage energies.


Draft Genome Sequence of Guar (Cyamopsis tetragonoloba L.) Microsymbiont Rhizobium sp. Strain RCAM05973.
Here, we present the draft genome sequence of Rhizobium sp. strain RCAM05973 which was isolated from a Cyamopsis tetragonoloba (guar) root nodule. The genome contains 6,937,221 bp in 2 contigs and has a GC content of 60%.


Epidural vs patient-controlled analgesia for postoperative pain after pectus excavatum repair: a prospective, randomized trial.
Management of postoperative pain is a challenge after the minimally invasive repair of pectus excavatum. Pain is usually managed by either a thoracic epidural or patient-controlled analgesia with intravenous narcotics. We conducted a prospective, randomized trial to evaluate the relative merits of these 2 pain management strategies. After obtaining permission/assent (Institutional Review Board no. 06 08 128), patients were randomized to either epidural or patient-controlled analgesia with fixed protocols for each arm. The primary outcome variable was length of stay with a power of .8 and α of .05. One hundred ten patients were enrolled. There was no difference in length of stay between the 2 arms. A longer operative time, more calls to anesthesia, and greater hospital charges were found in the epidural group. Pain scores favored epidural for the few days and favored patient-controlled analgesia thereafter. The epidural catheter could not be placed or was removed within 24 hours in 12 patients (22%). There is longer operating room time, increase in calls to anesthesia, and greater hospital charges with epidural analgesia after repair of pectus excavatum. Pain scores favor the epidural approach early in the postoperative course and patient-controlled analgesia later.


Exercise-induced cardiac injury: evidence from novel imaging techniques and highly sensitive cardiac troponin assays.
Prolonged endurance exercise in humans has been associated with an acute impairment in diastolic and systolic cardiac function and the release of cardiac troponin. In this chapter, we review recent evidence from studies using novel echocardiographic parameters and highly sensitive cardiac troponin assays. We demonstrate that the mechanics of left and right ventricular functions are acutely impaired after completion of prolonged exercise and that this reduction in function is likely multifactorial in etiology. However, we highlight that exercise-induced cardiac troponin release is not a marker of exercise-induced pathology but likely a physiologic response to exercise. Finally, we discuss the potential link between prolonged exercise and the increased incidence of cardiac pathology in veteran athletes.


Hippocampal neurogenesis and Arc expression are enhanced in high-fat fed prepubertal female pigs by a diet including omega-3 fatty acids and Bifidobacterium breve CECT8242.
Obesity during childhood has become a pandemic disease, mainly caused by a diet rich in sugars and fatty acids. Among other negative effects, these diets can induce cognitive impairment and reduce neuroplasticity. It is well known that omega-3 and probiotics have a beneficial impact on health and cognition, and we have hypothesized that a diet enriched with Bifidobacterium breve and omega-3 could potentiate neuroplasticity in prepubertal pigs on a high-fat diet. Young female piglets were fed during 10 weeks with: standard diet (T1), high-fat (HF) diet (T2), HF diet including B. breve CECT8242 (T3) and HF diet including the probiotic and omega-3 fatty acids (T4). Using hippocampal sections, we analyzed by immunocytochemistry the levels of doublecortin (DCX) to study neurogenesis, and activity-regulated cytoskeleton-associated protein (Arc) as a synaptic plasticity related protein. No effect of T2 or T3 was observed, whereas T4 increased both DCX+ cells and Arc expression. Therefore, a diet enriched with supplements of B. breve and omega-3 increases neurogenesis and synaptic plasticity in prepubertal females on a HF diet from nine weeks of age to sexual maturity. Furthermore, the analysis of serum cholesterol and HDL indicate that neurogenesis was related to lipidic demand in piglets fed with control or HF diets, but the neurogenic effect induced by the T4 diet was exerted by mechanisms independent of this lipidic demand. Our results show that the T4 dietary treatment is effective in potentiating neural plasticity in the dorsal hippocampus of prepubertal females on a HF diet.


Analysis of 21 Patients With Alcoholic Marchiafava-Bignami Disease in Chongqing, China.
This study aimed to investigate the characteristics and prognosis of patients with alcoholic Marchiafava-Bignami disease (MBD), a rare neurological disorder commonly associated with chronic alcoholism, in Chongqing, China. We conducted a retrospective analysis of clinical data from 21 alcoholic MBD patients treated at the First Affiliated Hospital of Chongqing University between 2012 and 2022. The study included 21 patients with alcoholic MBD who had a mean age of 59 ± 9.86 years and an average drinking history of 35.48 ± 8.65 years. Acute onset was observed in 14 (66.7%) patients. The primary clinical signs observed were psychiatric disorders (66.7%), altered consciousness (61.9%), cognitive disorders (61.9%), and seizures (42.9%). Magnetic resonance imaging revealed long T1 and long T2 signal changes in the corpus callosum, with lesions predominantly found in the genu (76.2%) and splenium (71.4%) of the corpus callosum. The poor prognosis group demonstrated an increased incidence of altered consciousness (100% vs 50%, P = 0.044), pyramidal signs (80% vs 18.8%, P = 0.011), and pneumonia (100% vs 31.3%, P = 0.007). Patients with a longer drinking history (45.0 ± 10.0 years vs 32.69 ± 5.99 years, p = 0.008) and a lower thiamine dose (p = 0.035) had a poorer prognosis at 1 year. This study identified altered consciousness, pyramidal signs, and pneumonia as predictors of a poor prognosis in patients with alcoholic MBD. A longer duration of alcohol consumption and inadequate thiamine supplementation were associated with a poorer prognosis.


