[Study on discrimination mode of cold and hot properties of traditional Chinese medicines based on biological effects].
To observe the effect of cold or hot properties of traditional Chinese medicines (TCM) on biological effect indexes, and analyze the contribution of variables on cold or hot properties, in order to preliminarily establish the discrimination mode for the biological effects of cold or hot properties. Rats were randomly divided into the blank control group, cold TCM groups (Coptidis Rhizoma, Scutellariae Radix, Phellodendri Cortex, Gardeniae Fructus, Sophorae Flavescentis Radix and Gentianae Radix) and hot TCM groups (Aconiti Lateralis Preparata Radix, Zingiberis Rhizoma, Alpiniae Officinarum Rhizoma, Zanthoxyli Pericarpium, Cinnamomi Cortex and Evodiae Fructus), and orally administered with 10 mL x kg(-1) of corresponding TCM water decoctions for 30 d, twice a day. Altogether 53 biological effect indexes correlated to cold or hot properties of traditional Chinese medicines were founded by searching literatures. The data warehouse were established by using data-mining software Clementine12.0. Data of the blank control group, cold TCM groups (Coptidis Rhizoma, Phellodendri Cortex, Gardeniae Fructus, Sophorae Flavescentis Radix, Gentianae Radix) and hot TCM groups (Aconiti Lateralis Preparata Radix, Zingiberis Rhizoma, Alpiniae Officinarum Rhizoma, Zanthoxyli Pericarpium, Cinnamomi Cortex) were selected into a training set. C5.0 algorithm and C&R classification and regression algorithm were adopted to define the importance of variable, create the decision trees, and test hot or cold properties of Evodiae Fructus and Scutellariae Radix. According to C&R classification and regression algorithm, SDH activity of livers was the most important hot or cold property, with the significance closed to 30%. It was followed by triglyceride, liver Na' -K' -ATPase enzyme, muscle glycogen and platelet distribution width, with the accuracy up to 97.39% in models. C5.0 algorithm showed that liver SDH activity was the most important hot or cold property, with the significance closed to 40%. It was followed by triglyceride, GOT, muscle glycogen and liver Na(+)-K(+)-ATPase enzyme, with the accuracy up to 98.26% in models. The possibilities that Evodiae Fructus is in hot property and Scutellariae Radix is in cold property were 100. 00% and 77.78% by using both C&R classification and regression algorithm and C5.0 algorithm. The SDH activity of liver is the most important biological effect index to distinguish cold and hot properties of TCMs. The discrimination pathway or mode of cold and hot properties is closely related to energy metabolism.


Association between public cardiopulmonary resuscitation education and the willingness to perform bystander cardiopulmonary resuscitation: a metropolitan citywide survey.
Bystander cardiopulmonary resuscitation (CPR) is an important factor associated with improved survival rates and neurologic prognoses in cases of out-of-hospital cardiac arrest. We assessed how factors related to CPR education including timing of education, period from the most recent education session, and content, affected CPR willingness. In February 2012, trained interviewers conducted an interview survey of 1,000 Daegu citizens through an organized questionnaire. The subjects were aged ≥19 years and were selected by quota sampling. Their social and demographic characteristics, as well as CPR and factors related to CPR education, were investigated. Chi-square tests and multivariate logistic regression analyses were used to evaluate how education-related factors affected the willingness to perform CPR. Of total 1,000 cases, 48.0% were male. The multivariate analyses revealed several factors significantly associated with CPR willingness: didactic plus practice group (adjusted odds ratio [AOR], 3.38; 95% confidence interval [CI], 2.3 to 5.0), group with more than four CPR education session (AOR, 7.68; 95% CI, 3.21 to 18.35), interval of less than 6 months from the last CPR education (AOR, 4.47; 95% CI 1.29 to 15.52), and education with automated external defibrillator (AOR, 5.98; 95% CI 2.30 to 15.53). The following were associated with increased willingness to perform CPR: practice sessions and automated electrical defibrillator training in public CPR education, more frequent CPR training, and shorter time period from the most recent CPR education sessions.


The leucocytosis of exercise. A review and model.
Exercise is known to induce an immediate leucocytosis, the magnitude of which is related, in most instances, to the intensity and duration of the work. On finishing exercise, however, the leucocyte count may change in any one of several different ways. The pattern of postexercise changes in the leucocyte count is determined mainly by the time which has elapsed since beginning exercise, rather than the work intensity or the total work done, if, for example, exercise has been intermittent. Consideration of, firstly, the circumstances under which the plasma concentrations of catecholamines and cortisol have been found separately to correlate with the leucocyte count at the finish of exercise, and, secondly, the effects on the leucocyte count of exogenous administration of these substances has led us to develop a model which can satisfactorily account for all of the principal changes in the leucocyte count that have been noted during and after exercise. It is proposed that catecholamines produced during exercise act to increase the ratio of circulating to non-circulating leucocytes, while cortisol acts, by a mechanism which involves a time lag, to increase the total number of leucocytes in the vascular compartment. Examination of previously published reports shows that many contain results which support this model. Using the model as a basis, some predictions are made that can be tested experimentally, and some experiments are suggested which should help elucidate the mode of action of catecholamines and cortisol.


Current and arc pushing force effects on the synthesis of single-walled carbon nanotubes by arc discharge.
The current and arc pushing force of arcing process effects on the synthesis of single-walled carbon nanotubes were investigated by a temperature-controlled arc discharging furnace with Co-Ni alloy powder as catalyst at 600 degrees C. By experimental investigations, the optimal parameters of the process were obtained. The appropriate conditions included the current and arc pushing force of arcing process was 100 A and 80 A respectively, the buffer gas was helium and the gas pressure was kept at 500 torr. The experimental results indicated that the cooperative function of current and arc pushing force of arcing process played an important role in the production rate and purity of single-walled carbon nanotubes. The uniform diameter of single-walled carbon nanotubes was about 1.27 nm and the production rate was about 7 g/h and the purity was around 70%.


IFNγ expression by an attenuated strain of Salmonella enterica serovar Typhimurium improves vaccine efficacy in susceptible TLR4-defective C3H/HeJ mice.
C3H/HeJ mice carry a mutated allele of TLR4 gene (TLR4 ( d )) and thus are hyporesponsive to the lethal effects of lipopolysaccharide (LPS). Characteristically, however, the mice are also hypersusceptible to infections, particularly by Gram-negative bacteria such as Salmonella enterica serovar Typhimurium (S. typhimurium) and are known to be difficult to vaccinate against virulent exposure. This is observed despite the expression of wild-type allele of Nramp1 gene, another important determinant of Salmonella susceptibility. In contrast, C3H/HeN mice (TLR4 ( n ) Nramp1 ( n )) express a functional TLR4 protein and are resistant to infection, even by virulent strains of S. typhimurium. In the present study, we describe the immune system-enhancing properties of an attenuated strain of S. typhimurium engineered to express murine IFN-γ. This strain (designated GIDIFN) was able to modulate immune responses following systemic inoculation by upregulating the production of inflammatory mediators (IL-6 and IL-12) and anti-bacterial effector molecules (nitric oxide; NO). Consequently, this led to a more effective control of bacterial proliferation in systemic target organs in both C3H/HeJ and C3H/HeN mice. Although evidence for the enhancement in immune responses could be observed as early as few hours post-inoculation, sustained improvements required 2-3 days to manifest. Vaccination of C3H/HeJ mice with GIDIFN strain, even at low doses, conferred a significantly higher degree of protection against challenge with virulent Salmonella in susceptible C3H/HeJ mice. Our data demonstrate that IFNγ-expressing Salmonella are immunogenic and confer excellent protection against virulent challenge in susceptible C3H/HeJ mice; in addition they may be used as an effective mucosal delivery vectors against virulent infection and for boosting immune responses in immunodeficient hosts.


Ursodeoxycholic acid induces apoptosis in hepatocellular carcinoma xenografts in mice.
To evaluate the efficacy of ursodeoxycholic acid (UDCA) as a chemotherapeutic agent for the treatment of hepatocellular carcinoma (HCC). BALB/c nude mice were randomized into four groups 24 h before subcutaneous injection of hepatocarcinoma BEL7402 cells suspended in phosphate buffered saline (PBS) into the right flank. The control group (n = 10) was fed a standard diet while treatment groups (n = 10 each) were fed a standard daily diet supplemented with different concentrations of UDCA (30, 50 and 70 mg/kg per day) for 21 d. Tumor growth was measured once each week, and tumor volume (V) was calculated with the following equation: V = (L × W(2)) × 0.52, where L is the length and W is the width of the xenograft. After 21 d, mice were killed under ether anesthesia, and tumors were excised and weighed. Apoptosis was evaluated through detection of DNA fragmentation with gel electrophoresis and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. Western blot analysis was performed to determine the expression of apoptosis-related proteins BAX, BCL2, APAF1, cleaved caspase-9, and cleaved caspase-3. UDCA suppressed tumor growth relative to controls. The mean tumor volumes were the following: control, 1090 ± 89 mm(3); 30 mg/kg per day, 612 ± 46 mm(3); 50 mg/kg per day, 563 ± 38 mm(3); and 70 mg/kg per day, 221 ± 26 mm(3). Decreased tumor volumes reached statistical significance relative to control xenografts (30 mg/kg per day, P < 0.05; 50 mg/kg per day, P < 0.05; 70 mg/kg per day, P < 0.01). Increasing concentrations of UDCA led to increased DNA fragmentation observed on gel electrophoresis and in the TUNEL assay (control, 1.6% ± 0.3%; 30 mg/kg per day, 2.9% ± 0.5%; 50 mg/kg per day, 3.15% ± 0.7%, and 70 mg/kg per day, 4.86% ± 0.9%). Western blot analysis revealed increased expression of BAX, APAF1, cleaved-caspase-9 and cleaved-caspase-3 proteins, which induce apoptosis, but decreased expression of BCL2 protein, which is an inhibitor of apoptosis, following administration of UDCA. UDCA suppresses growth of BEL7402 hepatocellular carcinoma cells in vivo, in part through apoptosis induction, and is thus a candidate for therapeutic treatment of HCC.


