Changes in Prescribing Practices of Dopaminergic Medications in Individuals with Parkinson's Disease by Expert Care Centers from 2010 to 2017: The Parkinson's Foundation Quality Improvement Initiative.
During the past decade, there has been increasing awareness of the side effects of dopamine agonists (DAs), including impulse control disorders. We hypothesized that there may be a shift toward more conservative use of DAs. To explore the change in prescribing practices for dopaminergic medications in Parkinson's disease between 2010 and 2017. Data were collected from the Parkinson's Foundation Quality Improvement Initiative registry. Baseline characteristics were compared between the 2010 and 2017 cohorts using chi-squared tests for discrete and t tests for continuous variables. Logistic regressions were conducted for each class of medications to assess the effect of time points (2010 vs. 2017) and prespecified covariates on the probability of prescribing. A total of 2,717 participants from 2010 and 2,900 participants from 2017 were included in the analysis. Mean (standard deviation) age was 67.4 (10) and 68.7 (9.3) for the 2010 and 2017 cohorts, respectively (P < 0.0001). After controlling for baseline characteristics, DA use was unchanged (P = 0.1172). The odds of using monoamine oxidase B inhibitors was 52% higher in 2017 than in 2010 (P < 0.0001), 38% lower for catechol-O-methyltransferase inhibitors (P < 0.0001), 25% lower for amantadine (P < 0.0001), and 31% lower for anticholinergics (P = 0.0153). There was no difference in the utilization of levodopa in the 2 cohorts (86.1% vs. 86.2%; P = 0.5783). Despite increasing awareness of impulse control disorders, there has been no reduction in the use of DAs during the past decade. Overall, there is less utilization of adjunctive classes of drugs except for an increase in the use of monoamine oxidase B inhibitors.


Dopamine transporter imaging with [(123)I]FP-CIT SPECT: potential effects of drugs.
[(123)I]N-omega-fluoropropyl-2beta-carbomethoxy-3beta-{4-iodophenyl}nortropane ([(123)I]FP-CIT) single photon emission computed tomography (SPECT) is a frequently and routinely used technique to detect or exclude dopaminergic degeneration by imaging the dopamine transporter (DAT) in parkinsonian and demented patients. This technique is also used in scientific studies in humans, as well as in preclinical studies to assess the availability of DAT binding in the striatum. In routine clinical studies, but also in scientific studies, patients are frequently on medication and sometimes even use drugs of abuse. Moreover, in preclinical studies, animals will be anesthetized. Prescribed drugs, drugs of abuse, and anesthetics may influence the visual interpretation and/or quantification of [(123)I]FP-CIT SPECT scans. Here, we discuss the basic principle of how drugs and anesthetics might influence the visual interpretation and/or quantification of [(123)I]FP-CIT SPECT scans. We also review drugs which are likely to have a significant influence on the visual interpretation and/or quantification of [(123)I]FP-CIT SPECT scans. Additionally, we discuss the evidence as to whether frequently prescribed drugs in parkinsonian and demented patients may have an influence on the visual interpretation and/or quantification of [(123)I]FP-CIT SPECT scans. Finally, we discuss our recommendations as to which drugs should be ideally withdrawn before performing a [(123)I]FP-CIT SPECT scan for routine clinical purposes. The decision to withdraw any medication must always be made by the specialist in charge of the patient's care and taking into account the pros and cons of doing so.


[Hepatic splenosis: a rare etiology of hepatic nodules].
Splenosis is the autotransplantation of splenic tissue, generally after traumatic splenic rupture. Usually, the peritoneal surface is affected. The viscera are rarely involved in this graft. We report a case of intrahepatic splenosis, which presented as a liver tumour on imagery in a 55-year-old man followed for lung carcinoma and chronic hepatitis C and who had undergone a splenectomy for trauma 22 years before. The different characteristics and diagnostic methods of 16 cases of hepatic splenosis are presented from the literature. These different reports emphasize the necessity of considering splenosis in the differential diagnosis of hepatic tumours.


Pfkfb (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase) isoforms display a tissue-specific and dynamic expression during Xenopus laevis development.
Pfkfb (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase) enzymes are bi-functional enzymes encoded by four different genes (pfkfb1, pfkfb2, pfkfb3, pfkfb4) in vertebrates. They are involved in the regulation of glycolysis: they catalyze the synthesis and the degradation of F-2,6-BP (fructose-2,6-bisphosphate), the most potent allosteric activator of phosphofructokinase 1 (Pfk1), a key glycolytic enzyme. By producing F-2,6-BP, Pfkfb enzymes allow glycolysis to proceed, while by degrading F-2,6-BP they block glycolysis. As major regulators of glycolysis, Pfkfb enzymes are involved in cancer: tumor cells have a higher glycolytic rate compared to normal cells, even in the presence of adequate oxygen levels (Warburg effect) and several cancer cell lines express elevated levels of Pfkfb enzymes. Glycolysis is also important for energy and metabolite production in proliferating cells. In embryos, however, the role of glycolysis and the expression of glycolysis regulators remain to be explored. Here, we provide a phylogenetic analysis of Pfkfb enzymes in vertebrates, and we detail the expression pattern of pfk1, pfkfb1, pfkfb2, pfkfb3, and pfkfb4 genes in Xenopus laevis embryos. We show that pfkfb transcripts expression is overlapping at blastula and gastrula stages and that from neurulation to tadpole stages, they display tissue-specific, complementary and dynamic expression patterns.


Cell surface changes accompanying viral transformation: N-acetylneuraminic acid ectotransferase system activity.
The activity of the sialyl ectotransferase system of normal chick embryo fibroblasts (CEF) and chick embryo fibroblasts transformed with the Schmidt-Ruppin strain of Rous sarcoma virus (SR-RSV) have been compared. Neuraminidase treatment of the intact cells increased the sialyl ectotransferase system activity of control and transformed cells two to three times. The ectotransferase system activity increased as the pH was decreased from 7.8 to 6.0. The temperature optimum for both systems was 40 degrees C. Approximately 60% of the 14C-sialic acid incorporated at pH 6.5 or above could be removed with neuraminidase. The activity of the transformed cell system with or without neuraminidase treatment was more stimulated by addition of Mn2+ ions, particularly above pH 7.0. This difference in ion sensitivity indicates that a different cell surface phenomenon is being studied after transformation.


Cordycepin prevents oxidative stress-induced inhibition of osteogenesis.
Oxidative stress is known to be involved in impairment of osteogenesis and age-related osteoporosis. Cordycepin is one of the major bioactive components of Cordyceps militaris that has been shown to exert antioxidant and anti-inflammatory activities. However, there are few reports available regarding the effects of cordycepin on osteogenesis and the underlying mechanism. In this study, we investigated the potential osteoprotective effects of cordycepin and its mechanism systematically using both in vitro model as well as in vivo mouse models. We discovered that hydrogen peroxide (H2O2)-induced inhibition of osteogenesis which was rescued by cordycepin treatment in human bone marrow mesenchymal stem cells (BM-MSCs). Cordycepin exerted its protective effects partially by increasing or decreasing expression of osteogenic and osteoclastogenesis marker genes. Treatment with cordycepin increased Wnt-related genes' expression whereas supplementation of Wnt pathway inhibitor reversed its protective effects. In addition, administration of cordycepin promoted osteogenic differentiation of BM-MSCs by reducing oxidative stress in both ovariectomized and aged animal models. Taken together, these results support the protective effects of cordycepin on oxidative stress induced inhibition of osteogenesis by activation of Wnt pathway.


Prevention of myocardial electrical activity during ischemic arrest with verapamil cardioplegia.
The effect of potassium cardioplegia and potassium cardioplegia containing verapamil hydrochloride on myocardial preservation and electrical activity during prolonged aortic occlusion was examined in 40 adult mongrel dogs. Twenty-four animals (Group 1) received potassium cardioplegia, and 16 animals (Group 2) received potassium verapamil cardioplegia. Potassium or potassium verapamil cardioplegia, 10 ml per kilogram of body weight, was administered after application of the aortic cross-clamp and at 30-minute intervals during the 90-minute arrest. Myocardial temperature was maintained within a range of 8 degrees to 10 degrees C with topical ice saline solution, and electrical activity was monitored with specially designed plunge electrodes. Plunge electrode activity was recorded from the myocardium during arrest in 16 of the 24 animals in Group 1; no electrical activity was present in the animals in Group 2 (p less than .001). The addition of verapamil to potassium cardioplegia increased the tolerance of the myocardium to prolonged ischemia and resulted in less depletion of high-energy phosphate stores and better preservation of mitochondrial ultrastructure and left ventricular function. These data suggest that verapamil augments the preservation provided by potassium cardioplegia by initiating and maintaining a more complete electrical arrest.


Theoretical derivation and experimental investigation of dynamic displacement reconstruction based on data fusion for beam structures.
Accurately obtaining the dynamic displacement response of the beam structure is of great significance. However, it is difficult to directly measure the dynamic displacement for large structures due to the low measurement accuracy or the installation difficulty of the sensor. Therefore, it is urgent to develop an indirect measurement method for displacement based on measurable physical quantities. Since acceleration and strain contain high and low frequency displacement information respectively, this paper proposes a displacement reconstruction algorithm that can realize the data fusion of the two, which is very helpful for the research of structural health monitoring. Firstly, the stochastic subspace identification (SSI) method is adopted to calculate the strain mode, and then the displacement is derived via the mode shape superposition method. Afterwards, the strain-derived displacement and acceleration are combined by the proposed algorithm to reconstruct the dynamic displacement. Both the numerical simulation and model experiment are conducted to verify the effectiveness of the proposed algorithm. Furthermore, the influences of noise, sampling rate ratio and measurement point position are analyzed. The results show that the proposed algorithm can accurately reconstruct both high-frequency and pseudo-static displacements, and the displacement reconstructed error in the model experiment is within 5%.


Determination of linear alkylbenzensulfonates in aqueous matrices by ion-pair solid-phase microextraction-in-port derivatization-gas chromatography-mass spectrometry.
Trace determination (low ng/ml) of linear alkylbenzensulfonates (LASs) in water was achieved by solid-phase microextraction (SPME) of ion-pairs formed with tetrabutylammonium. This ion-pairing reagent served two purposes. First, it allowed the extraction of LAS with the polydimethylsiloxane fiber by counterion association and second, the derivatization of the formed LAS ion pairs in the GC injection port at 300 degrees C to form the corresponding sulfonated butyl esters. The methodology developed allows the isomer specific determination of LAS at low detection limits (0.16-0.8 ng/ml), depending on the alkyl chain lengths of LASs with RSDs of 10-12%. Furthermore, the developed methodology was applied to urban wastewater and sea water and compared with a solid-phase extraction (SPE) method (e.g. C18 and strong anion-exchange sorbent) to obtain concordant values for urban wastewater. Moreover, the developed SPME methodology overcame the procedural blank and matrix-dependent recoveries found in the SPE methodologies at low LAS concentrations.