Systemic exposure to morphine and the risk of acute chest syndrome in sickle cell disease.
The etiology of acute chest syndrome, the most severe complication of the sickle cell crisis, is unknown. Our objective was to assess exposure to morphine as an etiologic factor for acute chest syndrome in sickle cell disease. A post hoc analysis of a randomized controlled trial comparing oral with continuous infusion of morphine was performed. Children (aged 5-17 years) with sickle cell crisis were randomized to receive oral sustained-release morphine, 1.9 mg. kg(-1). 12 h(-1), or a continuous intravenous infusion of morphine at 0.04 mg. kg(-1). h(-1) by use of a double-blind, placebo-controlled design. In a subgroup of 15 patients, the pharmacokinetics of morphine and its active metabolite morphine-6-glucuronide were also studied. At baseline, demographic and physiologic characteristics were similar between groups. There were no differences in the number of previous rescue doses per day, painful sites per episode, physician contacts per year, and hospitalizations per year between treatment arms. There was a 2-fold higher morphine area under the concentration-time curve at steady state (AUC(ss)) and a 3-fold higher morphine-6-glucuronide AUC(ss) with oral morphine than with a continuous intravenous infusion of morphine (P <.001 and P <.006, respectively). New onset of acute chest syndrome was 3-fold more prevalent in the oral group (57%) versus the continuous intravenous infusion group (17%) (P <.001). The risk of acute chest syndrome is significantly associated with high systemic exposure to morphine and its active metabolite morphine-6-glucuronide after oral administration of slow-release morphine. Morphine may facilitate respiratory deterioration by eliciting a decrease in oxygen saturation, by inducing histamine release, or through an as-yet-unidentified mechanism. The safe systemic exposure to morphine in terms of area under the concentration-time curve should be further studied in children with sickle cell disease.


The effect of botulinum neurotoxin-A on blood flow in rats: a potential mechanism for treatment of Raynaud phenomenon.
Botulinum neurotoxin-A (BoNTA) is used to treat several disorders, including Raynaud phenomenon. Recent investigations cite toxin-induced increases in blood flow, but no mechanism for BoNTA's actions is proposed. This study hypothesized that local application of BoNTA causes arteriolar vasodilation through sympathetic blockade and results in increased blood flow. Microvascular effects of BoNTA were assessed using a rat cremaster preparation. Cremaster microvascular diameters were measured in the muscle before and after treatment with the muscle paralytic agent gallamine triethiodide. Preparations were then treated with one of the following: BoNTA (4, 6, or 10 units), BoNTA dilution vehicle, or denatured BoNTA. Arteriolar diameters were measured repeatedly over the observation period. Additional preparations were treated with either tetrodotoxin or prazosin and rauwolscine before BoNTA to confirm that the observed vasodilatory responses were the result of sympathetic neural inhibition. The BoNTA application resulted in a significant dose-dependent vasodilation (13% to 15%) of observed cremaster arterioles. Control treatments did not cause vasodilation. Both tetrodotoxin and prazosin/rauwolscine treatments elicited similar vasodilatory effects, with no additional vasodilation elicited by BoNTA. Addition of sodium nitroprusside following BoNTA elicited further vasodilation. In addition, systemic arterial pressure was unaffected by the local administration of BoNTA. Local application of BoNTA results in arteriolar dilation that yields an approximate 69% increase in blood flow, without changing systemic arterial pressure. A BoNTA-mediated vasodilation through sympathetic blockade is a likely mechanism to explain the increase in blood flow reported after treatment with the toxin. The ability of BoNTA to inhibit sympathetic nervous input reduces vasoconstriction, which is the most likely mechanism for improvement seen in Raynaud phenomenon patients following BoNTA injection.


Cardiac sarcoidosis: recurrent disease in a heart transplant patient following pulmonary tuberculosis infection.
Cardiac transplantation is indicated for patients with end-stage cardiomyopathy secondary to cardiac sarcoidosis. Although rare, recurrent disease has been reported in two cases. The current report presents a case of recurrent cardiac sarcoidosis in a patient 45 months postorthotopic heart transplantation and 40 months following reactivation of latent Mycobacterium tuberculosis infection. The patient was the first to have recurrent disease following an infection that has been proposed to be involved in its pathogenesis. The patient's interval between transplant and recurrence is the longest reported to date.