Robust and Mechanically and Electrically Self-Healing Hydrogel for Efficient Electromagnetic Interference Shielding.
Autonomously self-healing hydrogels have received considerable attentions due to their capacity for repairing themselves spontaneously after suffering damage, which can provide a better stability and a longer life span. In this work, a robust and mechanically and electrically self-healing hydrogel with an efficient electromagnetic interference (EMI) shielding performance was successfully fabricated via the incorporation of multiwalled carbon nanotubes (MWCNTs) into the hydrophobically associated polyacrylamide (PAM) hydrogels by using cellulose nanofiber (CNF) as the dispersant. It was been found that CNF could not only assist the homogeneous dispersion of MWCNTs but also effectively enhance the mechanical property of the resultant hydrogels. As a result, the optimal tensile strength (≈0.24 MPa), electrical conductivity (≈0.85 S m-1), and EMI shielding effectiveness (≈28.5 dB) were achieved for the PAM/CNF/MWCNT composite hydrogels with 1 wt % MWCNTs and 0.3 wt % CNF, which showed 458, 844, and 90% increase over (≈0.043 MPa, ≈0.09 S m-1, and ≈15 dB, respectively) the PAM hydrogel. More encouragingly, these composite hydrogels could rapidly restore their electrical conductivity and EMI shielding effectiveness after mechanical damage at room temperature without any external stimulus. With outstanding mechanical and self-healing properties, the prepared composite hydrogels were similar to human skin, but beyond human skin owing to their additional satisfactory electrical and EMI shielding performances. They may offer promising and broad prospects in the field of simulate skin and protection of precision electronics.


Inhibitors of the bone morphogenetic protein (BMP) signaling pathway: a patent review (2008-2015).
The bone morphogenetic protein (BMP) is a critical signaling pathway and plays a diverse role in embryonic pattern formation and is implicated in a variety of disease processes, including anemia, bone formation, atherosclerosis, skin diseases, and cancers, among others. Areas covered: This review covers small molecule inhibitors/antagonists of BMP in patent applications between 2008 - 2015, along with brief synopses of the disclosed inhibitors in the primary literature. Expert opinion: The development of potent and selective BMP inhibitors is ongoing with most of the work centered around improving the selectivity and pharmacokinetic profile. Early work was for the treatment of the rare and neglected disease, fibrodysplasia ossificans progressiva (FOP). Recently, however, there has been increased interest in their use in a number of other diseases such as cancer, atherosclerosis, and anemia of chronic disease, to name a few. Although the primary participants in the early work were from academic laboratories, recently a significant surge from the pharmaceutical industry has elevated the interest in the development of BMP inhibitors for a wide-range of therapeutic indications. Due to this, expect a number of new approaches such as repurposing of other kinase inhibitors to be brought into clinical trials in the near future.


Characterization of the coagulation profile in children with liver disease and extrahepatic portal vein obstruction or shunt.
Chronic liver disease causes a disruption of procoagulant and anticoagulant factors, resulting in a fragile state, prone to increased rates of both bleeding and thrombosis. Currently, there is limited literature describing the changes observed in pediatric liver disease and extrahepatic portal vein obstruction or shunt. This study aimed to describe the changes that occur in children with chronic liver disease and extrahepatic portal vein obstruction or shunt. We measured the concentration and activity of key procoagulant and anticoagulant factors in children with liver disease, children with extrahepatic portal vein obstruction or shunt, and healthy children. Children with severe liver disease had coagulopathic changes, including either decreased concentration or activity of factor II, factor V, and factor VII. Nineteen percent (8/42) of the cohort had significant bleeding. Thrombophilic changes were also observed, including decreased concentration or activity of protein C, protein S, and antithrombin and increased concentration and activity of factor VIII and Von Willebrand factor. Similar coagulation factor changes were observed in children with extrahepatic portal vein obstruction or shunt. There was a trend toward greater changes in coagulation factor activity compared to concentration. This study provides a detailed description of the changes in both the concentration and activity of coagulation factors in pediatric liver disease and extrahepatic portal vein obstruction or shunt. Interestingly, procoagulant and anticoagulant factors were deranged in portal vein obstruction or shunt to a similar degree as in liver disease. An improved understanding of the coagulation profile in the pediatric setting will contribute to the improved management of liver disease and extrahepatic portal obstruction or shunt. PELD: pediatric end-stage liver disease score; MELD: model for end-stage liver disease score; ELISA: enzyme-linked immunosorbent assay; MCRI: Murdoch Childrens Research Institute; FII: factor II; FV: factor V; FVII: factor VII; FVIII: factor VIII; AT: antithrombin III; A2M: alpha-2-macroglobulin; vWF: Von Willebrand factor; PC: protein C; PS: protein S; ISTH-BAT: International Society on Thrombosis and Haemostasis Bleeding Assessment Tool.


Metal dendrimers: synthesis of hierarchically stellated nanocrystals by sequential seed-directed overgrowth.
Hierarchically organized structures are prevalent in nature, where such features account for the adhesion properties of gecko feet and the brilliant color variation of butterfly wings. Achieving artificial structures with multiscale features is of interest for metamaterials and biomimetic applications. However, the fabrication of such structures relies heavily on lithographic approaches, although self-assembly routes to superstructures are promising. Sequential seed-directed overgrowth is now demonstrated as a route to metal dendrimers, which are hierarchically branched nanocrystals (NCs) with a three-dimensional order analogous to that of molecular dendrimers. This method was applied to a model Au/Pd NC system; in general, the principle of sequential seed-directed overgrowth should enable the synthesis of new hierarchical inorganic structures with high symmetry.


[Drug clinics. Clinical drug trials: the importance and role of the general practitioner].
Clinical trials are an essential step in the development of a drug. They must be conducted according to strict rules called "Good Clinical Practice" or GCP. GCP requirements aim to guarantee a perfect methodology in the planning, realization and interpretation of clinical trials. The latter can be divided in four phases: phase 1 aiming to demonstrate the safety and to investigate the pharmacokinetics/metabolism of the drug in healthy volunteers; phase 2 aiming to study the intrinsic activity (generally versus a placebo) and safety of the compound in a rather small number of (hospitalized) patients; phase 3 aiming to confirm the comparative efficacy (versus a placebo or a reference drug) and safety of the pharmacological agent in a quite large number of (ambulatory) patients; and phase 4 carried out after commercialization, to verify the clinical utility of the drug in conditions of daily practice. Because he/she occupies a crucial position in the recruitment and follow-up of outpatients, the general practitioner should play a more active role in clinical trials, provided that he/she could work in collaboration with academic centers specialized in clinical pharmacology which can help to perform studies in accordance with GCP requirements.


Metastatic non-small cell lung cancer in Brazil: treatment heterogeneity in routine clinical practice.
Lung cancer is one of the main causes of cancer related deaths. Approximately three quarters of these tumors are non-small cell carcinomas. When diagnosed the majority of patients show the disease locally advanced or metastatic. The chemotherapy is the chosen therapy for patients with advanced lung cancer. The majority of published studies with chemotherapy are performed in academic centers under a strict control of research protocols. The aim of this study is to evaluate the usual management of metastatic NSCLC patients outside of a clinical trial setting in three different oncologic centers in Brazil. This is a retrospective study of patients with metastatic non-small cell lung cancer admitted for treatment in three different Cancer Centers in Brazil. 564 patients from Brazilian public heath system and private/health insurance system were considered for the present study. Among 564 patients in this study, 335 (59.4%) received chemotherapy. For all patients, 47 different regimens of chemotherapy were identified. The median follow-up time was eight months and the overall median survival of all patient population submitted to chemotherapy was 9.7 months. There was a great heterogeneity in the regimens of drugs to treat metastatic NSCLC patients. The overall survival was significantly better for patients treated with first line chemotherapy compared to patients that only received best supportive care. Results of prospective randomized clinical trials should be carefully analyzed before transferred to the daily clinical practice.


Correlation Decomposition between TCM Syndrome Types and Calcium and Phosphorus Metabolism in 50 Maintenance Hemodialysis Sufferers.
Aiming to reveal the relationship between TCM syndrome types and calcium and phosphorus metabolism in maintenance hemodialysis (MHD) sufferers, 50 sufferers diagnosed with MHD who were admitted to Suixi County Hospital in Anhui Province are selected for retrospective decomposition. The data of TCM classification and laboratory indicators of the sufferers are collected. The experimental results indicate that calcium and phosphorus metabolism disorder is common in maintenance hemodialysis patients, especially calcium and phosphorus product and blood phosphorus elevation. The increase of the calcium-phosphorus product is closely related to the mortality and calcification rate of the subcutaneous soft tissue. It can provide a reference for the diagnosis and therapy of abnormal calcium and phosphorus metabolism in sufferers, which is worthy of clinical application.


The protective effect of melatonin on chronic paradoxical sleep deprivation induced metabolic and memory deficit in rats.
Impaired sleep is independent risk factor of neurodegeneration and dementia. Chronic insomnia impairs melatonin (MEL) production that is directly proportionate to its duration. The underlying mechanisms linking sleep loss to dementia and the possible therapeutic effect of melatonin have not been fully elucidated. Previous research showed great controversy concerning the effects of paradoxical sleep deprivation (PSD) on body weight, serum lipoproteins, and inflammatory cytokines. To examine the effect of chronic paradoxical sleep deprivation (PSD) with and without MEL supplementation on memory using RAWM, parameters of metabolic syndrome (MS), liver enzymes, serum cortisol, and inflammatory cytokines as well as liver, colon, and brain histopathology. Forty rats were divided into four groups ten animals each; C: control, G: grid group, SD: sleep deprivation group, and SD+MEL sleep deprivation treated with melatonin. MEL supplementation reversed PSD-induced memory deficits (P<0.05), the elevation of serum cortisol (P<0.001), glucose (P<0.05), ALT (P<0.05), AST (P<0.001), TNF-alpha (P<0.001), IL-10 (P<0.01) and improved colon, liver, and brain architecture. Melatonin reduced body weight (P<0.05), total cholesterol, LDL-c, and triglycerides as well as increased HDL-c (P<0.001). MEL has a protective effect against chronic PSD-induced metabolic malfunction and cognitive deterioration by reducing stress, improving immunity, and maintaining colonic wall integrity.