Seasonal effects of pimozide and des Gly10 [D-Ala6] LH-RH ethylamide on gonadotrophin secretion in goldfish.
The seasonal changes in the gonadotrophin-release-inhibitory activity of dopamine and responsiveness to gonadotrophin-releasing hormone were investigated by determining the effects of injection of pimozide, a dopamine receptor antagonist, des-Gly10 [D-Ala6] LH-RH ethylamide (LRH-A), or the combination of pimozide plus LRH-A on serum gonadotrophin (GtH) levels of goldfish, held at 12 or 20 degrees C, at different stages of gonadal development. As in previous studies, pimozide greatly potentiated the GtH-release response to LRH-A. The highest concentrations of serum GtH induced by injection of pimozide or LRH-A alone, or the combination of pimozide plus LRH-A were in females in late stages of ovarian recrudescence; fish that were sexually regressed (males and females combined) were the least responsive, and fish that were in early stages of gonadal recrudescence, and mature females ( = prespawning, completed ovarian recrudescence) were intermediate. Fish held at 20 degrees C had a more rapid onset of GtH release and had higher serum GtH levels initially compared to fish at 12 degrees C at similar sexual stages; however, the fish held at 12 degrees C generally had a more prolonged increase in serum GtH levels, indicating that temperature influence the time course of the GtH-release response. The results indicate that there is a seasonal variation in responsiveness to injection of pimozide, LRH-A and the combination of pimozide plus LRH-A. These seasonal changes may be due to differences in the pituitary content of GtH, the ability of the pituitary to synthesize GtH, or changes in GtH cell receptors for GnRH and dopamine, or a combination of these and other unknown factors.


Efficacy of Shegan Mahuang Decoction for asthma: A systematic review and meta-analysis protocol.
Shegan Mahuang Decoction (SMD) was used widely for treatment of asthma in China; however, the clinical effect of SMD on asthma was not well concluded. Seven electronic databases (Medline, Cochrane library, EMBASE database, Chinese National Knowledge Infrastructure, Wanfang database, Chongqing VIP database, and Chinese Biomedicine database) will be searched for randomized controlled trials which meet the eligible criteria. Two reviewers will select studies and extract data independently. Risk of bias will be evaluated using modified Jadad score. Data synthesis will be carried out using RevMan 5.3. Sensitivity analysis and publication bias will also be investigated. This systematic review and meta-analysis will review and synthesis current clinical evidence of SMD for the treatment of asthma. This systematic review and meta-analysis will provide high quality evidence of SMD for the treatment of asthma. PROSPERO CRD42019141810.


Mutation identification in a canine model of X-linked ectodermal dysplasia.
X-linked hypohidrotic ectodermal dysplasia (XHED), an inherited disease recognized in humans, mice, and cattle, is characterized by hypotrichosis, a reduced number or absence of sweat glands, and missing or malformed teeth. In a subset of affected individuals and animals, mutations in the EDA gene (formerly EDI), coding for ectodysplasin, have been found to cause this phenotype. Ectodysplasin is a homotrimeric transmembrane protein with an extracellular TNF-like domain, which has been shown to be involved in the morphogenesis of hair follicles and tooth buds during fetal development. Some human XHED patients also have concurrent immunodeficiency, due to mutations in the NF-kappaB essential modulator protein (IKBKG; formerly NEMO), which is also encoded on the X chromosome. In a breeding colony of dogs with XHED, immune system defects had been suspected because of frequent pulmonary infections and unexpected deaths resulting from pneumonia. To determine if defects in EDA or IKBKG cause XHED in the dogs, linkage analysis and sequencing experiments were performed. A polymorphic marker near the canine EDA gene showed significant linkage to XHED. The canine EDA gene was sequenced and a nucleotide substitution (G to A) in the splice acceptor site of intron 8 was detected in affected dogs. In the presence of the A residue, a cryptic acceptor site within exon 9 is used, leading to a frame shift and use of a premature stop codon that truncates the translation of both isoforms, EDA-A1 and EDA-A2, resulting in the absence of the TNF-like homology domain, the receptor-binding site of ectodysplasin.


Use of nucleoside phosphorylases for the preparation of 5-modified pyrimidine ribonucleosides.
Enzymatic transglycosylation, a transfer of the carbohydrate moiety from one heterocyclic base to another, is catalyzed by nucleoside phosphorylases (NPs) and is being actively developed and applied for the synthesis of biologically important nucleosides. Here, we report an efficient one-step synthesis of 5-substitited pyrimidine ribonucleosides starting from 7-methylguanosine hydroiodide in the presence of nucleoside phosphorylases (NPs).


Considerations for sociotechnical design: experiences with an electronic patient record in a clinical context.
This paper argues that we should understand the process of IT design as the development of sociotechnical configurations. Drawing upon our experiences with an electronic patient record (EPR) on an Intensive Care Unit (ICU), we depict medical work practices as natural systems. Several considerations for design are developed. First, the EPR should not be overly structured with rationalistic and prefixed notions of the organization and content of medical work. Implementing structure is crucial, however, this should be derived from detailed, empirical knowledge of the practice involved. Second, it is crucial to ensure that the usage of the system will yield immediate benefits for primary users: the systems should support work, not generate it. Third, designing IT should include being aware of the socio political nature of seemingly 'neutral' tools as EPRs.


Disadvantages of VKA and requirements for novel anticoagulants.
Vitamin K antagonists have been in wide use for over 70 years. Warfarin, the most commonly used vitamin K antagonist, has been shown to be highly effective in treating and preventing thrombosis. Despite this, warfarin has many disadvantages, which has led to the development of a new class of oral anticoagulants targeted to specific coagulation factors designated as target-specific oral anticoagulants (TSOAs). TSOAs include the thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban). This chapter reviews the disadvantages of warfarin and evaluates both the advantages and disadvantages of the new oral anticoagulants.


A nano phototheranostic approach of toluidine blue conjugated gold silver core shells mediated photodynamic therapy to treat diabetic foot ulcer.
Diabetic foot infection caused by multidrug-resistant bacteria, is becoming serious problem. Moreover, polymicrobial biofilms contribute significantly to the persistent infections. In the present study, we investigated the effectiveness of novel toluidine blue conjugated chitosan coated gold-silver core-shell nanoparticles (TBO-chit-Au-AgNPs) mediated photodynamic therapy and demonstrate their use as a nontoxic antibacterial therapy to combat diabetic foot ulcer (DFU) caused by multi-drug resistant strains both in monomicrobial and polymicrobial state of infection. In vitro efficacy of TBO-chit-Au-AgNPs mediated photodynamic therapy (PDT) against polymicrobial biofilms was determined using standard plate count method and compared with that of monomicrobial biofilms of each species. Different anti-biofilm assays and microscopic studies were performed to check the efficacy of TBO-chit-Au-AgNPs mediated PDT, displayed significant decrease in the formation of biofilm. Finally, its therapeutic potential was validated in vivo type-2DFU. Cytokines level was found reduced, using nano-phototheranostic approach, indicating infection control. Expression profile of growth factors confirmed both the pathogenesis and healing of DFU. Hence, we conclude that TBO-chit-Au-AgNPs mediated PDT is a promising anti-bacterial therapeutic approach which leads to a synergistic healing of DFU caused by MDR bacterial strains.


Enhancing arachidonic acid production by Mortierella alpina ME-1 using improved mycelium aging technology.
Traditional mycelium aging technology was improved to enhance arachidonic acid (ARA) production by Mortierella alpina ME-1. Filtration step was skipped and additional carbon and nitrogen sources were fed during aging. The levels of the significant factors (time, temperature, ethanol, and KNO(3)) affecting ARA production during improved aging process were also optimized by applying response surface methodology (RSM), and the maximum ARA yield of 19.02 g/l was achieved in a 5 l fermentor at 5.6 days, temperature 13.7 degrees C, ethanol 42.44 g/l, and KNO(3) 2.62 g/l. This yield was 1.55 times higher than that of traditional aging technology. The improved mycelium aging technology is considered to be a useful strategy for enhancing ARA production.


Two antiphase oscillations occur in each suprachiasmatic nucleus of behaviorally split hamsters.
The suprachiasmatic nuclei (SCNs) control circadian rhythms of numerous behavioral and physiological responses. In hamsters, constant light causes "splitting" of circadian rhythms, such that a single daily bout of activity separates into two components, 12 h apart, with antiphase circadian oscillations in the left and right SCN. Given the phenotypic and functional heterogeneity of the SCN, in which ventrolateral but not dorsomedial neurons are retinorecipient, we asked how these two compartments respond to the constant lighting conditions that produce splitting, using three different phase markers of neuronal activity: PER1 (Period 1), c-FOS, and pERK (phosphorylated extracellular signal-regulated kinase). We report the emergence of a coherent novel network in which each side of the SCN exhibits two antiphase oscillating subregions, here termed "core-like" and "shell-like," in addition to the known antiphase oscillation between the right and left SCN. The novel SCN response entails a coherent rhythm in a core-like region of the SCN, which otherwise is not cycling. A mathematical model is presented, and this model interprets the observed changes in the proportion of in-phase and antiphase populations of SCN oscillators and suggests novel testable hypotheses. Finally, the functional significance of this network was explored by investigating the adjacent hypothalamus. Activation of the paraventricular nucleus is in-phase with the ipsilateral core-like SCN, whereas activation of the lateral subparaventricular zone is in-phase with the ipsilateral shell-like SCN, pointing to a multiplicity of SCN output signals. These results suggest a neural basis for internal coincidence of SCN oscillators, and a novel mechanism of plasticity in SCN neural networks and outputs.


Aluminum exposure from food in the population of Lebanon.
Widely used for a variety of applications, levels of dietary aluminum (Al) have seen a perpetual rise in Lebanon, leading to noticeable effects upon the human body. This study aims to estimate the rates of Al contaminated food consumption and quantify the Al present in different dietary matrices, revealing the major contributors to Al exposure for the Lebanese population. A cross-sectional study was conducted using a customized, self-reported Electronic Food Frequency Questionnaire (E-FFQ) using Curve®, targeting individuals between the ages of 18 and 64 from different Lebanese regions, distributed proportionally. The selection of food was based upon the results of the French EAT2 study. Al levels in food were analyzed using Flame Atomic Absorption Spectrometry (FAAS) after acid digestion. The E-FFQ was completed by 167 respondents. Data analysis was performed on SPSS version 25. Additionally, 97 food items were studied in 2018. Al levels had a mean of 3.56 ± 2.08 mg/kg (ranging from 0.14 to 9.37). The highest Al levels were found in vegetables, followed by sauces and condiments, candies, and ready meals. The Provisional Tolerable Weekly Intake (PTWI) of Al was set at 0.50 mg/kg body weight (60 Kg/person). Al mean Daily Dietary Exposure (DDE) was estimated to be 4341.18 μg/day, with the highest food exposure coming from lettuce, soft drinks, ice cream and tea. Al ingestion rates for the adult Lebanese population does not exceed the international established thresholds of tolerable intake (1 mg/kg/week). National recommendation should be developed to control the presence of metal for food safety purposes.