Minimal role of comorbid personality disorder on the quality of life in patients with anxiety spectrum disorders.
There is no consensus on the definition of Quality of life (QoL). It is considered to be comprised of both psychological and somatical well-being. A variety of tools has been developed to measure subjective and objective (QoL). A number of factors, including demographical and medical may have an impact on QoL. The aim of our study was to compare the QoL in selected anxiety disorders and evaluate the influence of comorbid personality disorder. We evaluated data from 278 patients suffering from social phobia, panic disorder and/or agoraphobia, adjustment disorder, generalized anxiety disorder and obsessive-compulsive disorder. Personality disorders were diagnosed in 90 probands. The Quality of Life Enjoyment and Satisfaction (Q-LES-Q) was used to assess patients´perceived QoL. Up to our data there was no statistical difference in overall score of quality of life in selected anxiety disorders. The only significant difference between patients was found in subscale "household." Comorbid personality disorder had no influence on the overall score or any domain of Q-LES-Q. Our study proved that presence of anxiety disorder means a decrease in QoL. Particular anxiety disorders did not differ in overall scores of Q-LES-Q. Furthermore, comorbid personality disorder had no impact on quality of life of patients.


Interleukin 7 receptor control of T cell receptor gamma gene rearrangement: role of receptor-associated chains and locus accessibility.
VDJ recombination of T cell receptor and immunoglobulin loci occurs in immature lymphoid cells. Although the molecular mechanisms of DNA cleavage and ligation have become more clear, it is not understood what controls which target loci undergo rearrangement. In interleukin 7 receptor (IL-7R)alpha-/- murine thymocytes, it has been shown that rearrangement of the T cell receptor (TCR)-gamma locus is virtually abrogated, whereas other rearranging loci are less severely affected. By examining different strains of mice with targeted mutations, we now observe that the signaling pathway leading from IL-7Ralpha to rearrangement of the TCR-gamma locus requires the gammac receptor chain and the gammac-associated Janus kinase Jak3. Production of sterile transcripts from the TCR-gamma locus, a process that generally precedes rearrangement of a locus, was greatly repressed in IL-7Ralpha-/- thymocytes. The repressed transcription was not due to a lack in transcription factors since the three transcription factors known to regulate this locus were readily detected in IL-7Ralpha-/- thymocytes. Instead, the TCR-gamma locus was shown to be methylated in IL-7Ralpha-/- thymocytes. Treatment of IL-7Ralpha-/- precursor T cells with the specific histone deacetylase inhibitor trichostatin A released the block of TCR-gamma gene rearrangement. This data supports the model that IL-7R promotes TCR-gamma gene rearrangement by regulating accessibility of the locus via demethylation and histone acetylation of the locus.


Correlation study on methoxylation pattern of flavonoids and their heme-targeted antiplasmodial activity.
A library of 33 polymethoxylated flavones (PMF) was evaluated for heme-binding affinity by biomimetic MS assay and in vitro antiplasmodial activity on two strains of P. falciparum. Stability of heme adducts was discussed using the dissociation voltage at 50% (DV50). No correlation was observed between the methoxylation pattern and the antiparasitic activity, either for the 3D7 chloroquine-sensitive or for the W2 chloroquine-resistant P. falciparum strains. However, in each PMF family an increased DV50 was observed for the derivatives methoxylated in position 5. Measurement of intra-erythrocytic hemozoin formation of selected derivatives was performed and hemozoin concentration was inversely correlated with heme-binding affinity. Kaempferol showed no influence on hemozoin formation, reinforcing the hypothesis that this compound may exert in vitro antiplasmodial activity mostly through other pathways. Pentamethoxyquercetin has simultaneously demonstrated a significant biological activity and a strong interaction with heme, suggesting that inhibition of hemozoin formation is totally or partially responsible for its antiparasitic effect.


Principles of connectivity among morphologically defined cell types in adult neocortex.
Since the work of Ramón y Cajal in the late 19th and early 20th centuries, neuroscientists have speculated that a complete understanding of neuronal cell types and their connections is key to explaining complex brain functions. However, a complete census of the constituent cell types and their wiring diagram in mature neocortex remains elusive. By combining octuple whole-cell recordings with an optimized avidin-biotin-peroxidase staining technique, we carried out a morphological and electrophysiological census of neuronal types in layers 1, 2/3, and 5 of mature neocortex and mapped the connectivity between more than 11,000 pairs of identified neurons. We categorized 15 types of interneurons, and each exhibited a characteristic pattern of connectivity with other interneuron types and pyramidal cells. The essential connectivity structure of the neocortical microcircuit could be captured by only a few connectivity motifs.


Advances in yeast alcoholic fermentations for the production of bioethanol, beer and wine.
Yeasts have a long-standing relationship with humankind that has widened in recent years to encompass production of diverse foods, beverages, fuels and medicines. Here, key advances in the field of yeast fermentation applied to alcohol production, which represents the predominant product of industrial biotechnology, will be presented. More specifically, we have selected industries focused in producing bioethanol, beer and wine. In these bioprocesses, yeasts from the genus Saccharomyces are still the main players, with Saccharomyces cerevisiae recognized as the preeminent industrial ethanologen. However, the growing demand for new products has opened the door to diverse yeasts, including non-Saccharomyces strains. Furthermore, the development of synthetic media that successfully simulate industrial fermentation medium will be discussed along with a general overview of yeast fermentation modeling.