Situated influences on perceived barriers to health behavior change: cultural identity and context in Kazakhstan.
The objective of this study was to identify the perceived barriers to lifestyle changes citizens of Kazakhstan suffering from cardiovascular disease and type II diabetes were experiencing. 14 focus groups were conducted with patients across two regions of Kazakhstan. Topics of discussion included accessing medical care, communicating with health care providers, and following doctor's recommendations. The text of the discussions were analysed for trends and themes across the different groups. Patients identified a series of external and internal barriers to lifestyle changes, including the environment, a dependency on health care providers, a health care system they feel powerless to change, and a low level of self-efficacy. Most notable, however, was a constructed ethnic identity whose boundaries included unhealthy behaviors, specifically diet and untimely access of health care. This identity both was blamed as a cause for the patient's condition and seen as an unchangeable barrier to health behavior change. Current provider efforts to encourage lifestyle changes to manage disease are not taking into account the broader issue of ethnic identity, namely negotiating a fragile and previously suppressed identity that mostly exists alongside other ethnicities. Therefore, maintaining distinctiveness may be a greater need than modifying health behaviors. Efforts towards healthier lifestyles for the public must include not only messages regarding health but also constructions of a Kazakh identity that allows for such lifestyles to fit within the identity framework.


Trace elements in water and congenital malformations of the central nervous system in South Wales.
The concentrations of 20 trace elements were determined by atomic absorption spectrophotometry on representative samples of tap-water collected from 48 local authority areas in South Wales. The associations between twelve trace elements and central nervous system (CNS) malformation rates for the 48 areas were examined. Significant correlations for four trace elements were observed. Of these, Al was positively correlated while for the remaining three-Ca, Ba, and Cu-negative associations were found. Regression analysis of the data suggested that the relationships between Ba and Cu with CNS malformation rates were improtant than those of Al and Ca.


Current evidence of acupuncture for symptoms related to breast cancer survivors: A PRISMA-compliant systematic review of clinical studies in Korea.
Breast cancer survivors experience various symptoms associated with their cancer interventions, and the benefits of acupuncture for these symptoms have been evaluated in clinical trials worldwide. The purpose of this review was to discuss the current status of clinical research regarding the use of acupuncture as a part of traditional Korean medicine (KM) for various symptoms associated with breast cancer therapies. We conducted a systematic review of the literature regarding the use of acupuncture as a part of traditional KM to treat symptoms associated with breast cancer therapies. The following databases were searched for content up to February 2017: MEDLINE, EMBASE, the Cochrane library, 4 Korean databases, and conference proceedings from major Korean medical societies. Among the 1228 identified articles, 8 observational studies (3 case series and 5 case reports), and 1 randomized controlled trial (RCT) were included in this review. Among these studies, 3 investigated lymphedema, 2 investigated chemotherapy-induced peripheral neuropathy, 1 investigated hot flushes, 1 investigated constipation, and 2 investigated miscellaneous symptoms in breast cancer survivors; all studies concluded that acupuncture can alleviate the symptom in question. However, we identified only 1 relevant RCT, and the included studies had limitations in terms of reporting quality. There is a lack of conclusive evidence regarding the benefits of acupuncture for the treatment of breast cancer survivors in Korea. More rigorous RCTs are necessary in the future to establish stronger clinical evidence regarding the use of acupuncture to better reflect the clinical context of Korea.


Nitrite-derived nitric oxide protects the rat kidney against ischemia/reperfusion injury in vivo: role for xanthine oxidoreductase.
In normal conditions, nitric oxide (NO) is oxidized to the anion nitrite, but in hypoxia, this nitrite may be reduced back to NO by the nitrite reductase action of deoxygenated hemoglobin, acidic disproportionation, or xanthine oxidoreductase (XOR). Herein, is investigated the effects of topical sodium nitrite administration in a rat model of renal ischemia/reperfusion (I/R) injury. Rats were subjected to 60 min of bilateral renal ischemia and 6 h of reperfusion in the absence or presence of sodium nitrite (30 nmol) administered topically 1 min before reperfusion. Serum creatinine, serum aspartate aminotransferase, creatinine clearance, fractional excretion of Na(+), and plasma nitrite/nitrate concentrations were measured. The nitrite-derived NO-generating capacity of renal tissue was determined under acidic and hypoxic conditions by ozone chemiluminescence in homogenates of kidneys that were subjected to sham, ischemia-only, and I/R conditions. Nitrite significantly attenuated renal dysfunction and injury, an effect that was abolished by previous treatment of rats with the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazole-1-oxyl-3-oxide (2.5 mumol intravenously 5 min before ischemia and 50 nmol topically 6 min before reperfusion). Renal tissue homogenates produced significant amounts of NO from nitrite, an effect that was attenuated significantly by the xanthine oxidoreductase inhibitor allopurinol. Taken together, these findings demonstrate that topically administered sodium nitrite protects the rat kidney against I/R injury and dysfunction in vivo via the generation, in part, of xanthine oxidoreductase-catalyzed NO production. These observations suggest that nitrite therapy might prove beneficial in protecting kidney function and integrity during periods of I/R such as those encountered in renal transplantation.


Cellular and molecular mechanisms of action of transcranial direct current stimulation: evidence from in vitro and in vivo models.
Transcranial direct current stimulation is a noninvasive technique that has been experimentally tested for a number of psychiatric and neurological conditions. Preliminary observations suggest that this approach can indeed influence a number of cellular and molecular pathways that may be disease relevant. However, the mechanisms of action underlying its beneficial effects are largely unknown and need to be better understood to allow this therapy to be used optimally. In this review, we summarize the physiological responses observed in vitro and in vivo, with a particular emphasis on cellular and molecular cascades associated with inflammation, angiogenesis, neurogenesis, and neuroplasticity recruited by direct current stimulation, a topic that has been largely neglected in the literature. A better understanding of the neural responses to transcranial direct current stimulation is critical if this therapy is to be used in large-scale clinical trials with a view of being routinely offered to patients suffering from various conditions affecting the central nervous system.


HNRNPC mediated m6A methylation of 5-methyltetrahydrofolate-homocysteine methyltransferase and involved in the occurrence of RSA.
N6-methyladenosine methylated modification has been shown to play roles in recurrent spontaneous abortion. We aimed to explore role of heterogeneous nuclear ribonucleoprotein C in the occurrence of recurrent spontaneous abortion. We collected embryonic villous tissues from 3 patients with recurrent spontaneous abortion (RSA group) and 3 normal control pregnancy patients. Methylated RNA immunoprecipitation sequencing, RNA sequencing, methylated RNA immunoprecipitation quantitative PCR were conducted to detect the differentially expressed m6A methylation modification gene and regulatory gene in patients with recurrent spontaneous abortion. Methylated RNA immunoprecipitation sequencing and RNA sequencing results showed that the mRNA expression level of heterogeneous nuclear ribonucleoprotein C significantly decreased in RSA group and mRNA expression level of 5-methyltetrahydrofolate-homocysteine methyltransferase increased. Real-time quantitative PCR confirmed the differential expression of heterogeneous nuclear ribonucleoprotein C and 5-methyltetrahydrofolate-homocysteine methyltransferase. Methylated RNA immunoprecipitation quantitative PCR result showed that mRNA m6A modification level of 5-methyltetrahydrofolate-homocysteine methyltransferase decreased in RSA group. The results of western blotting, real-time quantitative PCR, immunofluorescence, matrigel invasion and wound healing assays indicated that heterogeneous nuclear ribonucleoprotein C might regulate the expression of 5-methyltetrahydrofolate-homocysteine methyltransferase by mediating m6A modification, thereby reducing the proliferation and migration of trophoblast cell line, ultimately leading to the occurrence of recurrent spontaneous abortion.


Sudden cardiac death in a 20-year-old male swimmer.
In young adults, hypertrophic obstructive cardiomyopathy (HOCM) is an acknowledged risk factor for sudden cardiac death (SCD) in an otherwise healthy and active patient. While the incidence of SCD in young people is not high enough for extensive, wide-scale examinations, the potential for prevention of some deaths via pre-exercise imaging may be beneficial in certain patient populations, such as those with a family history of SCD or professional athletes. We present the case of a healthy 20-year-old man with no past medical history who died while swimming in a river, likely secondary to cardiac arrest in the setting of HOCM.


Role of membrane contact sites in protein import into mitochondria.
Mitochondria import more than 1,000 different proteins from the cytosol. The proteins are synthesized as precursors on cytosolic ribosomes and are translocated by protein transport machineries of the mitochondrial membranes. Five main pathways for protein import into mitochondria have been identified. Most pathways use the translocase of the outer mitochondrial membrane (TOM) as the entry gate into mitochondria. Depending on specific signals contained in the precursors, the proteins are subsequently transferred to different intramitochondrial translocases. In this article, we discuss the connection between protein import and mitochondrial membrane architecture. Mitochondria possess two membranes. It is a long-standing question how contact sites between outer and inner membranes are formed and which role the contact sites play in the translocation of precursor proteins. A major translocation contact site is formed between the TOM complex and the presequence translocase of the inner membrane (TIM23 complex), promoting transfer of presequence-carrying preproteins to the mitochondrial inner membrane and matrix. Recent findings led to the identification of contact sites that involve the mitochondrial contact site and cristae organizing system (MICOS) of the inner membrane. MICOS plays a dual role. It is crucial for maintaining the inner membrane cristae architecture and forms contacts sites to the outer membrane that promote translocation of precursor proteins into the intermembrane space and outer membrane of mitochondria. The view is emerging that the mitochondrial protein translocases do not function as independent units, but are embedded in a network of interactions with machineries that control mitochondrial activity and architecture.