Evaluation of the pressure ulcer prevention clinical decision report for bedside nurses in acute care hospitals.
Hospital stays for patients with pressure ulcers (PU) increased nearly 80% from 1992 to 2006. Most PU's developed during an admission, often despite preventive efforts from clinical staff. Data from Electronic medical records (EMR's) were used to prepare daily patient risk factor and PU information for nurses to help prevent PU development and exacerbations. THE OBJECTIVES OF THIS STUDY WERE TO DETERMINE WHETHER: 1) dissemination of an automated daily report with patient risk and current status of pressure ulcers ("PU Daily") helps prevent the development of pressure ulcers, and 2) using the PU Daily information impacts the severity of pressure ulcers that develop in an acute care setting. A pre-post study with four control units was designed to determine the impact of the PU Daily in intensive care units (ICU) in a large medical center. The control units included ICU's using the same EMR and similar complexity of cases with a high risk of developing a PU. The pre-post study took place over a six month period (March - August 2009). A total of 6,735 cases were included in the study. The intervention unit showed a significant decrease (p = 0.004) in PU's at post-evaluation; none of the four comparison units showed a decrease at the p<0.05 level. The intervention led to a significant reduction in the total number of PU's documented (p <0.000) and the number of Stage II PU's (p = 0.046). The intervention with the PU Daily showed a significant decrease in the total PU's and severity of PU's and allowed for implementation of interventions that help prevent the development of PU's. As EMR's become more widely available, this intervention showed a reduction in PU's. Future studies should further develop this intervention and include multiple institutions and patient populations.


Elimination of adult-born neurons in the olfactory bulb is promoted during the postprandial period.
Granule cells (GCs) in the mouse olfactory bulb (OB) continue to be generated in adulthood, with nearly half incorporated and the remainder eliminated. Here, we show that elimination of adult-born GCs is promoted during a short time window in the postprandial period. Under restricted feeding, the number of apoptotic GCs specifically increased within a few hours after the start of feeding. This enhanced GC apoptosis occurred in association with postprandial behaviors that included grooming, resting, and sleeping, and was particularly correlated with the length of postprandial sleep. Further, deprivation of olfactory sensory experience in the local OB area potentiated the extent of GC elimination in that area during the postprandial period. Sensory experience-dependent enhancement of GC elimination also occurred during postprandial period under natural feeding condition. These results suggest that extensive structural reorganization of bulbar circuitry occurs during the postprandial period, reflecting sensory experience during preceding waking period.


Predictive Effects of FT3/FT4 on Diabetic Kidney Disease: An Exploratory Study on Hospitalized Euthyroid Patients with T2DM in China.
This study aims to explore the correlation between the free-triiodothyronine (FT3)-to-free-thyroxine (FT4) ratio (FT3/FT4) and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM). This study retrospectively analyzed 1729 patients with T2DM hospitalized in the Department of Endocrinology, Peking University International Hospital, from January 2017 to August 2021, including 1075 males and 654 females. In accordance with the FT3/FT4, the patients were divided into three groups. (1) The levels of glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG) and postprandial blood glucose (PBG) among the three groups were significantly different, with the low FT3/FT4 group having the highest HbA1c, FBG and PBG among the three groups (F = 39.39, p < 0.01; F = 27.04, p < 0.01; F = 5.76, p = 0.03; respectively). (2) The proportion of DKD is the highest in the low FT3/FT4 group and the lowest in the high FT3/FT4 group (χ2 = 25.83, p < 0.01). (3) Logistic regression showed that low FT3/FT4 were independent risk factors for DKD (OR = 2.36, 95 CI% 1.63, 3.43; p = 0.01). A decrease in the FT3/FT4 is an independent predictor of DKD occurrence in patients with T2DM.


Penile and scrotal inversion vaginoplasty for male to female transsexuals.
A technique of penile and scrotal inversion vaginoplasty for the male to female transsexual has been used successfully in 11 gender-dysphoric patients. The depth of the neovagina is approximately 11 cm--a cosmetic and physiologic result that adds greatly to the patient's satisfaction with the operation. There were no complications of rectal or urethral fistulas. In 1 patient vaginal stenosis developed.


Interaction between hexon and L4-100K determines virus rescue and growth of hexon-chimeric recombinant Ad5 vectors.
The immunogenicity of recombinant adenovirus serotype 5 (rAd5) vectors has been shown to be suppressed by neutralizing antibodies (NAbs) directed primarily against hexon hypervariable regions (HVRs). Preexisting immunity can be circumvented by replacing HVRs of rAd5 hexon with those derived from alternate adenovirus serotypes. However, chimeric modification of rAd5 hexon HVRs tends to cause low packaging efficiency or low proliferation of rAd5 vectors, but the related mechanism remains unclear. In this study, several Ad5-based vectors with precise replacement of HVRs with those derived from Ad37 and Ad43 were generated. We first observed that a HVR-exchanged rAd5 vector displayed a higher efficacy of the recombinant virus rescue and growth improvement compared with the rAd5 vector, although most hexon-chimeric rAd5 vectors constructed by us and other groups have proven to be nonviable or growth defective. We therefore evaluated the structural stability of the chimeric hexons and their interactions with the L4-100K chaperone. We showed that the viability of hexon-chimeric Ad5 vectors was not attributed to the structural stability of the chimeric hexon, but rather to the hexon maturation which was assisted by L4-100K. Our results suggested that the intricate interaction between hexon and L4-100K would determine the virus rescue and proliferation efficiency of hexon-chimeric rAd5 vectors.


HDAC6 inhibitor TST strengthens the antiproliferative effects of PI3K/mTOR inhibitor BEZ235 in breast cancer cells via suppressing RTK activation.
NVP-BEZ235 (BEZ235), an available dual PI3K/mTOR inhibitor, showed antitumor effect and provided a therapy strategy in carcinomas. However, the acquired upregulation of multiple receptor tyrosine kinases (RTKs) by NVP-BEZ235 in tumors limits its clinical efficacy. HDAC6, a class II histone deacetylase, is associated with expressions of multiple RTKs. The aim of this study was to detect whether co-treatment with HDAC6 inhibitor Tubastatin A (TST) would enhance the anticancer effects of BEZ235 in breast cancer cells. In this study, we described that treatment of breast cancer cell lines (T47D, BT474, and MDA-MB-468) with BEZ235 significantly triggered PI3K/mTOR signaling inactivation and increased multiple RTK expression, including EGFR, HER2, HER3, IGF-1 receptor, insulin receptor, and their phosphorylation levels. The adding of TST destabilized these RTKs in those breast cancer cells. Co-treatment with BEZ235 and TST reduced cell proliferative rate by strengthening Akt inactivation. In addition, the combination of these two drugs also cooperatively arrested cell cycle and DNA synthesis. In conclusion, the co-treatment with PI3K/mTOR inhibitor BEZ235 and HDAC6 inhibitor TST displayed additive antiproliferative effects on breast cancer cells through inactivating RTKs and established a rationable combination therapy to treat breast cancer.


Statistical analysis of big data on pharmacogenomics.
This paper discusses statistical methods for estimating complex correlation structure from large pharmacogenomic datasets. We selectively review several prominent statistical methods for estimating large covariance matrix for understanding correlation structure, inverse covariance matrix for network modeling, large-scale simultaneous tests for selecting significantly differently expressed genes and proteins and genetic markers for complex diseases, and high dimensional variable selection for identifying important molecules for understanding molecule mechanisms in pharmacogenomics. Their applications to gene network estimation and biomarker selection are used to illustrate the methodological power. Several new challenges of Big data analysis, including complex data distribution, missing data, measurement error, spurious correlation, endogeneity, and the need for robust statistical methods, are also discussed.


Vertebral compression fracture. An unusual presentation of childhood acute lymphoblastic leukaemia.
Vertebral compression fracture is a rare presenting feature of childhood acute lymphoblastic leukaemia. These cases are often characterized by indicators of good prognosis and show a relatively good treatment outcome.


Ultrastructural changes of the early visceral yolk sac layer of mouse embryos after maternal injection of trypan blue.
The ultrastructural features of the early visceral yolk sac epithelium of normal mouse embryos on day 9 were compared to those whose mothers had received a single subcutaneous injection of 100mg/kg trypan blue on day 8. The following results were obtained: In normal embryos the visceral yolk sac cells are predominantly characterized by numerous membrane bounded inclusions localized in the supranuclear cytoplasm. In embryos of animals treated with trypan, blue, at about 12h after injection large single and only partly membrane bounded vacuoles are observed occupying most of the apical cytoplasm. Up to 24h after injection large cytoplasmic areas are seen which are in a stage of autodigestion possibly due to leakage of the vacuolar content. These alterations are exclusively limited to the visceral yolk sac epithelium whereas in the cells of the embryonic part, e.g. head process, no changes could be found. The observations are discussed in relation to the mechanism of the teratogenic activity of trypan blue.


Concentrations of prostaglandins in plasma, seminal vesicles, and ovaries of aging C57BL/6NNia mice.
Concentrations of prostaglandin E1 (PGE1), and prostaglandin E2 (PGE2) (combined in the same radioimmunoassay) and prostaglandin F2 alpha (PGF2 alpha) were analyzed in circulating plasma and seminal vesicles of 3- and 26 to 27-month-old males and in circulating plasma and ovaries of 3-, 6-, 14 to 18- and 26 to 30-month-old female C57BL/6NNia mice. The amount of PGE declined in the plasma (P less than 0.05) and seminal vesicles (P less than 0.02) of aged male mice, whereas PGF2 alpha concentrations remained unchanged. There were no statistical differences in plasma or ovarian concentrations of PGE or PGF2 alpha when comparing the various age groups of female mice. It does not appear as if age-related changes in prostaglandins play a significant role in reproductive senescence.