Systematic analysis of structural and spectroscopic properties of neptunimine (HN=NpH2) and plutonimine (HN=PuH2).
The structures, stabilities, nature of bonding, and spectroscopic properties of the new actinide imine molecules, neptunimine (HN=NpH2) and plutonimine (HN=PuH2), in the gas phase have been systematically explored at different levels of theory. Our calculation indicates that HN=AnH2 (An=Np, Pu) should be nonplanar and have a quartet ([Formula: see text]) and quintet ([Formula: see text]) ground state, respectively. The nature of the chemical bonding in these molecules were investigated by employing topological methods including electron localization function (ELF), atoms in molecules (AIM) as well as natural bond orbital analysis (NBO). The results showed that these actinide complexes possess relatively strong An=N multiple bonds between the An 6d-5f hybrid orbitals with N 2s-2p orbitals. The charge decomposition analysis (CDA) diagram demonstrated that the transition of electrons mainly happened inside the AnH2 of HN=AnH2. Total and partial density of state (TDOS and PDOS) and also overlap population density of state (OPDOS) diagrams analysis were implemented. The IR and Raman spectra were theoretically simulated as a convenient way to confirm the existence of the actinide imine complexes in further experiments.


A novel role of RGS9: inhibition of retinal guanylyl cyclase.
Cyclic GMP plays a key role in retinal phototransduction and its photoreceptor concentration is precisely controlled by the cooperative action of cGMP phosphodiesterase (PDE) and retinal guanylyl cyclase (retGC). However, studies of the relationship between these two systems have focused only on a Ca2+-mediated, indirect connection. This article summarizes our studies strongly suggesting that RGS9-1 is directly involved in the cooperative action of PDE and retGC, and that this ingenious mechanism plays an important role in tuning of cGMP concentration in photoreceptors.


Has cerumen a protective role in recurrent external otitis?
We investigated the bactericidal activity of the cerumen in patients with recurrent otitis externa. Cerumen samples were collected from 2 groups. Group A (n = 20) consisted of patients with recurrent otitis externa (2 or more acute otitis externa attack in the current year) and group B (n = 30) consisted of cerumen from a healthy population. We examined the bactericidal activity against the common microorganisms (Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa, and Enterococcus) that encounter the recurrent otitis externa. A significant decrease in the count of S epidermidis was observed in group A (P <.05) and B (P <.01) was observed. A comparison of decreases and increases in the percentages of microorganisms between the groups A and B showed that there was a significant difference only in the count of E coli (P <or=.05). The count of E coli decreased in cerumen suspension in group A, but it increased in the normal population. We did not confirm that cerumen from patients with recurrent otitis externa had less bactericidal activity than from a healthy population.


Current status of development of anticancer agents in Japan.
To investigate the current status of the development of anticancer agents in Japan, we examined the number of these agents developed after 1999, their target diseases, and the association between the number of approved agents and the number of patients with the diseases. The data were obtained via the Internet. Of the 487 agents approved from 1999 to April 2007, 84 were anticancer drugs. Of these 84, 46 were approved based on clinical trials and 38 were approved through the new drug application for off-label usages without clinical trials. The target diseases of the 46 agents approved through clinical trials were nonhematologic tumors in 29, hematologic malignancies in 13, and others in 4. Of the 38 approved through the new drug application for off-label usages, 31 were for nonhematologic tumors and 7 for hematologic malignancies. The number of approved anticancer agents for hematologic malignancies per unit patient population was 6.5-times as many as that for nonhematologic tumors. This study demonstrated that the situation regarding the development of anticancer agents differs among tumor types. The majority of anticancer agents developed target hematologic malignancies, while the newly developed anticancer agents have affected treatment strategies for solid tumors.


Thermal Degradation of Thaumatin at Low pH and Its Prevention Using Alkyl Gallates.
Thaumatin, a potent sweet tasting protein extracted from the Katemfe Plant, is emerging as a natural alternative to synthetic non-nutritive sweeteners and flavor enhancer. As a food additive, its stability within the food matrix during thermal processing is of great interest to the food industry. When heated under neutral or basic conditions, thaumatin was found to lose its sweetness due to protein aggregation caused by sulfhydryl catalyzed disulfide bond interchange. At lower pH, while thaumatin was also found to lose sweetness after heating, it does so at a slower rate and shows more resistance to sweetness loss. SDS-PAGE indicated that thaumatin fragmented into multiple smaller pieces under heating in acidic pH. Using BEMPO-3, a lipophilic spin trap, we were able to detect the presence of a free-radical within the hydrophobic region of the protein during heating. Protein carbonyl content, a byproduct of protein oxidation, also increased upon heating, providing additional evidence for protein cleavage by a radical pathway. Hexyl gallate successfully inhibited the radical generation as well as protein carbonyl formation of thaumatin during heating.