[Etiopathogenic, ultrasonographic and prognostic features of postpartum cardiomyopathy].
Peripartum cardiomyopathy is a classic but uncommon entity in African women about which there is little etiologic understanding. From January 1990 to March 1996 a series of 30 cases of peripartum cardiomyopathy was collected at the Principal Hospital in Dakar, Senegal. Peripartum cardiomyopathy was defined as the occurrence of cardiac insufficiency in a woman with no previous history of heart disease, during the period between the second and twentieth weeks after delivery confirmed by ultrasound evidence of dilated cardiomyopathy. The overall incidence of peripartum cardiomyopathy during the study period was 30 out of 1200 deliveries. The mean age of the women in the study was 34 years and mean parity was 5.2. In 13.3% of cases births involved twins. There were no predisposing socio-economic or climatic factors. The clinical picture was severe cardiac failure in 80.3% of cases and left ventricular insufficiency in 16.6%. In all cases ultrasound findings were typical of dilated cardiomyopathy. Serum selenium and vitamin B1 levels were normal. Measurements of T CD4 and CD8 in eight patients were normal. Conversion enzyme inhibitors were administered to twenty patients. Complete remission was achieved in 14 patients, three patients died, and thirteen patients presented ultrasonic evidence of persistent dilated cardiomyopathy. One patient relapsed after a subsequent delivery. These findings are in agreement with previous reports concerning the clinical and prognostic features of peripartum cardiomyopathy in Africa.


Lymphocytic-plasmacytic colitis in the cat.
Lymphocytic-plasmacytic colitis was diagnosed in 6 cats. Owners sought veterinary care because of semiformed -to-liquid feces, tenesmus , fresh blood and/or mucus in the feces, or increased frequency of defecation in their cats. Lymphocytic, plasmacytic infiltration in the colonic lamina propria was found on colon biopsies. Clinical signs resolved in all 6 cats after dietary management, utilizing lamb and rice, horsemeat , or a feline prescription diet. Clinical improvement also occurred in 1 cat following sulfasalazine therapy.


MIP-Based Sensors: Promising New Tools for Cancer Biomarker Determination.
Detecting cancer disease at an early stage is one of the most important issues for increasing the survival rate of patients. Cancer biomarker detection helps to provide a diagnosis before the disease becomes incurable in later stages. Biomarkers can also be used to evaluate the progression of therapies and surgery treatments. In recent years, molecularly imprinted polymer (MIP) based sensors have been intensely investigated as promising analytical devices in several fields, including clinical analysis, offering desired portability, fast response, specificity, and low cost. The aim of this review is to provide readers with an overview on recent important achievements in MIP-based sensors coupled to various transducers (e.g., electrochemical, optical, and piezoelectric) for the determination of cancer biomarkers by selected publications from 2012 to 2016.


Evaluation and Use of Registry Data in a GIS Analysis of Diabetes.
to evaluate registry data routinely collected by the Chronic Disease Electronic Management System (CDEMS) in the monitoring of type 2 diabetes mellitus (T2DM) in the Eastern half of the island and use the data to describe the spatial epidemiological patterns of T2DM. The starting point was access and retrival of all exsisting data on the diabetes registry. This data was subsequently validated using handwritten medical records. Several clinical indicators were selected to evaluate the registry. The address of each patient was extracted and georeferenced using ArcGIS 10.0 and several maps were created. The registry had data for thirteen (13) out of the sixteen (16) health facilities. We found that less than 15 percent of all patients actually had diabetic indicator tests done according to World Health Organization (WHO) standards. The overall prevalence of T2DM was 20.8 per 1000 population. The highest prevalence of diabetes occurred at the northeastern tip of the island. In addition 57.58% of patients with T2DM resided inland and 40.75% of patients residing on the coastal areas. In conclusion, we provide evidence that the data collected by the diabetes registry although lacking in many areas was adequate for spatial epidemiological analysis.


Restoration of human beta-globin gene expression in murine and human IVS2-654 thalassemic erythroid cells by free uptake of antisense oligonucleotides.
Correct human beta-globin mRNA has been restored in erythroid cells from transgenic mice carrying the human gene with beta-globin IVS2-654 splice mutation and from thalassemia patients with the IVS2-654/beta(E) genotype. This was accomplished in a dose- and time-dependent manner by free uptake of morpholino oligonucleotide antisense to the aberrant splice site at position 652 of intron 2 in beta-globin pre-mRNA. Under optimal conditions of oligonucleotide uptake, the maximal levels of correct human beta-globin mRNA and hemoglobin A in patients' erythroid cells were 77 and 54%, respectively. These levels of correction were equal to, if not higher than, those obtained by syringe loading of the oligonucleotide into the cells. Comparison of splicing correction results with the cellular uptake of fluorescein-labeled oligonucleotide indicated that the levels of mRNA and hemoglobin A correlate well with the nuclear localization of the oligonucleotide and the degree of erythroid differentiation of cultured cells. Similar but not as pronounced results were obtained after the oligonucleotide treatment of bone marrow cells from IVS2-654 mouse. The effectiveness of the free antisense morpholino oligonucleotide in restoration of correct splicing of IVS2-654 pre-mRNA in cultured erythropoietic cells from transgenic mice and thalassemic patients suggests the applicability of this or similar compounds in in vivo experiments and possibly in treatment of thalassemia.


[Surgical treatment of acetabular fractures. Long term outcomes].
acetabular fractures constitute between 0.3 and 0.6% of all observed fractures, being these injuries relatively infrequent. to evaluate clinical and radiological outcomes of surgical treatment of patients with acetabular fracture treated in our hospital with a minimal follow-up of 11.5 years. The secondary objective is to determine the rate of failure in the hip joint of these patients and establish risk factors that are involved. 23 patients with acetabular fractures that were treated by open reduction and internal fixation (ORIF) were retrospectively analysed. They were follow-up during an average of 14 years (range 11.5-17.5). Fractures were classified by Judet y Letournel as simple or complex. Clinical and radiological outcomes were analysed by Harris scale. We obtained an average of 81.90/100 on the Harris scale, aiming at better outcomes on simple fractures compare to those that were complex (p = 0.027). Higher scores were also achieved on those patients with an anatomical reduction (p = 0.033). Three patients required revision and placement of a total arthoplasty (13%). However, patients with body mass index (BMI) > 30 tend to achieve poor clinical results (p = 0.151). ORIF may be suggested for acetabular fractures since good clinical and radiological outcomes were recorded on a long-term follow-up. Complex fractures, non-anatomical reduction and BMI > 30 were identified as risk factors to coxarthrosis progression.


A rare case report of squamous-cell carcinoma arising from mature cystic teratoma of ovary.
The most frequent ovarian germ cell tumors are mature cystic teratomas (MCTs), composing 10-25% of all ovarian neoplasms. MCTs have the potential of undergoing malignant transformation, typically in postmenopausal women, with a frequency of 0.17-3%, with squamous cell carcinoma being the most common malignant tumor arising from MCT. We present the rare clinical entity of a squamous cell carcinoma arising from a mature cystic teratoma in a 56-year-old premenopausal woman as well as diagnostic and therapeutic route followed.


After 18 months of antiretroviral therapy, total HIV DNA decreases more pronouncedly in patients infected by CRF01_AE than in those infected by subtype B and CRF07_BC.
Whether the amount of HIV DNA is associated with the subtype of HIV-1 after antiretroviral therapy (ART) has not been reported. In the present study, the amount of HIV DNA and RNA and CD4+T counts in blood and semen prior to and after 18 months of ART were compared in 48 patients infected by CRF01_AE, subtype B or CRF07_BC of HIV-1. Viral RNA was suppressed and CD4 cell count recovery achieved in all patients. The level of HIV DNA were similar before ART; however, patients with CRF01_AE had less HIV DNA after ART than those with subtype B and CRF07_BC infection. According to prediction of co-receptor usage by Geno2Pheno and PSSM in combination, more than 35.6% of clones for CRF01_AE were predicted as CXCR4-using before ART, whereas less than 6% of those for subtype B and CRF07_BC were predicted as CXCR4-using. After 18 months of ART, no CXCR4-using clones were predicted in any of the subtypes. Despite more HIV RNA and fewer CD4 + T cells in patients with CRF01_AE before therapy, no significant differences (P > 0.05) in viral RNA or CD4 cell counts were observed between the subtypes after 18 months of ART. Thus, 18 months of antiretroviral therapy was more efficient in patients with CRF01_AE. Considering that successful ART dramatically reduces the viral load in both blood and semen, risks of sexual transmission of HIV were reduced, contributing to prevention of rapid spread of HIV among men who have sex with men in the region.


Long-term evaluation of the use of the transdermal contraceptive patch in adolescents.
The transdermal contraceptive patch, Ortho Evra, was approved in December 2001 and released on the market in June 2002. In this study, we reviewed clinical data of young women who started the patch between June 2002 and December 2003 in the adolescent medicine clinic at a university-based outpatient center. A total of 62 patients started the patch in that period and two of them were lost to follow-up. Mean age of patients was 17.9 years and mean length of use was 10 cycles. Only 10 patients (16.7%) discontinued use. Reasons for discontinuation were moderate to severe skin irritation (3 patients, 5%), complete detachment (3 patients, 5%), and economic reasons (4 patients, 6.7%). Compliance was excellent overall and the side-effects profile was good. No pregnancies occurred during this period. These results confirmed that the transdermal contraceptive patch is easy to use and an effective method of birth control that may be better tolerated by young women. It also seemed to improve contraceptive compliance in this population.