Cellular systems for studying human oral squamous cell carcinomas.
The human oral squamous epithelium plays an important role in maintaining a barrier function against mechanical, physical, and pathological injury. However, the self-renewing cells residing on the basement membrane of the epithelium can give rise to oral squamous cell carcinomas (OSCC), now the sixth most common cancer in the developed world, which is still associated with poor prognosis. This is due, in part, to the limited availability of well-defined culture systems for studying oral epithelial cell biology, which could advance our understanding of the molecular basis of OSCC. Here, we describe methods to successfully isolate large cultures of human oral epithelial cells and fibroblasts from small pieces of donor tissues for use in techniques such as three-dimensional cultures and animal grafts to validate genes suspected of playing a role in OSCC development and progression. Finally, the use of isolated oral epithelial cells in generating iPS cells is discussed which holds promise in the field of oral regenerative medicine.


The gestational weight gain and perinatal outcomes among underweight women with twin pregnancies: Propensity score matched analysis from a three-year retrospective cohort.
No recommendations are available for gestational weight gain (GWG) in underweight women with twin pregnancies. We aimed to evaluate whether underweight women with twin pregnancies should gain more weight than normal-weight women in order to optimize perinatal outcomes. This retrospective cohort study compared the GWG and perinatal outcomes among normal-weight and underweight women who gave birth to viable twins between 2015 and 2018 at the Maternal and Child Health Hospital in Foshan, China. Gestational weight gain (GWG) was categorized as adequate or inadequate GWG, based on the US Institute of Medicine 2009 guidelines for normal-weight women (≥ 0.46 kg/week). The outcomes of interest included spontaneous preterm birth (sPTB) <37 weeks, <35 and <32 weeks, small for gestational age (SGA), gestational hypertensive disorder (GHD), gestational diabetes mellitus (GDM), birth weight discordance (BDW) ≥20%, neonatal intensive unit (NICU) admission and neonatal respiratory distress syndrome (NRDS). Propensity score matching (PSM, in a 1:1 ratio) was utilized to minimize the effects of confounders on the differences in the two cohorts. Multivariable logistic models were also used to verify the results from PSM analysis. There were 475 normal-weight and 111 underweight women included in the analysis. Our results suggested that the incidence of adequate GWG was comparable between underweight and normal-weight women (37.5% vs. 45.1%, P = 0.141). The prevalence of GDM was significantly lower among underweight women (9.9%) than among normal-weight women (20.4%) (P = 0.010). There was no evidence of differences in other perinatal outcomes between the two groups. 102 underweight women and 102 normal-weight women were included in PSM analyses. There was a lower incidence of GDM in underweight women than in normal-weight women, but the difference was not significant (9.8% vs. 18.6%, P = 0.071). No evidence of any differences in the other outcomes, including sPTB, GHD, BWD≥20%, SGA, NICU admission and NRDS, was found between the underweight and normal-weight women. Multivariable logistic regression models yielded similar results. For Chinese twin pregnant women with twin pregnancies, our data does provide evidence to suggest underweight women need to gain more weight than normal-weight women to optimize perinatal outcomes. Future studies with larger number of underweight women with twin gestations are warranted to establish an optimal range of GWG.


Statin Use and Reduced Hepatocellular Carcinoma Risk in Patients With Nonalcoholic Fatty Liver Disease.
Recent evidence suggests potential clinical benefits of statin in cancer chemoprevention and treatment. Nonalcoholic fatty liver disease (NAFLD) is expected to become the leading cause of hepatocellular carcinoma (HCC). We aimed to investigate the association between statin initiation and the risk of HCC among patients with NAFLD. In this study using the Optum de-identified Clinformatics database, Cox proportional hazards regression model was performed to determine the risk of HCC in statin initiators versus nonusers. We incorporated inverse probability of treatment weighting (IPTW) to minimize potential confounding. Among 272,431 adults with NAFLD diagnosis, IPTW model shows that statin initiators had 53% less risk of developing HCC compared with nonusers (hazard ratio [HR], 0.47; 95% confidence interval, 0.36-0.60). In the subcohort with fibrosis-4 index data available, statin initiation was associated with 56% hazard reduction of developing HCC in NAFLD after adjusting for fibrosis-4 index score (HR, 0.44; 0.30-0.65). The association between statin initiation and lower risk of HCC development was observed for both lipophilic statin (HR, 0.49; 0.37-0.65) and hydrophilic statin (HR, 0.40; 0.21-0.76). Moreover, we observed greater hazards reduction as the dose and duration of statin use increased. NAFLD patients with more than 600 cumulative defined daily doses of statin had 70% reduction in hazards of developing HCC (HR, 0.30; 0.20-0.43). Our study provides strong evidence for the association between statin initiation and reduced risk of HCC development in NAFLD patients. These findings imply that statin can be used as a protective medication for NAFLD patients to reduce the risk of HCC.


The Sertoli cell hormones inhibin-B and anti Müllerian hormone have different patterns of secretion in prepubertal cryptorchid boys.
The Sertoli-cells produce inhibin-B and Anti-Müllerian-Hormone (AMH). Much is still unknown about these hormones in prepubertal cryptorchids. The Sertoli-cells are mandatory for germ cell development. The aim of the study was to investigate if there are differences in secretion pattern of Sertoli-cell hormones and their gonadotropin feed-back mechanisms. Included were 94 prepubertal cryptorchid boys 0.5-13.1years with measurements of serum-inhibin-B, Anti-Müllerian-Hormone (AMH), Luteinizing Hormone (LH) and Follicle Stimulation Hormone (FSH). The serum values were measured using commercially available kits. The hormonal values were related to age-matched normal values. Testicular biopsy was taken at orchiopexy. Inhibin-B positively correlated to AMH for 1-13year-old patients (p<0.0001), but not for 0.5-1year-old patients (p=0.439). For 0.5-1year-old patients inhibin-B-values tended to decrease (p=0.055), in contrast to AMH-values (p=0.852). LH was elevated more often than FSH (p=0.014). FSH and LH were positively associated in patients both 0.5-1year (p=0.042) and 1-13years of age (p<0.0001). LH correlated positively to inhibin- B (p=0.001). In contrast, FSH did not correlate to inhibin-B or AMH (p=0.755 and p=0.528). The number of A-dark spermatogonia per tubular transverse section was positively correlated to inhibin-B serum level. Our new finding of an association between LH and inhibin-B in infancy of cryptorchid boys may be essential for the transformation of gonocytes to A-dark spermatogonia. Previously, LH associated to inhibin-B was described in early puberty only. During the first year of life inhibin-B values decreased faster than AMH. The AMH-levels may just reflect the increased Sertoli cell number that occurs during the first 3months of life.


The development and measurement properties of the trauma NOn-TECHnical skills (T-NOTECHS) scale: A scoping review.
Conduct a scoping review to critically appraise the development and summarize the evidence on the measurement properties of T-NOTECHS including sensibility, reliability, and validity. A literature search was performed using Pubmed and Ovid databases. Studies that described the development process of T-NOTECHS and primary studies that presented evidence of reliability and validity were identified and included. Measurement properties of T-NOTECHS was assessed and summarized under the following: scale development, sensibility, reliability, and validity. The literature search yielded 245 articles with 24 studies meeting inclusion criteria. The T-NOTECHS was developed with an acceptable robust methodology. It has good sensibility with adequate content, face validity, and feasibility. It is a reliable measure of non-technical skills in the setting of trauma video review, which improves with expert raters or extensive training. The T-NOTECHS is a valid discriminative and evaluative instrument that measures non-technical skills of multidisciplinary trauma teams. T-NOTECHS provides reliable and valid measurements of non-technical skills of trauma teams, particularly when assessing trauma video review and non-technical skills training interventions by expert raters.


Prevention of endophthalmitis by intraocular solution filtration and antibiotics.
Gentamicin sulfate was used in a millipore-filtered irrigating solution for 12,000 cases of anterior segment surgery (extracapsular cataract extraction with posterior chamber lens implantation) without one occurrence of endophthalmitis. One instance of endophthalmitis occurred in eight cases in which unfiltered gentamicin sulfate solution was used. No side effects have been associated with the use of the millipore-filtered irrigating solution.


The rat alpha1, 3-fucosyltransferase (rFucT-IV) gene encodes both long and short forms of the enzyme which share the same intracellular location.
Fucosyltransferase (FucT) activity has been detected on the surface of mouse germ cells and rat Sertoli cells, and has been postulated to play a role in cell-cell interactions. A recently cloned rat FucT (rFucT-IV) is expressed in the testes, and thus is a candidate for encoding the cell-surface FucT activity. This study maps the 5'-ends of several rFuc-T-IV mRNAs, and these results suggest that initiation of transcription may occur both upstream of the first ATG, as well as between the first two closely spaced, in-frame ATGs. Thus, in certain tissues, notably spleen, significant amounts of both a long and a short form of rFucT-IV would be predicted. This study also determines some basic properties of both the long and short forms of rFucT-IV, and investigates whether the use of alternative ATGs would allow FucT activity to be expressed both on the cell surface and in the Golgi. Plasmids that encode FLAG-epitope-labeled rFucT-IVs that initiate from either of the two ATGs were constructed, and rFucT-IV was expressed either in vitro using cell-free rabbit reticulocyte lysate, or after transfection in tissue culture. The results from these studies demonstrate that rFucT-IV is a glycosylated, transmembrane protein with a short cytoplasmic tail, and that either of the two ATGs in the 5' region of the rFucT-IV gene are capable of acting as functional initiators of translation in vitro, to produce enzymatically active glycoproteins. However, no difference in the intracellular localization between the transferase containing a 48 amino acid or a 15 amino acid cytoplasmic tail was detected by immunocytochemistry, as both show the same pattern of Golgi-like staining in several different cell types, with no indication of surface expression. Thus, the additional amino-terminal 33 amino acids of the long form of rFucT-IV do not appear to influence its intracellular location in the cell types investigated.


Treatment of androgenetic alopecia by exosomes secreted from hair papilla cells and the intervention effect of LTF.
Androgenetic alopecia (AGA) is the most common cause of chronic progressive hair loss in men, and AGA has a severe negative impact on the quality of life and physical and mental health of patients. Four female C57BL/6 mice were isolated from DP cells in culture (≤4 generations) after stimulation of DPC proliferation by herbal concentrations obtained by the CCK-8 method, and exosomes were isolated by differential centrifugation at low temperature. Testosterone propionate and topical hair removal treatments were used together to establish the C57BL/6 mouse AGA model, which was treated with LTF, 5% minoxidil, and LTF-DPC-EXO, respectively. ELISA was used to detect serum hormone levels, in vivo tracing was used to observe dynamic changes in exosomes, H&E staining showed changes in mouse hair follicle tissue, and (q) RT-PCR and WB were used to detect dorsal skin VEGF, AKT1, and CASP3 expression in dorsal skin tissues. Hair regeneration was significant in the LTF group, minoxidil group, and LTF-DPC-EXO group mice, and the hair growth was only seen in the local skin in the model group. The hormone T in all treatment groups was lower than that in the model group, and e2 was higher than that in the model group. (q) RT-PCR and western blot showed that VEGF and AKT1 expressions were upregulated and Caspase3 expression was downregulated in the skin sections of mice in the treatment groups. DPC-EXO obtained through LTF may activate AKT1 and VEGF in the PI3K/AKT signaling pathway to inhibit CASP3, thereby protecting DPC to restore the hair growth.