An indigenous bacterium with enhanced performance of microbially-induced Ca-carbonate biomineralization under extreme alkaline conditions for concrete and soil-improvement industries.
The advantages of microbial induced carbonate mineralization for soil-stabilization and building-material industries are under extensive investigation. The pH is one of the influential parameters on the desired calcium carbonate mineralization due to the resulting textures of this mineral. Moreover, the decrease in microbial growth under the extreme alkaline environment compatible with the sustainability of concrete has been the bottleneck for an effective application of Microbial Induced Carbonate Precipitation (MICP) in the concrete industry. Microbial consortia have shown more robustness in their resistance to environmental fluctuations than pure cultures. In addition, microorganisms obtained from alkaline environments could facilitate their adaptation to extreme alkalinity. The aim of this study was to obtain urease producing bacteria (UPB) able to maintain a high MICP performance under extremely alkaline conditions compatible with concrete by adapting native microorganisms obtained from extreme environments. The growth performance, urease activity, strength of the generated biocement, and CaCO3 mineralogy were compared with the best-performer urease-producing bacteria (UPB), S. pasteurii DSMZ 33. The native bacteria presented a similar performance in growth and urease activity than S. pasteurii under extreme alkaline conditions (pH 12.5). However, the generated biocement of native Sporosarcina sp. achieved 461 % more unconfined compressive strength (UCS) and 120 % more CaCO3 content than the biocement generated by S. pasteurii DSMZ 33. The careful adaptation process performed in this study for native UPB and S. pasteurii DSMZ 33 is an interesting approach with promising and projectable results for future engineering and biotechnological applications. These results have important implications for the design of engineering solutions involving MICP. STATEMENT OF SIGNIFICANCE: A consolidated and strong biocement was generated by a native species obtained from extreme ecosystems in an effort of bioprospecting to enhance the performance of biotechnological solutions for geotechnical applications in the concrete and soil-improvement industries. Biocement generated by the native species was stronger than the generated by one of the best-described biocementation performers. This native species was able to actively growing and do perform microbial-induced-carbonate-mineralization under extreme alkalinity conditions after a careful laboratory adaptation process. The native species presented unique and differentiating traits that gave it a better adaptability and biocementation performance. The same occurs with a priceless microbial diversity inhabiting little explored and unprotected extreme ecosystems. Extreme environments house a fascinating biodiversity with potential value for ecosystem services.


Ion-triggered calcium hydroxide microcapsules for enhanced corrosion resistance of steel bars.
Herein, we synthesized Ca(OH)2 microcapsules with ion-responsive shells composed of cross-linked poly-ionic liquids (CPILs). By exchanging PF6 - with Cl- in water, the hydrophobic poly-ionic liquids (PILs) on the shell are converted to hydrophilic channels. The encapsulated Ca(OH)2 can permeate through the hydrophilic channels and release OH-. Meanwhile, the Cl- content can be reduced. The release rate of Ca(OH)2 is influenced by the content of monomers and concentration of Cl- ions in water. SO4 2- can also trigger the release of Ca(OH)2 from the microcapsule. With these microcapsules, Q235 steel exhibited promising corrosion resistance in simulated seawater. These results indicate that encapsulation of corrosion inhibitors is highly desirable for enhanced corrosion resistance of steel bars and the proposed approach can be used to encapsulate various corrosion inhibitors and functional materials for a wide range of applications.


Activation of STAT1 transcription factor precedes up-regulation of coxsackievirus-adenovirus receptor during viral myocarditis.
The coxsackievirus-adenovirus receptor (CAR) was originally described as a transmembrane protein involved in viral infection and was later found to be required for normal heart development. However, the role of CAR in virus-induced myocarditis has not been investigated so far. The purpose of this study was to assess myocardial CAR expression in response to cytokine-induced inflammatory reactions during the course of coxsackievirus-induced myocarditis. In Balb/c mice intraperitoneally infected with either 2x10(4) plaque-forming units (PFUs) of coxsackie B3 virus (CVB3) or 10(2) PFUs CVB3, CAR expression and tyrosine phosphorylation of signal transducer and activator of transcription 1 (STAT1), a known cytokine-inducible transcription factor involved in viral defense, were determined. Our results demonstrated that within the first 7 days after virus inoculation, when the viral replication and STAT1 activation in the heart tissue was most prominent, the expression of CAR did not surpass that of uninfected controls. However, the up-regulation of CAR was observed 9 weeks later, when enteroviral RNA was no longer detectable and activation of STAT1 had already ceased. In contrast to the STAT1 target genes Mig and Irf1, interferon gamma stimulation failed to up-regulate Car expression in isolated cardiomyocytes. In human endomyocardial biopsies, Car expression was found to be elevated in approximately one third of patients with dilated cardiomyopathy (9 of 30 patients) as compared with controls. Thus, activation of STAT1 clearly precedes the enhanced CAR expression observed during tissue reorganization, suggesting an essential role of STAT1 transcription factors in orchestrating the sequential actions involved in adaptive immune response.