Pathogenicity of Serratia marcescens Strains in Honey Bees.
Although few honey bee diseases are known to be caused by bacteria, pathogens of adult worker bees may be underrecognized due to social immunity mechanisms. Specifically, infected adult bees typically abandon the hive or are removed by guards. Serratia marcescens, an opportunistic pathogen of many plants and animals, is often present at low abundance in the guts of honey bee workers and has recently been isolated from Varroa mites and from the hemolymph of dead and dying honey bees. However, the severity and prevalence of S. marcescens pathogenicity in honey bees have not been fully investigated. Here we characterized three S. marcescens strains isolated from the guts of honey bees and one previously isolated from hemolymph. In vivo tests confirmed that S. marcescens is pathogenic in workers. All strains caused mortality when a few cells were injected into the hemocoel, and the gut-isolated strains caused mortality when administered orally. In vitro assays and comparative genomics identified possible mechanisms of virulence of gut-associated strains. Expression of antimicrobial peptide and phenoloxidase genes was not elevated following infection, suggesting that these S. marcescens strains derived from honey bees can evade the immune response in their hosts. Finally, surveys from four locations in the United States indicated the presence of S. marcescens in the guts of over 60% of the worker bees evaluated. Taken together, these results suggest that S. marcescens is a widespread opportunistic pathogen of adult honey bees and that it may be highly virulent under some conditions such as perturbation of the normal gut microbiota or the presence of Varroa mites that puncture the integument, thereby enabling entry of bacterial cells.IMPORTANCE Recently, it has become apparent that multiple factors are responsible for honey bee decline, including climate change, pests and pathogens, pesticides, and loss of foraging habitat. Of the large number of pathogens known to infect honey bees, very few are bacteria. Because adult workers abandon hives when diseased, many of their pathogens may go unnoticed. Here we characterized the virulence of Serratia marcescens strains isolated from honey bee guts and hemolymph. Our results indicate that S. marcescens, an opportunistic pathogen of many plants and animals, including humans, is a virulent opportunistic pathogen of honey bees, which could contribute to bee decline. Aside from the implications for honey bee health, the discovery of pathogenic S. marcescens strains in honey bees presents an opportunity to better understand how opportunistic pathogens infect and invade hosts.


Octopus senescence: the beginning of the end.
Senescence is a normal stage of an octopus's life cycle that often occurs before death. Some of the following symptoms typify it: lack of feeding, retraction of skin around the eyes, uncoordinated movement, increased undirected activity, and white unhealing lesions on the body. There is inter- and intraspecific variability. Senescence is not a disease or a result of disease, although diseases can also be a symptom of it. Both males and females go through a senescent stage before dying-the males after mating, the females while brooding eggs and after the eggs hatch. There are many aspects of octopus senescence that have not yet been studied. This study discusses the ecological implications of senescence.


Epidermal growth factor receptor and its inhibition in radiotherapy: in vivo findings.
Increasing evidence shows that dysregulated epidermal growth factor receptor (EGFR) signalling plays an important part in neoplasia. When over expressed or mutated, EGFR is frequently associated with more aggressive tumour growth, poor patient prognosis and resistance of tumours to cytotoxic agents, including radiation. The present studies with murine carcinomas showed that there is an inverse correlation between the level of EGFR and tumour radiocurability. Likewise, the present clinical study in patients with head and neck cancer shows that EGFR over expression correlates with poorer tumour response to radiotherapy. Adding EGFR to tumour cells in vitro protected cells against the cytotoxic action of radiation, whereas blocking EGFR with anti-EGFR antibodies enhanced cell radiosensitivity. A casual relationship between EGFR and increased cellular resistance to radiation was established by transferring the EGFR gene into low EGFR-expressing radiosensitive tumour cells, which then become radioresistant. Radiation activated EGFR and its downstream signalling pathways in radioresistant but not in radiosensitive tumours, and this effect was associated with increased resistance to radiation, and enhanced repopulation in irradiated tumours. Increasing evidence shows that blockage of EGFR or interference with any of the steps in its signal transduction cascade can counteract negative outcomes of EGFR signalling, which has recently been explored as a therapeutic strategy in cancer treatment. The present findings demonstrate that treatment of human tumour xenografts with C225, an anti-EGFR monoclonal antibody, dramatically enhanced tumour response to radiation. Overall, the findings show that over expression of EGFR may serve as a predictor of tumour treatment outcome by radiotherapy and as a therapeutic target to enhance the efficacy of radiotherapy.


PEX1 mutations in complementation group 1 of Zellweger spectrum patients correlate with severity of disease.
The peroxisome biogenesis disorders (PBD) are a group of autosomal-recessive diseases with complex developmental and metabolic phenotypes, including the Zellweger spectrum and rhizomelic chondrodysplasia punctata. The diseases are caused by defects in peroxisomal matrix protein import and are characterized by the loss of multiple peroxisomal metabolic functions. In humans, 12 complementation groups have been identified, with complementation group 1 accounting for more than two thirds of all PBD patients. Mutations in the PEX1 gene encoding a member of the AAA protein family of ATPases are responsible for the defects in this group, and a variety of PEX1 mutant alleles have been described. We characterized the PEX1 gene mutations and associated haplotypes in a group of thoroughly documented Zellweger spectrum patients in complementation group 1 who represent the broad range of phenotypic variation. We compared the type of mutation with the age of survival, clinical manifestations, and biochemical alterations and found a close relationship between genotype and age of survival. Missense mutations cause a milder form of disease, whereas insertions, deletions, and nonsense mutations are associated with severe clinical phenotypes. Thus, knowing the PEX1 gene mutation is helpful in predicting the course of disease in individual cases.


Impact of Desensitization on Antiviral Immunity in HLA-Sensitized Kidney Transplant Recipients.
Viral infections represent significant morbidity and mortality factors in kidney transplant recipients, with CMV, EBV, and BKV infections being most common. Desensitization (DES) with IVIg and rituximab with/without plasma exchange followed by kidney transplantation with alemtuzumab induction increased successful transplant rates in HLA-sensitized patients but may represent an increased risk for viral infections due to severe lymphocyte depletion. Here, we report on the posttransplant viral infection status in 372 DES versus 538 non-DES patients. CMV and EBV viremia were significantly lower in DES patients, while BKV viremia was similar. This trend was observed primarily in CMV sero(-), EBV sero(+), and sero(-) patients. No patient developed PTLD. The incidence of BKAN, allograft, and patient survival was similar in both groups. These viral infections were not associated with subsequent allograft rejection which occurred within 6 months after the infection. Conclusions. The IVIg + rituximab desensitization combined with alemtuzumab induction with triple immunosuppression maintenance does not increase the risk for CMV, EBV, and BKV infections. Possible factors include, in addition to posttransplant antiviral prophylaxis and PCR monitoring, presence of memory T cells and antibodies specific to CMV and likely EBV, NK cell-mediated ADCC despite lymphocyte depletion, elimination of EBV and CMV reservoirs by rituximab and alemtuzumab, and use of IVIg with antiviral properties.


Larvicidal and Nematicidal Activities of 3-Acylbarbituric Acid Analogues against Asian Tiger Mosquito, Aedes albopictus, and Pine Wood Nematode, Bursaphelenchus xylophilus.
Widespread concern for the occurrence of resistant strains, along with the avoidance of the use of highly toxic insecticides and their wide environmental dispersal, highlights the need for the development of new and safer pest control agents. Natural products provide inspiration for new chemical entities with biological activities, and their analogues are good lead compounds for the development of new pest control agents. For this purpose, we evaluated the larvicidal and nematicidal activities of 48 3-acylbarbituric acid analogues against the Asian tiger mosquito, Aedes albopictus and the pine wood nematode, Bursaphelenchus xylophilus, organisms of increasing global concern. Among the 48 3-acylbarbituric acid analogues, four compounds-10, 14d, 14g and 19b-showed >90% larvicidal activity against Ae. albopictus at 10 μg/mL concentration, and one (compound 10) showed the strongest larvicidal activity against Ae. albopictus, with a LC50 value of 0.22 μg/mL. Only compound 18 showed strong nematicidal activity against pine wood nematode. Most active compounds possessed similar physicochemical properties; thus, actives typically had ClogP values of around 1.40-1.50 and rel-PSA values of 16-17% and these similar cheminformatic characteristics reflect their similar structure. This study indicates that active 3-acylbarbituric acids analogues have potential as lead compounds for developing novel mosquito control agents.


Demethylation of the coding region triggers the activation of the human testis-specific PDHA2 gene in somatic tissues.
Human PDHA2 is a testis-specific gene that codes for the E(1)α subunit of Pyruvate Dehydrogenase Complex (PDC), a crucial enzyme system in cell energy metabolism. Since activation of the PDHA2 gene in somatic cells could be a new therapeutic approach for PDC deficiency, we aimed to identify the regulatory mechanisms underlying the human PDHA2 gene expression. Functional deletion studies revealed that the -122 to -6 promoter region is indispensable for basal expression of this TATA-less promoter, and suggested a role of an epigenetic program in the control of PDHA2 gene expression. Indeed, treatment of SH-SY5Y cells with the hypomethylating agent 5-Aza-2'-deoxycytidine (DAC) promoted the reactivation of the PDHA2 gene, by inducing the recruitment of the RNA polymerase II to the proximal promoter region and the consequent increase in PDHA2 mRNA levels. Bisulfite sequencing analysis revealed that DAC treatment induced a significant demethylation of the CpG island II (nucleotides +197 to +460) in PDHA2 coding region, while the promoter region remained highly methylated. Taken together with our previous results that show an in vivo correlation between PDHA2 expression and the demethylation of the CpG island II in testis germ cells, the present results show that internal methylation of the PDHA2 gene plays a part in its repression in somatic cells. In conclusion, our data support the novel finding that methylation of the PDHA2 coding region can inhibit gene transcription. This represents a key mechanism for absence of PDHA2 expression in somatic cells and a target for PDC therapy.


Adapting concepts from systems biology to develop systems exposure event networks for exposure science research.
Systems exposure science has emerged from the traditional environmental exposure assessment framework and incorporates new concepts that link sources of human exposure to internal dose and metabolic processes. Because many human environmental studies are designed for retrospective exposure evaluations they often do not provide practical toxicological outcome parameters. Our goal was to examine concepts from systems biology research and adapt them to a network approach that maps forward to a perturbation event using two hypothetical examples. The article proposes that environmental exposure studies should not only retrospectively document exposure levels, but also measure biological parameters that can be used to inform relevant systemic changes.