Body distribution of poly-DL-lactide-poly(ethylene glycol) microspheres with entrapped leptospira interrogans antigens following intravenous and oral administration to guinea-pigs.
Poly-DL-lactide-poly(ethylene glycol) (PELA) microspheres with entrapped antigens were administered intravenously and orally into guinea-pigs to quantitatively determine the in-vivo distribution and release profiles. PELA microspheres containing 125I-labelled outer-membrane protein Leptospira interrogans antigens (125I-OMP) were prepared by double-emulsion solvent extraction procedure, and characterized with respect to size, morphology and in-vitro release profiles. The fractured sections of liver and spleen were inspected by scanning electron microscopy, which indicated that microspheres had successfully been entrapped within the above tissues after intravenous injection and oral administration. At predetermined intervals, the blood and such tissues as the liver, spleen, kidney, thyroid, small intestine and mesentery were collected, and the radioactivity was measured by gamma scintillation counting. Following intravenous administration, 56.7% of administered microspheres were accumulated in immunization-related tissues, and 40.1% of microspheres were located in the liver and spleen. However, there was limited uptake efficiency (8.33%) following oral administration, and 49.5% of the absorbed microspheres were located in the intestinal mucosa. Compared with in-vitro release, the in-vivo release profiles of 125I-OMP from PELA microspheres, determined from the decreasing radioactivity in the above tissues, were much faster and the burst effect was higher. Antigen-loaded PELA microspheres were efficiently entrapped within immunization-related tissues after intravenous administration, but orally administered PELA microspheres showed limited uptake efficiency. Further investigation is needed to improve intestinal absorption.


Expression of the breast cancer resistance protein in breast cancer.
The breast cancer resistance protein (BCRP) is involved in in vitro multidrug resistance and was first identified in the breast cancer cell line MCF7/AdrVp. The aim of this study was to investigate the role of BCRP in resistance of breast cancer to anthracycline treatment. BCRP mRNA was determined with real-time reverse transcription-PCR and immunostaining in nine breast cancer cell lines and in samples of 25 primary breast carcinomas and 27 patients who received preoperative anthracycline-based therapy. Tumor response to treatment and patient survival were recorded. In cell lines, only MCF7 and BT20 had BCRP mRNA levels coinciding with membrane-bound immunostaining. In clinical samples, BCRP expression varied widely (range, 0.01-0.86). With immunohistochemistry, BCRP was detected in vessels and normal breast epithelium but not in tumor cells. There was no difference in BCRP expression between anthracycline-naïve and treated tumor samples. BCRP expression was not associated with decreased response or survival. There is no indication that elevated BCRP expression in breast carcinomas confers resistance to anthracyclines. Expression was not detectable with immunohistochemistry.


Quantitative autoradiographic localization of cholecystokinin receptors in rat and guinea pig brain using 125I-Bolton-Hunter-CCK8.
The autoradiographic localization of receptors for the brain-gut peptide cholecystokinin (CCK) has shown differences in receptor distribution between rat and guinea pig brain. However the full anatomical extent of the differences has not been determined quantitatively. In the present study, 125I-Bolton-Hunter-CCK8 (125I-BH-CCK8) was employed in a comparative quantitative autoradiographic analysis of the distribution of CCK receptors in these two species. The pharmacological profile of 125I-BH-CCK8 binding in guinea pig forebrain sections was comparable to those previously reported for rat and human. Statistically significant differences in receptor binding between rat and guinea pig occurred in olfactory bulb, caudate-putamen, amygdala, several cortical areas, ventromedial hypothalamus, cerebellum, and a number of midbrain and brainstem nuclei. The results of this study confirm the presence of extensive species-specific variation in the distribution of CCK receptors, suggesting possible differences in the physiological roles of this peptide in different mammalian species.


A microcomputer system for long term monitoring, collecting, analyzing and reporting noninvasive oxygen saturation.
The characteristics of a microcomputer based system for long term monitoring, collecting, analyzing and reporting oxygen saturation are described. Every two seconds SaO2 is transmitted to the microcomputer via the serial port of the oximeter and verified by the program. The microcomputer's real time display and internal data structures are updated. At the end of the data collection period, accumulated data is stored to disk. Report generation modules calculate summary statistics and generate graphs depicting the cumulative time distribution of SaO2, the frequency distribution of SaO2, and an hour by hour representation of the real time display. This inexpensive microcomputer based system allows accurate collection and timely presentation of oxygen saturation levels with monitoring periods of any length replacing tedius and time consuming manual recording, digitizing and analysis.


Prevalence of HFE mutations in California newborns.
Advances in molecular diagnostics have led to an increased interest in expanding population-based screening to include genetic diseases that occur outside the newborn period. Hereditary hemochromatosis may be a candidate for large-scale screening in populations with a high prevalence of the common HFE mutations. To determine race-specific frequencies of the HFE mutations, C282Y and H63D, the authors applied an automated, high-throughput genotyping method to dried blood spot samples from a representative population of California newborns. In this sample of 3989 newborns, C282Y and H63D allele frequencies were highest in white (C282Y: 5.5 +/- 0.5%; H63D: 13.4 +/- 0.76%) and Hispanic (C282Y: 1.8 +/- 0.29%; H63D: 11.9 +/- 0.72%) newborns, and lowest in black (C282Y: 1.3 +/- 0.25%; H63D: 3.0 +/- 0.38%) and Asian (C282Y 0.5 +/- 0.16%; H63D 2.9 +/- 0.37%) newborns. The estimated prevalence of C282Y homozygotes in this multiracial population is 1.4/1000. As additional genetic and environmental risk factors for HHC are identified, neonatal screening may become an acceptable strategy to follow susceptible individuals and prevent clinical disease.


Surgical correction of penoscrotal transposition associated with hypospadias and bifid scrotum: our experience of two-stage repair.
To assess the results of surgical correction of incomplete penoscrotal transposition and bifid scrotum using the Glenn-Anderson technique, and its impact on subsequent definitive urethroplasties and final outcome. We retrospectively reviewed 31 children that underwent two-stage repair for incomplete penoscrotal transposition with severe hypospadias and bifid scrotum. Patient age at stage 1 ranged from 12 to 24 months (average 16 months). The operative principle was based on achieving a normal anatomical position of the penis and scrotum using the Glenn-Anderson technique. In cases with associated scrotal or perineal hypospadias this was transformed into a penoscrotal hypospadias. Final stage urethroplasty was performed after a period of 6 months with a modified Thiersch-Duplay technique. Cosmetic and functional results of the Glenn-Anderson operation were excellent. No major complications were observed. Of 31 patients, 12 (38%) had complications secondary to urethral repair. The Glenn-Anderson technique for reconstruction of penoscrotal transposition and bifid scrotum is a simple technique, free of major complications. The purpose of this intervention is to improve the cosmetic appearance and function of the penis. A minimum period of 6 months between consecutive urethroplasties is important. The final stage guarantees good functional and cosmetic results preserving the prepuce.


Structure-specific DNA replication-fork recognition directs helicase and replication restart activities of the PriA helicase.
DNA replication restart, the essential process that reinitiates prematurely terminated genome replication reactions, relies on exquisitely specific recognition of abandoned DNA replication-fork structures. The PriA DNA helicase mediates this process in bacteria through mechanisms that remain poorly defined. We report the crystal structure of a PriA/replication-fork complex, which resolves leading-strand duplex DNA bound to the protein. Interaction with PriA unpairs one end of the DNA and sequesters the 3'-most nucleotide from the nascent leading strand into a conserved protein pocket. Cross-linking studies reveal a surface on the winged-helix domain of PriA that binds to parental duplex DNA. Deleting the winged-helix domain alters PriA's structure-specific DNA unwinding properties and impairs its activity in vivo. Our observations lead to a model in which coordinated parental-, leading-, and lagging-strand DNA binding provide PriA with the structural specificity needed to act on abandoned DNA replication forks.


Diabetes and the outcome of infrainguinal bypass for critical limb ischaemia.
To examine the influence of diabetes mellitus (DM) on the outcome of infrainguinal bypass operations performed for critical foot ischaemia in Chinese patients. A prospective audit of 265 consecutive infrainguinal bypass operations. Diabetic patients suffered more frequently from ischaemic heart disease (48% vs 25%, P=0.001) and tissue loss (90% vs 79%, P=0.01) at presentation. Cigarette smoking was more prevalent in the non-diabetic (NDM) group (72% vs 51%, P=0.001). Arterial segments distal to the common femoral artery were more often used as inflow to bypass graft in DM patients (36% vs 22%, P=0.02). Operative mortality (seven DM vs one NDM, P=0.19). Early graft failure (7% in DM group vs 10% in NDM group, P=0.24), wound infection rate (24% in DM group vs 17% in NDM group, P=0.21), early limb loss (9% in DM group vs 6% in NDM group, P=0.66) were comparable. However, hospital mortality was higher in DM patients (8% vs 1%, P=0.04). DM patients more frequently required further surgical debridement postoperatively (20% vs 9%, P=0.04). Long-term, patient survival was inferior in the DM group (43% NDM vs 33% DM at 5 years, P=0.03). Primary graft patency (46% DM vs 34% NDM at 4 years P=0.19), secondary graft patency (57% DM vs 47% NDM at 4 years P=0.14) and limb salvage rate (78% vs 81% at 5 years, P=0.79) were comparable. Diabetes mellitus adversely affects hospital mortality and long-term survival. Graft patency and limb salvage are not compromised by the presence of DM.


Medical practice and anthropological bias.
The purpose of this article is twofold: to describe some of the biases common to anthropological investigations of healing, particularly Biomedical healing; and to suggest that the physician-anthropologist is uniquely positioned to avoid some of these biases and to make valid contributions to the understanding of the practice of healing. Biases described are methodological (the tendency to formal-symbolic analyses rather than practical-instrumental understanding of behavior, transference and the observer effect), ontological (due to the estrangement of the anthropologist from his culture, other disciplines and his subjects, romanticization of the Other and celebration of the exotic over the mundane), and conventional or stylistic (the minimal importance given to emotional or psychological aspects of behavior, the emphasis on visual and linguistic understanding over other forms of investigation, unsophisticated use of medical texts as an indicator of clinical practice, a characteristic mode of reductionism, and the failure to elicit the responses of the subjects to interpretations made by anthropologists). As native-ethnographer, the M.D./Ph.D. physician-anthropologist may avoid some of these biases and offer complementary interpretations of healing.