Risk factors for preoperative deep venous thrombosis in hip fracture patients: a meta-analysis.
A meta-analysis. Hip fracture (HF), as common geriatric fracture, is related to increased disability and mortality. Preoperative deep vein thrombosis (DVT) is one of the most common complications in patients with hip fractures, affecting 8-34.9% of hip fracture patients. The study aimed to assess the risk factors of preoperative DVT after hip fractures by meta-analysis. An extensive search of the literature was performed in the English databases of PubMed, Embase, and the Cochrane Library; and the Chinese databases of CNKI and WAN FANG. We collected possible predictors of preoperative DVT from included studies, and data analysis was conducted with RevMan 5.3 and STATA 12.0. A total of 26 English articles were included, and the rate of DVT was 16.6% (1627 of 9823 patients) in our study. Our findings showed that advanced age [p = 0.0003, OR = 0.13 95% CI (0.06, 0.21)], female patients [p = 0.0009, OR = 0.82 95% CI (0.72, 0.92)], high-energy injury [p = 0.009, OR = 0.58 95% CI (0.38, 0.87)], prolonged time from injury to admission [p < 0.00001, OR = 0.54 95% CI (0.44, 0.65)], prolonged time from injury to surgery [p < 0.00001, OR = 2.06, 95% CI (1.40, 2.72)], hemoglobin [p < 0.00001, OR = - 0.32 95% CI (- 0.43, - 0.21)], coronary heart disease [p = 0.006, OR = 1.25 95% CI (1.07, 1.47)], dementia [p = 0.02, OR = 1.72 95% CI (1.1, 2.67)], liver and kidney diseases [p = 0.02, OR = 1.91 95% CI (1.12, 3.25)], pulmonary disease [p = 0.02, OR = 1.55 95% CI (1.07, 2.23)], smoking [p = 0.007, OR = 1.45 95% CI (1.11, 1.89)], fibrinogen [p = 0.0005, OR = 0.20 95% CI (0.09, 0.32)], anti-platelet drug [p = 0.01, OR = 0.51 95% CI (0.30, 0.85)], C-reactive protein [p = 0.02, OR = 5.95 95% CI (1.04, 10.85)], < 35 g/l albumin [p = 0.006, OR = 1.42 95% CI (1.1, 1.82)], and thrombosis history [p < 0.00001, OR = 5.28 95% CI (2.85, 9.78)] were risk factors for preoperative DVT. Many factors, including advanced age, female patients, high-energy injury, prolonged time from injury to admission, prolonged time from injury to surgery, patients with a history of coronary heart disease, dementia, liver and kidney diseases, pulmonary disease, smoking, and thrombosis, fibrinogen, C-reactive protein, and < 35 g/l albumin, were found to be associated with preoperative DVT. Our findings suggested that the patient with above characteristics might have preoperative DVT. Level III.


Host immunity and KLF 11 deficiency together promote fibrosis in a mouse model of endometriosis.
Endometriosis is a debilitating disease typically characterized by prolific fibrotic scarring. Earlier we reported downregulation of two transcription factors belonging TGF-βR signaling pathway Sp/Krüppel-like factor 11 (KLF11) and 10 (KLF10) in human endometriosis lesions. Here we investigated the role of these nuclear factors and immunity in the scaring fibrosis associated with endometriosis. We used a well characterized experimental mouse model of endometriosis. WT, KLF10 or KLF11 deficient mice were compared. The lesions were evaluated histologically, fibrosis was quantified with Masons' Trichome staining, immune-infiltrates were quantified by immunohistochemistry, peritoneal adhesions were score, gene expression was evaluated by bulk RNA sequencing. Intense fibrotic reactions and large changes in gene expression were detected in KLF11 deficient implants associated with squamous metaplasia of the ectopic endometrium, as compared to KLF10 deficient or WT implants. Fibrosis was mitigated with pharmacologic agents that blocked histone acetylation or TGF-βR signaling or with genetic deficiency for SMAD3. The lesions were richly infiltrated with T-cells, regulatory T-cells, and innate immune cells. Fibrosis was exacerbated when implants expressed ectopic genes implicating autoimmunity as a major factor contributing to the scaring fibrosis. Our findings identify KLF11 and TGF-βR signaling as cell intrinsic mechanisms and autoimmune responses as cell extrinsic mechanisms of scaring fibrosis in ectopic endometrium lesions. Immunological factors associated with inflammation and tissue repair drive scaring fibrosis in experimental endometriosis, providing the rationale for immune therapy of endometriosis.