Studies on human high molecular weight (HMW) kininogen. II. Structural change of HMW kininogen by the action of human plasma kallikrein.
We have investigated in detail the cleavage of human high molecular weight (HMW) kininogen by human plasma kallikrein and revealed the formation of a nicked kininogen and a novel kinin-free protein (KFP) as intermediate cleavage products. The cleavage of a single chain HMW kininogen (Mr=120,000) by plasma kallikrein was a three-step reaction. The first cleavage yielded a nicked kininogen composed of two disulfide-linked 62,000 and 56,000 daltons chains. The second cleavage yielded kinin and an intermediate kinin-free protein, KFP-I, which was apparently of equal size to the nicked kininogen. The third cleavage yielded a stable kinin-free protein, KFP-II, composed of two disulfide-linked 62,000 and 45,000 daltons chains. The liberation of an 8,000 daltons fragment was identified when the 56,000 daltons chain isolated by SP-Sephadex C-50 chromatography of reduced and alkylated KFP-I was cleaved by plasma kallikrein into the 45,000 daltons chain. Although the antiserum against HMW kininogen cross-reacted with low molecular weight (LMW) kininogen, the antiserum against the 45,000 daltons chain was specific for HMW kininogen. These results suggest that the antigenic determinant groups common to HMW and LMW kininogens are located in the 62,000 daltons heavy chain, while those specific for HMW kininogen are located in the 45,000 daltons light chain, which is known to retain blood coagulation activity.


Curcumin Sensitizes Kidney Cancer Cells to TRAIL-Induced Apoptosis via ROS Mediated Activation of JNK-CHOP Pathway and Upregulation of DR4.
Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), is a selective anticancer cytokine capable of exerting a targeted therapy approach. Disappointingly, recent research has highlighted the development of TRAIL resistance in cancer cells, thus minimising its usefulness in clinical settings. However, several recent studies have demonstrated that cancer cells can be sensitised to TRAIL through the employment of a combinatorial approach, utilizing TRAIL in conjunction with other natural or synthetic anticancer agents. In the present study, the chemo-sensitising effect of curcumin on TRAIL-induced apoptosis in renal carcinoma cells (RCC) was investigated. The results indicate that exposure of kidney cancer ACHN cells to curcumin sensitised the cells to TRAIL, with the combination treatment of TRAIL and curcumin synergistically targeting the cancer cells without affecting the normal renal proximal tubular epithelial cells (RPTEC/TERT1) cells. Furthermore, this combination treatment was shown to induce caspase-dependent apoptosis, inhibition of the proteasome, induction of ROS, upregulation of death receptor 4 (DR4), alterations in mitogen-activated protein kinase (MAPK) signalling and induction of endoplasmic reticulum stress. An in vivo zebrafish embryo study demonstrated the effectiveness of the combinatorial regime to inhibit tumour formation without affecting zebrafish embryo viability or development. Overall, the results arising from this study demonstrate that curcumin has the ability to sensitise TRAIL-resistant ACHN cells to TRAIL-induced apoptosis.


Carotid body of Camelus dromedarius.
The carotid body of the camel is located between a mass of loose connective tissue at the point of separation of the internal carotid artery from the carotid trunk. A capsule-like connective tissue sheath sends strands in between the parenchyme of this organ and separates lobes and lobules, making it disseminated in type, as in man and in the horse. Two distinct types of cells were found in the parenchyma. Type I cells with specific electton-dense, cored vesicles, and type II cells with protoplasmic extensions. Unlike the previously reported arrangement in the carotid body of some species, the type I cells have direct contact with the basement membrane of glomi and capillaries. Synaptic contacts were seen on both cell types.


Inhibition of dopamine-beta-hydroxylase, A copper enzyme, by bleomycin.
Bleomycin was found to be one of the most potent inhibitors of dopamine-beta-hydroxylase. Bleomycin-A2 at 8 X 10(-8) M inhibited the enzyme activity by 50%. Kinetic studies showed that the inhibition by bleomycin-A2 was of the competitive type with both the substrate and the cofactor, ascorbate, and was not affected by fumarate, a stimulator for the enzyme. The inhibition mechanism is possibly due to chelating action of bleomycin toward the copper atom at the active site of the enzyme together with some other kinds of binding, for the addition of the cupric ions or extensive dialysis completely reversed the inhibition and bleomycin Cu(II)-complex did not inhibit the enzyme.


Dihydroartemisinin enhances Apo2L/TRAIL-mediated apoptosis in pancreatic cancer cells via ROS-mediated up-regulation of death receptor 5.
Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has recently shown antitumor activity in various cancer cells. Apo2 ligand or tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is regarded as a promising anticancer agent, but chemoresistance affects its efficacy as a treatment strategy. Apoptosis induced by the combination of DHA and Apo2L/TRAIL has not been well documented, and the mechanisms involved remain unclear. Here, we report that DHA enhances the efficacy of Apo2L/TRAIL for the treatment of pancreatic cancer. We found that combined therapy using DHA and Apo2L/TRAIL significantly enhanced apoptosis in BxPC-3 and PANC-1 cells compared with single-agent treatment in vitro. The effect of DHA was mediated through the generation of reactive oxygen species, the induction of death receptor 5 (DR5) and the modulation of apoptosis-related proteins. However, N-acetyl cysteine significantly reduced the enhanced apoptosis observed with the combination of DHA and Apo2L/TRAIL. In addition, knockdown of DR5 by small interfering RNA also significantly reduced the amount of apoptosis induced by DHA and Apo2L/TRAIL. These results suggest that DHA enhances Apo2L/TRAIL-mediated apoptosis in human pancreatic cancer cells through reactive oxygen species-mediated up-regulation of DR5.


A multimodal approach to improving human papillomavirus vaccination in a community pharmacy setting.
Community pharmacy has become a major access point for several types of vaccinations. Despite the success of vaccination programs like influenza, pneumococcal, and herpes zoster, the rates of human papillomavirus vaccination continue to lag. The primary objective is to describe and report on the impact of a multimodal series of pharmacist-led educational interventions on human papillomavirus vaccination rates in a community pharmacy setting. The primary outcome of this study was change in pharmacist-delivered human papillomavirus vaccination throughout a corresponding 8-week period in 2014 and 2015. A single-center, quasi-experimental interrupted time series mixed-methods pilot study was used to investigate a pharmacist-led, multimodal educational intervention approach to improve human papillomavirus vaccination rates in the community. During the 2014 control period, there were no human papillomavirus vaccines dispensed or administered according to the internal prescription dispensing software. In 2015, a total of 10 patients indicated that they were vaccinated, with 9 patients receiving their first dose and 1 patient receiving his or her second dose at the pharmacy. Pharmacist recommendation was the most reported education method for increasing patient awareness of the human papillomavirus vaccine (n = 10). This study demonstrates pharmacist designed, educational interventions may impact human papillomavirus vaccination rates in the community. Further community-based research with larger sample sizes is warranted to verify these results. Due to the unique barriers to human papillomavirus vaccination, a multimodal and inter-professional approach such as the one presented here is warranted.


Comparison of neurotoxic potency between a novel chinbotulinumtoxinA with onabotulinumtoxinA, incobotulinumtoxinA and lanbotulinumtoxinA in rats.
Four botulinumtoxin type A (BoNT/A) products, onabotulinumtoxinA (A/Ona), incobotulinumtoxinA (A/Inco), lanbotulinumtoxinA (A/Lan) and chinbotulinumtoxinA (A/Chin), are applied in the present study, among which A/Chin is newly produced. We aimed to compare the neurotoxic potency of these toxins by the gauge of muscle strength reduction. Furthermore, potential molecular and cellular mechanisms were also explored. According to our data, muscle strengths in the four toxin groups were all significantly decreased after injection for 1 week. A/Chin achieved the most obvious reduction in muscle strength as compared to the other three products at the dose of 0.5 U. However, there was no difference between the four toxins when increased to 2 U. As the toxins wore off, muscle strength recovered to basal level 12 weeks postinjection. We further measured the expression levels of key factors involved in neuromuscular junction stabilization and muscle genesis. Our results showed that nicotinic acetylcholine receptor, myogenic regulatory factors and muscle-specific receptor tyrosine kinase were all significantly upregulated upon BoNT/A treatment. Consistent with the result of muscle strength, A/Chin had the most obvious induction of gene expression. Moreover, we also found local inflammation response following BoNT/A injection. Owing to lack of complexing proteins, both A/Inco and A/Chin stimulated relatively lighter inflammation compared to that of A/Ona and A/Lan groups. In conclusion, our study provided evidence for the efficacy of the novel A/Chin and its similar functional mode to that of A/Ona, A/Inco and A/Lan. In addition, A/Chin has superiority in inducing muscle paralysis and inflammation stimulation, which may indicate faster onset and longer duration of this novel A/Chin.


[Epithelial advanced ovarian carcinoma in the central region of Tunisia: therapeutic results and prognostic factors on 104 patients].
Between 1994 and 2004, 104 patients with epithelial advanced ovarian cancer were treated in the central region of Tunisia (81 stage III and 23 stage IV). Average age of patients was 54 years. Primary surgery was optimal (residue < 2 cm) in 40 cases (38,5 % of patients). Fifty nine patients were treated with neo adjuvant chemotherapy based on platinum, associated to paclitaxel in 19 % of cases. Interval debulking surgery interested 30 patients and was optimal in 66,7 % of cases. Global survive was 57 % at 2 years and 27 % at 5 years. Survival rate for patients treated with optimal debulking surgery was similar to that of those treated with initial optimal surgery. Prognostic factors for a better survive were : age < 40 years (p < 0,05), stage III (p < 0,01), a normal level of CA125 after surgery (p < 0,01), primary optimal initial surgery (p < 0,02) and response to neoadjuvant chemotherapy (p < 0,01). Prognosis of ovarian carcinoma is worse in Tunisia as like as in the world. In case of extensive tumor, the neoadjuvant chemotherapy before interval debulking surgery permits to improve survive and quality of life in some patients.