Integrative analysis of metabolome and transcriptome profiles to highlight aroma determinants in Aglianico and Falanghina grape berries.
The biochemical makeup of grape berries at harvest is essential for wine quality and depends on a fine transcriptional regulation occurring during berry development. In this study, we conducted a comprehensive survey of transcriptomic and metabolomic changes occurring in different berry tissues and developmental stages of the ancient grapes Aglianico and Falanghina to establish the patterns of the secondary metabolites contributing to their wine aroma and investigate the underlying transcriptional regulation. Over two hundred genes related to aroma were found, of which 107 were differentially expressed in Aglianico and 99 in Falanghina. Similarly, 68 volatiles and 34 precursors were profiled in the same samples. Our results showed a large extent of transcriptomic and metabolomic changes at the level of isoprenoids (terpenes, norisoprenoids), green leaf volatiles (GLVs), and amino acid pathways, although the terpenoid metabolism was the most distinctive for Aglianico, and GLVs for Falanghina. Co-expression analysis that integrated metabolome and transcriptome data pinpointed 25 hub genes as points of biological interest in defining the metabolic patterns observed. Among them, three hub genes encoding for terpenes synthases (VvTPS26, VvTPS54, VvTPS68) in Aglianico and one for a GDP-L-galactose phosphorylase (VvGFP) in Falanghina were selected as potential active player underlying the aroma typicity of the two grapes. Our data improve the understanding of the regulation of aroma-related biosynthetic pathways of Aglianico and Falanghina and provide valuable metabolomic and transcriptomic resources for future studies in these varieties.


T cell responses to Chlamydia trachomatis.
Chlamydia trachomatis is the most common cause of bacterial sexually transmitted disease in the United States, as well as the leading cause of preventable blindness worldwide. Immunity to C. trachomatis requires a variety of cell types, each employing an array of effector functions. Recent work has demonstrated that both CD4+ and CD8+ T lymphocytes play a major role in protective immunity to C. trachomatis, predominantly through their secretion of interferon-gamma. This review describes the generation of acquired immunity to C. trachomatis and focuses on how T cells contribute to both protection and immunopathology.


Breast reconstruction using DIEP flap: The free flap alone be enough? Quality of life and satisfaction analysis after complementary surgeries.
Breast reconstruction using Deep Inferior Epigastric Perforator (DIEP) flap involves complementary surgeries such as lipofilling, symmetrization, and nipple-areolar complex (NAC) reconstruction. Their role and impact have not been explored yet after the DIEP flap use. A retrospective study was performed to evaluate the impact of complementary surgeries on the quality of life of 75 patients after DIEP flap breast reconstruction between 2012 and 2021, comparing the BREAST-Q© score of two groups, patients with DIEP flap only reconstruction and patients with DIEP flap and additional surgeries. Satisfaction for each surgery was assessed using a numeric visual scale on five dimensions (esthetic, self-image, confidence in society, pain, and intimate relationship). Complications and healthcare pathways were also recorded. Psychosocial well-being (Q1 BREAST-Q©), satisfaction with medical team (Q9) and with surgeon (Q11) was superior in group 2 (p = 0041, p = 0.001 and p = 0.001 respectively). NAC reconstruction improved BREAST-Q© (p = 0029) by regression analysis and was deemed indispensable by 64% of the patients. An important satisfaction is observed after each surgery (DIEP flap, symmetrization, lipofilling and NAC reconstruction). Complications were uncommon (0-4%) for lipofilling and NAC reconstruction and notable but harmless for symmetrization (wound dressings more than a month in 17%). Complementary surgeries, especially NAC reconstruction, improved BREAST-Q© score, and have a major impact on satisfaction with minor complications. These surgeries should always be proposed to the patients to assess a satisfactory breast reconstruction using DIEP flap.


Effect of bexarotene on differentiation of glioblastoma multiforme compared with ATRA.
Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor. Since differentiation can attenuate or halt the growth of tumor cells, an image-based phenotypic screening was performed to find out drugs inducing morphological differentiation of GBMs. Bexarotene, a selective retinoid X receptor agonist, showed strong inhibition of neurospheroidal colony formation and migration of cultured primary GBM cells. Bexarotene treatment reduced nestin expression, while significantly increasing glial fibrillary acidic protein (GFAP) expression. The effect of bexarotene on gene expression profile was compared with the activity of all-trans retinoic acid (ATRA), a well-known differentiation inducer. Both drugs largely altered the gene expression pattern into a tumor-ameliorating direction. These drugs increased the gene expression levels of Krüppel-like factor 9 (KLF9), regulator of G-protein signaling 4 (RGS4), growth differentiation factor 15 (GDF15), angiopoietin-like protein 4 (ANGPTL4), and lowered the level of chemokine receptor type 4 (CXCR4). However, transglutaminase 2 (TG2) induction, an adverse effect of ATRA, was much weaker in bexarotene treated primary GBM cells. Consistently, the TG2 enzymatic activity was negligibly affected by bexarotene treatment. It is important to control TG2 overexpression since its upregulation is correlated with tumor transformation and drug resistance. Bexarotene also showed in vivo tumoricidal effects in a GBM xenograft mouse model. Therefore, we suggest bexarotene as a more beneficial differentiation agent than ATRA for GBM.


Association between use of self-prescribed complementary and alternative medicine and menopause-related symptoms: a cross-sectional study.
To examine the association between self-prescribed complementary and alternative medicine use and menopause-related symptoms, stratified by menopausal status. Data were obtained from a cross-sectional survey of a nationally representative sample of 10,011 menopausal women from the Australian Longitudinal Study on Women's Health, conducted in 2010. Multivariable logistic regression models were applied to identify if the use of selected self-prescribed complementary and alternative medicine was significantly associated with a range of menopause-related symptoms. Vitamins/minerals were more likely to be used by natural menopausal women experiencing anxiety (adjusted OR=1.20) and/or stiff/painful joints (adjusted OR=1.16). Yoga/meditation was more likely to be used by women with hysterectomy (adjusted OR=1.76) or natural menopausal women (adjusted OR=1.38) experiencing anxiety. Herbal medicines were more likely to be used by natural menopausal women experiencing anxiety (adjusted OR=1.22), tiredness (adjusted OR=1.20), and/or stiff/painful joints (adjusted OR=1.17), and by women with oophorectomy experiencing tiredness (adjusted OR=1.45). Aromatherapy oils were more likely to be used by natural menopausal women experiencing night sweats (adjusted OR=1.25) and by women with hysterectomy experiencing anxiety (adjusted OR=2.02). Chinese medicines were more likely to be used by women with oophorectomy experiencing stiff/painful joints (adjusted OR=4.06) and/or palpitations (adjusted OR=3.06). Our study will help improve the patient-provider communication regarding complementary and alternative medicine use for menopause, and we conclude that menopausal status should be taken into account by providers for menopause care. The women's experience and motivations of such use warrant further research.


Distribution of vasoactive intestinal polypeptide-like immunoreactivity in the olfactory bulb of the rainbow trout (Salmo gairdneri).
The distribution of vasoactive intestinal polypeptide-like structures in the olfactory bulb of the rainbow trout was studied using an indirect-immunoperoxidase technique. Olfactory fibres were very strongly labelled, whereas the fibres or cell bodies in the remaining strata of the olfactory bulb showed no immunoreactivity. In addition, the olfactory nerve fibres were not immunoreactive for methionine- and leucine-enkephalins, motilin, neuropeptide Y, substance P, cholecystokinin-8 and tyrosine-hydroxylase.


Propagation of histone marks and epigenetic memory during normal and interrupted DNA replication.
Although all nucleated cells within a multicellular organism contain a complete copy of the genome, cell identity relies on the expression of a specific subset of genes. Therefore, when cells divide they must not only copy their genome to their daughters, but also ensure that the pattern of gene expression present before division is restored. While the carrier of this epigenetic memory has been a topic of much research and debate, post-translational modifications of histone proteins have emerged in the vanguard of candidates. In this paper we examine the mechanisms by which histone post-translational modifications are propagated through DNA replication and cell division, and we critically examine the evidence that they can also act as vectors of epigenetic memory. Finally, we consider ways in which epigenetic memory might be disrupted by interfering with the mechanisms of DNA replication.


Factors related to performance-based mobility and self-reported physical activity in individuals 1-3 years after stroke: a cross-sectional cohort study.
Low mobility and low level of physical activity is common after stroke. The objective of this study was to relate these outcomes to physical, psychological, and demographic determinants. In this cross-sectional cohort study, a consecutive sample of 195 community-living individuals, 65-85 years of age (74±5 years, 71% men) with a previous stroke was included. Exclusion criteria were severe aphasia and severe cognitive dysfunction. Mobility status was measured by the Short Physical Performance Battery (SPPB, 0-12 points), and physical activity was measured using the Physical Activity Scale for the Elderly (PASE). Mobility (SPPB, median 9 points) and level of physical activity were low (mean PASE 97±66 points), and walking speed was slow (1.10±.86 m/s), in relation to a healthy population-based sample. In multiple regression analyses, age (P=.001), physical activity (P<.001), fall-related self-efficacy (P=.001), and health-related quality of life (HRQoL) (P=.02) were associated with mobility (SPPB). Mobility (P<.001), HRQoL (P=.014), and fall-related self-efficacy (P=.031) were likewise associated with self-reported physical activity as the dependent variable. The regression models described 42% and 31% of the variance in mobility and physical activity, respectively. Individuals perceived disabilities that are partly potentially modifiable 1-3 years after stroke. Future poststroke rehabilitation studies need to evaluate if actions to improve fall-related self-efficacy and mobility could promote the physical activity level in this patient population.


UK survey of attitudes to local anaesthesia for vitreoretinal surgery.
The use of local anaesthesia (LA) for vitreoretinal (VR) surgery is growing although surgeons in the UK traditionally use general anaesthesia. To assess the use and attitudes towards local anaesthesia for VR surgery among the members of the British and Eire Association of Vitreo-retinal Surgeons (BEAVRS). A questionnaire was sent to members of BEAVRS. Use of LA was assessed for the following procedures: macular hole; diabetic vitrectomy; vitrectomy; cryopexy and gas; buckling and re-buckling procedures. Attitudes of surgeons generally using LA for primary retinal detachment surgery (> 50% of cases) were compared with those generally using general anaesthesia (GA) (> 50% of cases). 33.6% of surgeons preferred LA for macular hole; 26.2% for diabetic vitrectomy; 23.3% for vitrectomy, cryopexy and gas; 21.4% for buckling procedures; and 9.35% for re-buckling procedures. When surgeons routinely using LA were compared with those regularly using GA they considered LA less stressful for patients and surgeon, patients tolerant to longer operations, and buckling or redo surgery no more difficult under LA. However, both groups considered surgery on young patients and teaching relatively more difficult under LA. The use of LA may convey benefits for VR surgery and faster rehabilitation for patients. However, we identified wide variations in the use of and attitudes to LA for VR surgery in British surgeons.