Development of automated brightfield double in situ hybridization (BDISH) application for HER2 gene and chromosome 17 centromere (CEN 17) for breast carcinomas and an assay performance comparison to manual dual color HER2 fluorescence in situ hybridization (FISH).
Human epidermal growth factor receptor 2 (HER2) fluorescence in situ hybridization (FISH) is a quantitative assay for selecting breast cancer patients for trastuzumab therapy. However, current HER2 FISH procedures are labor intensive, manual methods that require skilled technologists and specialized fluorescence microscopy. Furthermore, FISH slides cannot be archived for long term storage and review. Our objective was to develop an automated brightfield double in situ hybridization (BDISH) application for HER2 gene and chromosome 17 centromere (CEN 17) and test the assay performance with dual color HER2 FISH evaluated breast carcinomas. The BDISH assay was developed with the nick translated dinitrophenyl (DNP)-labeled HER2 DNA probe and DNP-labeled CEN 17 oligoprobe on the Ventana BenchMark(R) XT slide processing system. Detection of HER2 and CEN 17 signals was accomplished with the silver acetate, hydroquinone, and H2O2 reaction with horseradish peroxidase (HRP) and the fast red and naphthol phosphate reaction with alkaline phosphatase (AP), respectively. The BDISH specificity was optimized with formalin-fixed, paraffin-embedded xenograft tumors, MCF7 (non-amplified HER2 gene) and BT-474 (amplified HER2 gene). Then, the BDISH performance was evaluated with 94 routinely processed breast cancer tissues. Interpretation of HER2 and CEN 17 BDISH slides was conducted by 4 observers using a conventional brightfield microscope without oil immersion objectives. Sequential hybridization and signal detection for HER2 and CEN 17 ISH demonstrated both DNA targets in the same cells. HER2 signals were visualized as discrete black metallic silver dots while CEN 17 signals were detected as slightly larger red dots. Our study demonstrated a high consensus concordance between HER2 FISH and BDISH results of clinical breast carcinoma cases based on the historical scoring method (98.9%, Simple Kappa = 0.9736, 95% CI = 0.9222 - 1.0000) and the ASCO/CAP scoring method with the FISH equivocal cases (95.7%, Simple Kappa = 0.8993%, 95% CI = 0.8068 - 0.9919) and without the FISH equivocal cases (100%, Simple Kappa = 1.0000%, 95% CI = 1.0000 - 1.0000). Automated BDISH applications for HER2 and CEN 17 targets were successfully developed and it might be able to replace manual two-color HER2 FISH methods. The application also has the potential to be used for other gene targets. The use of BDISH technology allows the simultaneous analyses of two DNA targets within the context of tissue morphological observation.


T-cell depleted bone marrow transplantation for plasma cell myeloma. Report of a case and review of the results of BMT for myeloma.
A 37-year-old male patient with advanced refractory plasma cell myeloma underwent T-cell depleted bone marrow transplantation (BMT) after 7 years of active disease previously treated with combination chemotherapy and irradiation. After the BMT there was marked clinical improvement and the patient is currently in good clinical condition two years after the BMT was performed. However, residual myeloma cells are still seen in the marrow and stable levels of paraprotein are still present in the serum. No GVHD was encountered after BMT. The problems of BMT in myeloma are discussed with a review of the current pertinent literature.


Chloride ion transport and its inhibition in thylakoid membranes.
Cl- translocation across energized and nonenergized thylakoid membranes was found to be inhibited by piretanide, an inhibitor of active Cl- transport in fish intestinal epithelia. Piretanide has no effect on photophosphorylation catalyzed by phenazine methosulfate or on Ca2+-dependent ATPase activity of isolated chloroplast coupling factor (CF1). Light-dependent Cl- uptake, contrary to H+ uptake, is severalfold greater at pH 8.0 than at pH 6.7.


Distribution of carbohydrate residues in normal skin.
Sections of biopsies of normal skin obtained from 11 individuals were incubated with 8 lectins using an avidin-biotin complex (ABC). All sections when incubated with the appropriate lectin showed the presence of the following carbohydrate residues: L-fucose, beta-(1-4)-D-GlcNAc)2 (N-acetylglucosamine), acetylneuraminic acid, Gal-beta-(1-3)-GalNAc (N-acetyl-galactosamine), beta-D-galactose, alpha-D-glucose, and alpha-D-mannose. In addition, sections of individuals with blood group A showed alpha-D-GalNAc and sections of individuals with blood group B showed alpha-D-galactose. In the stratum (str.) basale, carbohydrates were present in small quantities, but as the cells matured and moved upward, the incorporation of carbohydrates into the cell membranes increased considerably. In the str. granulosum, lectin reactivity was absent in many sections, probably due to masking by phospholipids. The dark cells in the eccrine glands showed reactivity with all lectins except in the one nonsecretor with blood group A1, whose dark cells showed no L-fucose and alpha-D-GalNAc. The endothelial cells of the blood vessels showed lectin reactivity except when incubated with concanavalin A. The sebaceous glands showed both cytoplasmic and membrane staining when incubated with various lectins.


Constructing productive engagement: pre-engagement tools for emerging technologies.
Engagement with stakeholders and civil society is increasingly important for new scientific and technological developments. Preparation of such engagements sets the stage for engagement activities and thus contributes to their outcomes. Preparation is a demanding task, particularly if the facilitating agent aims for timely engagement related to emerging technologies. Requirements for such preparation include understanding of the emerging science & technology and its dynamics. Multi-level analysis and socio-technical scenarios are two complementary tools for constructing productive engagement. Examination of the emergence of nanotechnologies in the food packaging sector demonstrates how these tools work. In light of recent policy demands for responsible innovation, but also more generally, the role of organizers of engagement activities is one that deserves reflection insofar as it can extend beyond that of preparation and facilitation.