Pyrrolizidine alkaloid profiles of the Senecio cineraria group (Asteraceae).
Alkaloid profiles of five Senecio species (Asteraceae), including S. ambiguus subsp. ambiguus, S. ambiguus subsp. nebrodensis, S. gibbosus subsp. bicolor, S. gibbosus subsp. gibbosus, and S. gibbosus subsp. cineraria, were studied. Eleven pyrrolizidine alkaloids were identified and their content was evaluated by GLC-MS and GLC analysis. Otosenine and florosenine were found to be the major alkaloids in all studied species. It is interesting that only S. ambiguus subsp. nebrodensis was characterized by a high content of the alkaloids jacobine, jacoline, jaconine, and jacozine.


An epidemic outbreak of papular and follicular contact dermatitis to tocopheryl linoleate in cosmetics. Swiss Contact Dermatitis Research Group.
In Spring 1992, an epidemic outbreak of papular and follicular rashes caused by a new line of cosmetics occurred throughout Switzerland. Epidemiological and clinical data were collected in order to identify the offending agent and to specify the pathophysiological mechanisms. The data concerning 263 patients seen by dermatologists plus 642 additional cases directly reported by consumers to the manufacturer were analyzed. Seventy-seven patients were patch-tested, 26 extensively, and 15 performed a repeated open application test for a duration of 4 weeks. Control patch and use tests were performed in 73 and 25 patients, respectively. The results were analyzed statistically. In addition, 12 skin biopsies were performed for histological examination. Biochemical studies on the cosmetics (final products and offending ingredient) supplemented the clinical studies. The lesions were mainly papular and follicular, widely distributed, with pronounced pruritus, which was aggravated by sweating or heat exposure, and were long lasting. In a few cases, the papules were located on intensely erythematous, well-defined plaques, suggesting irritation rather than allergy. Both immediate and delayed onsets of the lesions were observed. Skin biopsies showed signs of folliculitis and perifolliculitis with little alteration of the interfollicular epidermis. Patch and use testing disclosed vitamin E linoleate (a mixture of tocopheryl esters, mainly tocopheryl linoleate) as the offending agent. An in vitro time-dependent formation of oxidative products under storage or oxidation-stimulating conditions was observed. Though vitamin E esters have been widely and safely used for decades in dermatological preparations and in cosmetics, vitamin E linoleate was the cause of about 1,000 cases of unusual papular mainly follicular contact dermatitis. Oxidized vitamin E derivatives could act in vivo as haptens and/or irritants, possibly with synergistic effects.


Regulation of mucociliary transport. Response of mucous cells to stimulation by amiloride applied to the frog palate in vitro.
Mucociliary transport (MCT) over the surface of isolated frog palatal epithelium was significantly inhibited by the diuretic drug amiloride (50% at 10(-5)M); this occurred when the drug was applied to the mucosal but not to the submucosal surface. The rate of ciliary beating was unchanged by treatment with amiloride (13.5 +/- 1.3 Hz, amiloride; 13.4 +/- 1.4 Hz, control). Spontaneous reversal of inhibition of MCT occurred after extended rinsing (1.5 to 3 h) with Ringer's solution; however, addition of mucus immediately restored MCT to control level. Amiloride applied to the mucosal surface stimulated 2.5 to 3 times as many cells to discharge mucus; this was correlated with an increase of 28% in apparent viscoelasticity of the mucus transport layer measured in situ (approximated by determining breaking strength of mucus using a surface tension balance). Other effects of mucosal application of amiloride included reduction of the transepithelial electrical potential by 62% and increased sodium (17%) in secreted mucus. This is the first report of a stimulatory effect by amiloride on mucous secretory cells.


Development of micro-flow hydrothermal monitoring systems and their applications to the origin of life study on Earth.
Continuous extensive studies on thermophilic organisms have suggested that life emerged on hydrothermal systems on primitive Earth. Thus, it is well known that hydrothermal reactions are, therefore, very important to study fields deeply related to the origin-of-life study. Furthermore, the importance of hydrothermal and solvothermal systems is now realized in both fundamental and practical areas. Here, our recent investigations are described for the development of real-time and in situ monitoring systems for hydrothermal reactions. The systems were primarily developed for the origin-of-life study, but it was also applicable to fundamental and practical areas. The present techniques are based on the concept that a sample solution is injected to a narrow tubing flow reactor at high temperatures, where the sample is rapidly heated up in a very short time by exposure at to a high-temperature narrow tubing flow reactor with a very short time scale. This enables millisecond to second time-scale monitoring in real time and/or in situ at temperatures of up to 400°C. By using these techniques, a series of studies on the hydrothermal origin-of-life have been successfully carried out.


A randomized noninferiority trial of condensed protocols for genetic risk disclosure of Alzheimer's disease.
Conventional multisession genetic counseling is currently recommended when disclosing apolipoprotein E (APOE) genotype for the risk of Alzheimer's disease (AD) in cognitively normal individuals. The objective of this study was to evaluate the safety of brief disclosure protocols for disclosing APOE genotype for the risk of AD. A randomized, multicenter noninferiority trial was conducted at four sites. Participants were asymptomatic adults having a first-degree relative with AD. A standard disclosure protocol by genetic counselors (SP-GC) was compared with condensed protocols, with disclosures by genetic counselors (CP-GC) and by physicians (CP-MD). Preplanned co-primary outcomes were anxiety and depression scales 12 months after disclosure. Three hundred and forty-three adults (mean age 58.3, range 33-86 years, 71% female, 23% African American) were randomly assigned to the SP-GC protocol (n = 115), CP-GC protocol (n = 116), or CP-MD protocol (n = 112). Mean postdisclosure scores on all outcomes were well below cut-offs for clinical concern across protocols. Comparing CP-GC with SP-GC, the 97.5% upper confidence limits at 12 months after disclosure on co-primary outcomes of anxiety and depression ranged from a difference of 1.2 to 2.0 in means (all P < .001 on noninferiority tests), establishing noninferiority for condensed protocols. Results were similar between European Americans and African Americans. These data support the safety of condensed protocols for APOE disclosure for those free of severe anxiety or depression who are actively seeking such information.


Glycine Perturbs Local and Global Conformational Flexibility of a Transmembrane Helix.
Flexible transmembrane helices frequently support the conformational transitions between different functional states of membrane proteins. While proline is well known to distort and destabilize transmembrane helices, the role of glycine is still debated. Here, we systematically investigated the effect of glycine on transmembrane helix flexibility by placing it at different sites within the otherwise uniform leucine/valine repeat sequence of the LV16 model helix. We show that amide deuterium/hydrogen exchange kinetics are increased near glycine. Molecular dynamics simulations reproduce the measured exchange kinetics and reveal, at atomic resolution, a severe packing defect at glycine that enhances local hydration. Furthermore, glycine alters H-bond occupancies and triggers a redistribution of α-helical and 310-helical H-bonds. These effects facilitate local helix bending at the glycine site and change the collective dynamics of the helix.


Pharmacological effects of several drugs on the myoepithelium and the vascular smooth muscle of the lactating mammary gland in goats.
The present experiments were performed to investigate whether the responses of the myoepithelium to several drugs would be of a parallel nature with those of the vascular smooth muscle in the lactating mammary gland of goats. The drugs were injected into the mammary artery. Kallikrein, bradykinin, oxytocin, and acetylcholine caused marked milk-ejection with vasodilation in a dose-dependent manner. Marked milk-ejections with high doses of oxytocin were observed despite of accompanying vasoconstriction. The relative order of their potency in milk-ejection activity was kallikrein greater than bradykinin greater than oxytocin greater than acetylcholine: 1 greater than 1/100 greater than 3/1000 greater than 5/1000000. As for the vasodilator activity, the relative potency of the drugs was in the same order: 1 greater than 1/10 greater than 1/1000 greater than 1/10000. Catecholamines, histamine, serotonin, angiotensin-II, vasopressin and high doses of prostaglandin E2 caused dose-dependent vasoconstriction. Isoprenaline, pilocarpine, adenosine, PGI2 and low doses of PGE2 caused dose-dependent vasodilation. But these drugs did not affect milk-ejection. PGE1 decreased milk-ejection and was accompanied by vasodilation. From these experiments it is suggested that the relative order of the potency of secretagogues in milk-ejection activity and in vasodilator activity is nearly equal. It is also suggested that some drugs are different in their effects on the myoepithelium and on the vascular smooth muscle of the lactating mammary gland.


Discovery of Modified Metabolites, Secondary Metabolites, and Xenobiotics by Structure-Oriented LC-MS/MS.
Exogenous compounds and metabolites derived from therapeutics, microbiota, or environmental exposures directly interact with endogenous metabolic pathways, influencing disease pathogenesis and modulating outcomes of clinical interventions. With few spectral library references, the identification of covalently modified biomolecules, secondary metabolites, and xenobiotics is a challenging task using global metabolomics profiling approaches. Numerous liquid chromatography-coupled mass spectrometry (LC-MS) small molecule analytical workflows have been developed to curate global profiling experiments for specific compound groups of interest. These workflows exploit shared structural moiety, functional groups, or elemental composition to discover novel and undescribed compounds through nontargeted small molecule discovery pipelines. This Review introduces the concept of structure-oriented LC-MS discovery methodology and aims to highlight common approaches employed for the detection and characterization of covalently modified biomolecules, secondary metabolites, and xenobiotics. These approaches represent a combination of instrument-dependent and computational techniques to rapidly curate global profiling experiments to detect putative ions of interest based on fragmentation patterns, predictable phase I or phase II metabolic transformations, or rare elemental composition. Application of these methods is explored for the detection and identification of novel and undescribed biomolecules relevant to the fields of toxicology, pharmacology, and drug discovery. Continued advances in these methods expand the capacity for selective compound discovery and characterization that promise remarkable insights into the molecular interactions of exogenous chemicals with host biochemical pathways.