[Gastroduodenal ulcer: resection procedures (author's transl)].
In recent years vagotomy has become more and more prefered in ulcer surgery. Based on the results of prospective trials, gastric resection should be abandoned as treatment of uncomplicated duodenal ulcer. Resections are still indicated for most ulcer complications, such as bleeding, penetration of chronic ulcer, and in recurrent ulcers after vagotomy. The same is true for gastric ulcer type I. Questionnaires indicate, however, that German surgeons still favor the two-thirds resection.


Cisplatin-induced nephrotoxicity and targets of nephroprotection: an update.
Cisplatin is a highly effective antitumor agent whose clinical application is limited by the inherent nephrotoxicity. The current measures of nephroprotection used in patients receiving cisplatin are not satisfactory, and studies have focused on the investigation of new possible protective strategies. Many pathways involved in cisplatin nephrotoxicity have been delineated and proposed as targets for nephroprotection, and many new potentially protective agents have been reported. The multiple pathways which lead to renal damage and renal cell death have points of convergence and share some common modulators. The most frequent event among all the described pathways is the oxidative stress that acts as both a trigger and a result. The most exploited pathways, the proposed protective strategies, the achievements obtained so far as well as conflicting data are summarized and discussed in this review, providing a general view of the knowledge accumulated with past and recent research on this subject.


Buyang Huanwu Decoction promotes angiogenesis in myocardial infarction through suppression of PTEN and activation of the PI3K/Akt signalling pathway.
Myocardial infarction (MI) is the most severe subtype of coronary artery disease. Recent studies have demonstrated that the repair process and prognosis of MI are closely related to microcirculatory function in myocardial tissue. Buyang Huanwu Decoction (BYHWD) has shown great potential in the treatment of MI. However, the effects and mechanisms of BYHWD on angiogenesis post-MI remain unclear. The study aimed to explore the promotion of angiogenesis by BYHWD post-MI and the potential mechanisms in vivo and in vitro. MI in mice was induced by permanent ligature of the coronary artery. The sample was divided into sham, model, and BYHWD treatment groups. After four weeks, the effects of BYHWD treatment on cardiac function were evaluated by echocardiography and HE and Masson staining. Angiogenesis was detected by CD 31 immunofluorescence staining in vivo. Then, various databases were searched to identify the corresponding targets of BYHWD in order to explore the molecular mechanisms underlying its effects in MI. Moreover, Western blot and immunohistochemistry were employed to measure the PTEN/PI3K/Akt/GSK3β signalling pathway and VEGFA expression in MI mice. Finally, the effects of BYHWD on cell angiogenesis and the activation of the PTEN/PI3K/Akt/GSK3β pathway in primary HUVECs were investigated. Overexpression of PTEN was achieved by an adenovirus vector encoding PTEN. BYHWD significantly promoted angiogenesis and improved cardiac function in MI mice. Target prediction analysis suggested that BYHWD ameliorates MI via the PI3K/Akt pathway. BYHWD promoted angiogenesis post-MI by suppressing PTEN and activating the PI3K/Akt/GSK3β signalling pathway in vivo and in vitro. Moreover, the effects of BYHWD on HUVEC angiogenesis and the expression of PI3K/Akt/GSK3β signalling pathway-associated proteins were partially abrogated by the overexpression of PTEN. Collectively, this study demonstrates that BYHWD exerts cardioprotective effects against MI by targeting angiogenesis. These effects are related to suppressing PTEN and activating the PI3K/Akt/GSK3β signalling pathway by BYHWD.


Comparative porphyrin content in tumors with contiguous non-neoplastic tissues.
The porphyrin content in primary human carcinomas, their metastases and the contiguous non-neoplastic tissues were compared. The level of porphyrins in primary internal organ tumors was greater, and in endocrine gland tumors lesser, than in their contiguous non-neoplastic tissues. Neoplastic metastases to the liver contained less porphyrin than the host tissue. Metastases both to the liver and to the kidney were characterized by higher pyrrole pigment content than that in the primary tumors.


Nalmefene combined noninvasive positive-pressure ventilation in Chinese patients with chronic obstructive pulmonary disease coupled with type II respiratory failure: A meta-analysis.
Nalmefene is an opioid system modulator with antagonist activity at the μ and δ receptors and partial agonist activity at the κ receptor. Previous studies have suggested that nalmefene could improve respiratory function in patients with chronic obstructive pulmonary disease (COPD). However, there is no comprehensive systematic review published regarding the clinical efficacy of nalmefene. We explored the following electronic bibliographic databases: EMBASE, Web of Science, PubMed, Wanfang, and Chinese national knowledge infrastructure. To collect data from randomized controlled trials on the therapy of COPD coupled with type II respiratory failure and nalmefene + noninvasive ventilator treatment. The retrieved articles were screened to determine the final inclusion criteria and to extract relevant data, such as the clinical efficacy rate, pulmonary function, blood gas analysis, and adverse reactions. In our study, we used relative risk and weighted mean deviation, as well as a 95% confidence interval for describing nalmefene effectiveness and safety while treating COPD with type II respiratory failure. The outcomes of the meta-analysis demonstrated that the clinical efficacy rate of the nalmefene + noninvasive ventilation group was higher than that of the naloxone + noninvasive ventilation and noninvasive ventilation groups. Moreover, the improvement indices of pH value, partial pressure and saturation of blood oxygen, partial pressure of carbon dioxide, and pulmonary function of the nalmefene + noninvasive ventilation group were better than those of the noninvasive ventilation group, and there was no increase in the occurrence of adverse drug reactions. Nalmefene combined with noninvasive ventilation can significantly improve the blood gas index and lung function in patients with COPD combined with type II respiratory failure.


Assessment of antioxidant reserves and oxidative stress in cerebrospinal fluid after severe traumatic brain injury in infants and children.
Studies in experimental traumatic brain injury (TBI) support a key role for oxidative stress. The degree of oxidative injury in clinical TBI, however, remains to be defined. We assessed antioxidant defenses and oxidative stress in pediatric TBI by applying a comprehensive battery of assays to cerebrospinal fluid samples. Using a protocol approved by our institutional review board, 87 cerebrospinal fluid samples from 11 infants and children with severe TBI (Glasgow Coma Scale score < or = 8) and 8 controls were studied. Cerebrospinal fluid was drained as standard care after TBI. CSF was assessed on d 1, 2, and 5-7 after ventricular drain placement. Biochemical markers of oxidative stress included F(2)-isoprostane and protein sulfhydryl (detected by ELISA and fluorescence assay, respectively). Antioxidant defenses were measured by determination of total antioxidant reserve (via chemiluminescence assay), and ascorbate (via HPLC) and glutathione (via fluorescence assay) concentrations. Free radical production (ascorbate radical) was assessed by electron paramagnetic resonance spectroscopy. F(2)-isoprostane was markedly increased versus control, maximal on d 1 (93.8 +/- 30.8 pg/mL versus 7.6 +/- 5.1 pg/mL, p < 0.05). Total antioxidant reserve was reduced versus control. Reduction was maximal on d 5-7 (81.8 +/- 3.7 microM versus 178.9 +/- 2.2 microM, p < 0.05). Ascorbate was remarkably reduced (53.8 +/- 8 microM versus 163.8 +/- 21 microM on d 1, p < 0.05). Ascorbate depletion was likely associated with its free radical oxidation, as evidenced by electron paramagnetic resonance spectroscopy. Glutathione levels increased on d 1, then decreased versus control (0.19 +/- 0.05 microM versus 1.2 +/- 0.16 microM, p < 0.05). This is the first comprehensive study of antioxidant reserve and oxidative injury in clinical TBI. Progressive compromise of antioxidant defenses and evidence of free radical-mediated lipid peroxidation are noted. These markers could be used to monitor antioxidant strategies in clinical trials.


A small molecule targeting the interaction between human papillomavirus E7 oncoprotein and cellular phosphatase PTPN14 exerts antitumoral activity in cervical cancer cells.
Human papillomavirus (HPV)-induced cancers still represent a major health issue for worldwide population and lack specific therapeutic regimens. Despite substantial advancements in anti-HPV vaccination, the incidence of HPV-related cancers remains high, thus there is an urgent need for specific anti-HPV drugs. The HPV E7 oncoprotein is a major driver of carcinogenesis that acts by inducing the degradation of several host factors. A target is represented by the cellular phosphatase PTPN14 and its E7-mediated degradation was shown to be crucial in HPV oncogenesis. Here, by exploiting the crystal structure of E7 bound to PTPN14, we performed an in silico screening of small-molecule compounds targeting the C-terminal CR3 domain of E7 involved in the interaction with PTPN14. We discovered a compound able to inhibit the E7/PTPN14 interaction in vitro and to rescue PTPN14 levels in cells, leading to a reduction in viability, proliferation, migration, and cancer-stem cell potential of HPV-positive cervical cancer cells. Mechanistically, as a consequence of PTPN14 rescue, treatment of cancer cells with this compound altered the Yes-associated protein (YAP) nuclear-cytoplasmic shuttling and downstream signaling. Notably, this compound was active against cervical cancer cells transformed by different high-risk (HR)-HPV genotypes indicating a potential broad-spectrum activity. Overall, our study reports the first-in-class inhibitor of E7/PTPN14 interaction and provides the proof-of-principle that pharmacological inhibition of this interaction by small-molecule compounds could be a feasible therapeutic strategy for the development of novel antitumoral drugs specific for HPV-associated cancers.


Classical-like Ehlers-Danlos syndrome: a clinical description of 20 newly identified individuals with evidence of tissue fragility.
Currently, 31 patients with classical-like EDS (clEDS) due to tenascin-X deficiency have been reported in the literature. We report on the clinical and molecular characteristics of 20 additional patients with clEDS to expand knowledge and to enable improved management of this rare genetic disorder. Patients diagnosed with clEDS by the national EDS service in the UK (n = 21) and abroad (n = 1) were asked for consent for publication of their clinical and molecular data. Of 22 patients, 20 consented. All patients had typical features of clEDS: joint hypermobility, easy bruising, and skin hyperextensibility without atrophic scars. Importantly, 3/20 patients experienced gastrointestinal complications consisting of small or large bowel ruptures and one esophageal rupture. Other notable observations included two separate occurrences of spontaneous compartment syndrome, suspicion of nonaccidental injury due to significant bruising, and significant clinical variability regarding the debilitating effect of joint dislocations. We propose a predisposition to tissue fragility, particularly of the gastrointestinal tract in patients with clEDS. As such, clinical and molecular confirmation of this diagnosis is essential. It is recommended to follow up these patients closely to understand the natural history to develop better recommendations for management.