Prediction of perioperative myocardial infarction/injury in high-risk patients after noncardiac surgery.
Perioperative myocardial infarction/injury (PMI) is a surprisingly common yet difficult-to-predict cardiac complication in patients undergoing noncardiac surgery. We aimed to assess the incremental value of preoperative cardiac troponin (cTn) concentration in the prediction of PMI. Among prospectively recruited patients at high cardiovascular risk (age ≥65 years or ≥45 years with preexisting cardiovascular disease), PMI was defined as an absolute increase in high-sensitivity cTnT (hs-cTnT) concentration of ≥14 ng/L (the 99th percentile) above the preoperative concentration. Perioperative myocardial infarction/injury was centrally adjudicated by two independent cardiologists using serial measurements of hs-cTnT. Using logistic regression, three models were derived: Model 1 including patient- and procedure-related information, Model 2 adding routinely available laboratory values, and Model 3 further adding preoperative hs-cTnT concentration. Models were also compared vs. preoperative hs-cTnT alone. The findings were validated in two independent cohorts. Among 6944 patients, PMI occurred in 1058 patients (15.2%). The predictive accuracy as quantified by the area under the receiver operating characteristic curve was 0.73 [95% confidence interval (CI) 0.71-0.74] for Model 1, 0.75 (95% CI 0.74-0.77) for Model 2, 0.79 (95% CI 0.77-0.80) for Model 3, and 0.74 for hs-cTnT alone. Model 3 included 10 preoperative variables: age, body mass index, known coronary artery disease, metabolic equivalent >4, risk of surgery, emergency surgery, planned duration of surgery, haemoglobin, platelet count, and hs-cTnT. These findings were confirmed in both independent validation cohorts (n = 722 and n = 966). Preoperative cTn adds incremental value above patient- and procedure-related variables as well as routine laboratory variables in the prediction of PMI.


Adrenal gland involvement in mice with hereditary obesity and diabetes mellitus. Morphological studies.
The contribution of the adrenal gland to the development of the spontaneous syndrome of obesity and diabetes in Yellow-KK (Y-KK) mice was studied. Six-month old Y-KK mice exhibited hyperadrenocorticism and adrenal cortex enlargement. Light microscopic morphometric studies of Y-KK adrenals revealed an expanded volume of the adrenal cortex resulting from hyperplasia of zona fasciculata and reticularis cells. Ultrastructural studies revealed fewer lipid droplets, increased numbers of mitochondria and a more extensively developed Golgi system with zona fasciculata and reticularis cells. This cytological evidence of enhanced steroid biosynthetic and secretory activity was consistent with increased levels of plasma immunoreactive corticosterone. Structural and functional abnormalities of Y-KK adrenals were preceded by the development of obesity, hyperglycaemia and hyperinsulinaemia. It is unlikely, therefore, that the adrenal plays a casual role in the syndrome's pathogenesis, although, hyperadrenocorticism may be in part responsible for an exacerbation of the observed phenomena.


Blood monitoring of perfluorocarbon compounds (F-tert-butylcyclohexane, perfluoromethyldecalin and perfluorodecalin) by headspace-gas chromatography-tandem mass spectrometry.
A headspace-gas chromatography-tandem mass spectrometry (HS-GC-MS/MS) method for the trace measurement of perfluorocarbon compounds (PFCs) in blood was developed. Due to oxygen carrying capabilities of PFCs, application to doping and sports misuse is speculated. This study was therefore extended to perform validation methods for F-tert-butylcyclohexane (Oxycyte(®)), perfluoro(methyldecalin) (PFMD) and perfluorodecalin (PFD). The limit of detection of these compounds was established and found to be 1.2 µg/mL blood for F-tert-butylcyclohexane, 4.9 µg/mL blood for PFMD and 9.6 µg/mL blood for PFD. The limit of quantification was assumed to be 12 µg/mL blood (F-tert-butylcyclohexane), 48 µg/mL blood (PFMD) and 96 µg/mL blood (PFD). HS-GC-MS/MS technique allows detection from 1000 to 10,000 times lower than the estimated required dose to ensure a biological effect for the investigated PFCs. Thus, this technique could be used to identify a PFC misuse several hours, maybe days, after the injection or the sporting event. Clinical trials with those compounds are still required to evaluate the validation parameters with the calculated estimations.


Efficient production of GlcNAc in an aqueous-organic system with a Chitinolyticbacter meiyuanensis SYBC-H1 mutant.
Shellfish waste is a primary source for making N-acetyl-D-glucosamine. Thus, establishing a high-efficiency and low-cost bioconversion method to produce N-acetyl-D-glucosamine directly from shellfish waste was promising. A mutant C81 was obtained from Chitinolyticbacter meiyuanensis SYBC-H1 via 60Co-γ irradiation. This mutant C81 showed the highest chitinase activity of 9.8 U/mL that was 85% higher than the parent strain. The mutant C81 exhibted improved antioxidant activities, including total antioxidant capacity, superoxide radical ability, and hydroxyl radical scavenging ability, compared to that of the parent strain. Four out of nine organic solvents increased the chitinase activity by 1.9%, 6.8%, 11.7%, and 15.8%, corresponding to methylbenzene, n-heptane, petroleum ether, and n-hexane, respectively. The biphase system composed of aqueous and hexane presented a five-fold reduction of cell viability compared to the control. Using a continuous fermentation bioconversion process, 4.2 g/L GlcNAc was produced from crayfish shell powder with a yield of 80% of the chitin content. This study demonstrated that the mutant C81 is suitable for converting crayfish shell powder into GlcNAc in an aqueous-organic system.