Stereotactic interstitial radiosurgery with a miniature X-ray device in the minimally invasive treatment of selected tumors in the thalamus and the basal Ganglia.
The aim of this study was to evaluate the role of interstitial radiosurgery (IR) using the photon radiosurgery system (PRS) in the treatment of selected tumors within the thalamus and the basal ganglia. The PRS is a miniature X-ray generator that was developed for interstitial irradiation. This series included 14 patients (5 with glioblastomas, 4 with low-grade astrocytomas and 5 with metastases) harboring spheroidal lesions with dimensions ranging from 13 to 42 mm (mean 30 mm). After stereotactic biopsy, a radiation dose ranging from 6 to 15.4 Gy (mean 11.3 Gy) was delivered at the target volume margins. Follow-up varied from 3 to 26 months (mean 10.2 months). In the group of glioblastomas, 3 patients died (3-12 months after the procedure) because of tumor progression, while the remaining had tumor control. Two patients with metastases died from systemic disease (4-9 months after the treatment), and 3 were alive and well at the end of the study. Local control was achieved in all metastases. Patients with low-grade astrocytomas were well and imaging studies showed tumor control PRS IR is a minimally invasive procedure for the treatment of selected glial or secondary brain tumors. Compared to conventional radiosurgery (brachytherapy and external radiosurgery), PRS IR presents dose delivery characteristics useful for the treatment of tumors in the thalamus and basal ganglia, without inconveniences such as handling radioisotopes, the need of expensive facilities and radiation protection measures. Although the clinical value needs further investigations, PRS IR seems to be effective in metastases while it provides less benefit in malignant gliomas. PRS IR could have a major role in the treatment of low-grade astrocytomas.


Pleiotrophin: Activity and mechanism.
Pleiotrophin (PTN) is a potent mitogenic cytokine with a high affinity for the polysaccharide glycosaminoglycan (GAG). Although it is most strongly associated with neural development during embryogenesis and the neonatal period, its expression has also been linked to a plethora of other physiological events including cancer metastasis, angiogenesis, bone development, and inflammation. A considerable amount of research has been carried out to understand the mechanisms by which PTN regulates these events. In particular, PTN has now been shown to bind a diverse collection of receptors including many GAG-containing proteoglycans. These interactions lead to the activation of many intracellular kinases and, ultimately, activation and transformation of cells. Structural studies of PTN in complex with both GAG and domains from its non-proteoglycan receptors reveal a binding mechanism that relies on electrostatic interactions and points to PTN-induced receptor oligomerization as one of the possible ways PTN uses to control cellular functions.


[Conductometric microdosage of blood and urine urea by use of a semi-automatic analyser].
The authors present the principle of a new method of urea estimation based on conductimetry. Its results are compared with those given by the colorimetric method using diacetylmonoxime. Correlation of the results was satisfactory. With the apparatus studied, it was possible to estimate very simply plasma and urinary urea with low volume samples 10 microliter). The titration took 30 seconds.


What's bugging your teen?-The microbiota and adolescent mental health.
Human adolescence is a time of enormous developmental change, second only to infancy and early childhood in terms of brain shaping and growth. It is also a period in life when the young adult is faced with distinct environmental challenges and stressors. Interestingly, we now know that these external sources of stress all have an impact on the intestinal microbiota. Given that there is now a significant body of knowledge indicating a role for the microbiota-gut-brain axis in development and function of the brain, and potentially the emergence of psychiatric illnesses, we need to draw our attention to the intestinal microbiota in the adolescent. As psychiatric illnesses frequently first manifest during the teenage years it may be that the intestinal bacteria are playing an as yet unidentified role in disease pathogenesis. Identifying a role for the microbiota in psychiatric illnesses opens up an exciting opportunity for therapeutic advances via bacterial manipulation. This could prove to be a beneficial and novel avenue for treatment of mental illnesses in the developing teen.


Biotremology.
Animal communication, including that among humans, is fascinating in its efficiency, diversity and its complexity. The evolution of a communication signal requires that the encoded content sent by an organism (sender) is detected and decoded by a receiver, who then must respond in such a way that the fitness of the sender is increased. The signal could be visual, such as bright coloration or some stereotypical movement that attracts attention through the sense of sight. It could be chemical, such as a pheromone we detect by smell or taste, or it could be tactile, involving direct physical touch. It could be an acoustic wave, detected by an auditory organ as sound and perceived through the sense of hearing, or it could be a vibrational wave detected by a vibration receiver of another sort. The medium through which the signal is transmitted could be any that exists on the Earth (solid, liquid or gas), and each type of medium influences the type of signal that is able to most efficiently move through it.


Beta2-adrenoceptor polymorphisms relate to insulin resistance and sympathetic overactivity as early markers of metabolic disease in nonobese, normotensive individuals.
The genes responsible for insulin resistance are also candidate genes for insulin resistance-related diseases, such as obesity and hypertension. Functional polymorphisms in the beta2- and beta3-adrenergic receptors have been reported to be associated with diabetes, hypertension, and obesity. To clarify the relevance of the beta-adrenergic receptor polymorphisms to insulin resistance, we studied their association with polymorphisms of beta2 (Arg16Gly, Gln27Glu) and beta3 (Trp64Arg) adrenoceptor genes. We studied 155 young, nonobese Japanese men using the homeostasis model assessment of insulin resistance (HOMA-IR) to divide individuals into insulin-sensitive and insulin-resistant groups. Insulin resistance in the participants was defined as HOMA-IR equal to or greater than the average plus 1 SD of 3.1. There were 69 men who were insulin resistant and 86 men who were insulin sensitive. Body mass index (BMI), blood pressure (BP), plasma glucose, insulin, leptin, norepinephrine (NE) levels, and the polymorphisms of Arg16Gly and Gln27Glu of the beta2- and Trp64Arg of the beta3-adrenoceptor polymorphisms were measured in all participants. The insulin-resistant group had higher frequency of the Gly16 allele of Arg16Gly compared with the insulin-sensitive group, whereas the frequencies of genotypes or alleles of Gln27Glu and Trp64Arg were similar. The insulin-resistant group had a higher mean HOMA-IR, fasting insulin, NE, and total fat mass compared with levels in the insulin-sensitive group, but the BMI and leptin levels were similar. The subjects carrying the Gly16 allele of the beta2-adrenoceptor gene had a higher mean HOMA-IR, fasting insulin, NE, body fat mass, and BP than those without the Gly16 allele. The Gly16 mutation of the beta2-adrenoceptor gene is associated with increased insulin resistance, adiposity, and BP accompanied by higher plasma NE levels early in the metabolic disease in developing obesity. These findings show an important role of beta2-adrenoceptor gene polymorphisms in the association of insulin resistance in hypertension and obesity.


LAG3 (CD223) and autoimmunity: Emerging evidence.
Immune checkpoint molecules play pivotal roles in maintaining the immune homeostasis. Targeting these molecules, such as the classical Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) and Programmed Cell Death Protein 1 (PD1), achieves great success in treating cancers. However, not all the patients respond well. This urges the immunologists to identify novel immune checkpoint molecules. Lymphocyte activation gene-3 (LAG3; CD223) is a newly identified inhibitory receptor. It is expressed on a variety of immune cells, including CD4+ T cells, CD8+ T cells, Tregs, B cells, and NK cells. Its unique intracellular domains, signaling patterns as well as the striking synergy observed in its targeted therapy with anti-PD1 indicate the important role of LAG3 in maintaining immune tolerance. Currently, a variety of agents targeting LAG3 are in clinical trials, revealing great perspectives in the future immunotherapy. In this review, we briefly summarize the studies on LAG3, including its structure, isoforms, ligands, signaling, function, roles in multiple diseases, as well as the latest targeted therapeutic advances, with particular concern on the potential association of LAG3 with autoimmune diseases.


Quality of life in patients with lower limb ischemia; revised suggestions for analysis.
Quality of life (QoL) is a crucial outcome measure in patients with lower limb ischemia (LLI). The Short Form 36 (SF36) has been proposed as the gold standard instrument for generic QoL analysis in patients with LLI. The Short Form 8 (SF8) was developed from the SF36 and we aim to compare these two instruments in terms of validity, reliability, and responsiveness. One hundred ninety-three patients, 135 men and 58 women, median age 66 (range, 44-84) years with LLI completed the SF36 and the SF8. Disease severity was graded according to International Society of Cardiovascular Surgery (ISCVS) suggested reporting standards. Correlation between the two instruments' like domains and non-like domains reflects convergent and divergent validity respectively. A subgroup of 58 patients (44 men) completed two sets of questionnaires, with an intervening period of 2 weeks. Correlation between these two sets of questionnaires was used to analyze test/retest reliability. Spearman's rank correlation was used to analyze validity and reliability. Responsiveness of the individual domains across the whole group was analyzed using the Kruskall-Wallis analysis of variance (ANOVA) test, while responsiveness between the groups of patients with varying severity of LLI was analyzed using the Mann-Whitney U test. There was greater correlation between like domains of SF36 and the SF8 than the non-like domains suggesting good convergent-divergent validity. Test/retest reliability was significant for both instruments (r(s) > 0.7). Increasing LLI resulted in a statistically significant deterioration in all eight domains of both instruments. The time taken was significantly shorter and less assistance was required to complete the SF8 than the SF36. The SF8 is a valid and reliable QoL instrument in patients with LLI, and as it is simpler and quicker to complete, we suggest it may challenge the SF36 as the gold standard generic QoL analysis instrument in LLI.


Cerebral blood flow before and after cardioversion of atrial fibrillation.
In nine patients with atrial fibrillation (AF) of less than 3 months' duration, CBF was measured the day before and after and again 30 days after electrical cardioversion therapy to sinus rhythm. The day before cardioversion therapy, median CBF (expressed as initial slope index 1, ml/100 g.min-1) was 35.8 and the day after it was 37.1. After 30 days in sinus rhythm, CBF was 39.4 (NS), although the end-tidal PCO2 values were lower than the pretreatment values. After correction for changes in end-tidal PCO2, the median CBF had increased significantly from 35.8 to 40.3 on day 1 and to 46.7 on day 30. The reduced CBF during AF could be a contributing factor in the development of cerebrovascular complications in patients with AF.