Oral delivery of vancomycin by tetraether lipid liposomes.
Despite the outstanding progress in modern medicine, the oral delivery of peptide drugs is limited until today due to their instability in the gastrointestinal tract and low mucosa penetration. To overcome these hurdles, liposomes containing the specific tetraether lipid GCTE (glycerylcaldityltetraether lipid) were examined. For this purpose, the glycopeptide antibiotic vancomycin was used as model substance and liposomes were prepared by DAC (dual assymetric centrifugation). These liposomes showed a size and polydispersity index comparable to standard liposomes. A high encapsulation efficiency of 58.53±1.76% of the peptide drug vancomycin could be obtained as detected by HPLC. FCS analysis showed that in average each liposome contains 30 molecules of vancomycin. TEM and Cryo-EM micrographs verified the size and lamellarity of the liposomal formulations. Cytotoxicity tests in Caco-2 cells showed no significant cytotoxicity for all liposomal concentrations tested, indicating the good tolerability of these formulations. Furthermore, the use of sucrose as lyoprotector enabled the long term storage of the liposomal formulation for at least three months. The potency of this drug delivery system could be proven in an animal model using Wistar rats. One hour after oral application, 4.82±0.56% of the administered dose of vancomycin could be found in the blood as detected by immunoassay measurements. This transport did also not affect the integrity of the peptide as verified by immunoassay measurements. In combination with long term storage stability, this formulation appears to be a promising delivery system for oral application of peptide drugs.


MicroRNA-mediated gene silencing.
MicroRNAs are 20-21 nucleotides-long noncoding RNAs that function as posttranscriptional regulators of gene expression in a variety of organisms ranging from plants to mammalian cells. These regulators are encoded by approximately 800 genes in the mammalian genome and target half of the mRNAs in mammalian cells. While the biogenesis of microRNAs is fairly well understood, the mechanism by which target genes are regulated remains controversial. The recent discoveries that viruses encode microRNAs or subvert host cell microRNAs has enhanced our knowledge about biological functions of microRNAs during disease and has suggested that microRNAs could be used as targets in antiviral gene therapy. This review will provide a brief history of microRNA research, discuss the biogenesis and mechanisms of microRNAs, and summarize findings that have employed inhibitors of microRNA miR-122 to treat hepatitis C virus-induced liver disease.


Holmium laser angioplasty.
The investigational solid-state, pulsed-wave, mid-infrared (2.1 microns) holmium:YAG laser can be applied for plaque ablation and thrombus dissolution. A multicentre study reports 87% laser success and 94% final procedural success. It has established the safety and efficacy of this laser in ischaemic syndromes and acute myocardial infarction treating lesions considered 'not ideal' for balloon angioplasty. These include thrombotic occlusions, total occlusions, calcified obstructions, de novo and restenosis lesions within native coronary arteries and saphenous vein grafts. Unfortunately, the laser does not significantly reduce restenosis rate. Processes related to laser-tissue interactions such as gas vapour formation and generation of acoustic waves with tremendous intraplaque pressures mandate application of appropriate lasing technique to ensure clinical success.


Discrepancy between biological activity of thymosin and its cyclic nucleotide-modulating activity.
We have studied cyclic adenosine 3':5'-monophosphate (cAMP) and cyclic 3':5'-guanosine monophosphate (cGMP) concentration in cord blood lymphocytes (CBL) and in adult peripheral blood lymphocytes (PBL) after stimulation with thymosin V-1 and V-2. At concentrations of 100 micrograms/ml, thymosin V-1 produced an 85% increase of cAMP in adult PBL, alterations being demonstrated within 1 min, whereas it did not affect the cAMP level in CBL which have a nine times higher basal level than PBL. On the other hand, thymosin V-1 did not have any effect on cGMP in CBL nor in adult PBL. Thymosin V-2 which inhibits E-rosette formation also increased cAMP in adult PBL like thymosin V-1. The increasing effect of thymosin V-1 on cAMP was observed even when cAMP phosphodiesterase was completely inhibited with isobutyl methylxanthine. From these data it was assumed that thymosin probably acts through the stimulation of adenylate cyclase.


Transcriptome-Wide Identification of the GRAS Transcription Factor Family in Pinus massoniana and Its Role in Regulating Development and Stress Response.
Pinus massoniana is a species used in afforestation and has high economic, ecological, and therapeutic significance. P. massoniana experiences a variety of biotic and abiotic stresses, and thus presents a suitable model for studying how woody plants respond to such stress. Numerous families of transcription factors are involved in the research of stress resistance, with the GRAS family playing a significant role in plant development and stress response. Though GRASs have been well explored in various plant species, much research remains to be undertaken on the GRAS family in P. massoniana. In this study, 21 PmGRASs were identified in the P. massoniana transcriptome. P. massoniana and Arabidopsis thaliana phylogenetic analyses revealed that the PmGRAS family can be separated into nine subfamilies. The results of qRT-PCR and transcriptome analyses under various stress and hormone treatments reveal that PmGRASs, particularly PmGRAS9, PmGRAS10 and PmGRAS17, may be crucial for stress resistance. The majority of PmGRASs were significantly expressed in needles and may function at multiple locales and developmental stages, according to tissue-specific expression analyses. Furthermore, the DELLA subfamily members PmGRAS9 and PmGRAS17 were nuclear localization proteins, while PmGRAS9 demonstrated transcriptional activation activity in yeast. The results of this study will help explore the relevant factors regulating the development of P. massoniana, improve stress resistance and lay the foundation for further identification of the biological functions of PmGRASs.


Kinetics and bioenergetics of light-limited photoautotrophic growth of Spirulina platensis.
Blue-green algae, Spirulina platensis, is cultivated under photoautotrophic growth conditions designed to have nearly uniform growth rate throughout the fermentor by illumination both sides of a rectangular vessel. The results show that growth rate and bioenergetic yield are a function of light intensity. Several kinetic models are considered to express the relationship between growth rate and light intensity.


Do surgeons have a sell-by date?
When should surgeons retire? Do they have a defined shelf life and a sell-by date? At what point should they chuck in the scalpel and hang up their gloves? The answer to these questions for young and old surgeons is found by them merely looking around themselves: the young to make continuous mental notes about what to do (and not to do) when they get older; older surgeons to do so as a reality or insight check. The first gaze is at the theory and understanding that underpins surgery - academic surgery if you will - and the second gaze is at the craft of cutting, for surgeons are really just journeymencraftsmen, the better ones with well-developed cognitive and manipulative skills.


[Transferrin receptor imaging for tracing mesenchymal stem cells implanted in the spinal cord].
To explore the feasibility of tracing mesenchymal stem cells in vivo with scintigraphy. Transferrin receptor expression of cultured mesenchymal stem cells (hMSCs) was quantified with radioligand-receptor binding assay before the cells were transplanted into the spinal cord of rabbits. (131)I-labeled transferrin was then administered into the subarachnoid space of the rabbits, and scintigraphic images were acquired with a gamma camera at different time points after the administration. In the control experiments, (131)I-labeled human serum albumin was used in stead of (131)I-transferrin as the tracer, or only PBS was injected without stem cell transplantation. The images were semi-quantitatively analyzed with region of interest (ROI) techniques, and the phosphor imaging on the spinal sections were performed. Radioligand-receptor binding assay showed 10 770 binding sites with high affinity (KD=0.982 nmol/L) for Fe saturated transferrin on each human mesenchymal cell. Visible accumulation of radioactivity at the cell transplantation sites was observed 16 h and 24 h after intrathecal injection of (131)I-transferrin tracer, but not in two control groups. ROI analysis showed that the difference between (131)I-transferrin and the control groups was statistically significant (P<0.05). Phosphor imaging further verified that it was the specific coupling of transferrin to the implanted cells that resulted in radioactivity accumulation at the transplantation sites. Transferrin receptor imaging is capable of in vivo tracing of the implanted stem cells, and has the potential for use in non-invasive monitoring for stem cell transplantation therapy after further technical improvements.


Evaluating challenges for improving medically unexplained symptoms in US military veterans via provider communication.
Medically unexplained symptoms (MUS) are common, with particularly high rates observed in military veterans. Effective patient-provider-communication is thought to be a key aspect of care; however there have been few empirical studies on the association between communication and outcomes for patients with MUS. We evaluate whether discussing veterans' MUS-illness representations and good interpersonal skills have the potential to promote MUS-treatment adherence and improvement. Veterans experiencing MUS (n=204) reported on their primary care providers' communication about illness representations and interpersonal skills; correlation, regression, and bootstrap-mediation analyses were conducted to test hypotheses regarding veteran-reported outcomes. Main outcomes included satisfaction with the provider, MUS-treatment adherence, intentions to adhere, and expectations for MUS improvement. Veterans reported infrequent discussion of MUS illness representations but high degrees of provider interpersonal skills. Communication regarding patients' illness representations and treatment expectations was significantly related to treatment adherence and adherence intentions; provider interpersonal skills were not. Both were related to veteran satisfaction. Providers' interpersonal skills may be important in chronic illness contexts, such as MUS, by contributing to satisfaction with the provider. The current study suggests that providers may better promote MUS-treatment adherence through discussing MUS illness representations and treatment expectations.


Can metal-free silicon-doped hexagonal boron nitride nanosheets and nanotubes exhibit activity toward CO oxidation?
Si-doped hexagonal boron nitride nanosheets (Si-BNNS) and nanotubes (Si-BNNT) have been investigated by first-principle methods. The strong interaction between the silicon atom and the hexagonal boron nitride nanosheet or nanotube with a boron vacancy indicates that such nanocomposites should be very stable. The significant charge transfer from the Si-BNNS substrate to the O2 molecule, which could occupy the antibonding 2π* orbitals of O2, results in the activation of the adsorbed O2. The catalytic activity of the Si-BNNS for CO oxidation is explored and the calculated barrier (0.29 eV) of the reaction CO + O2→ CO2 + O is much lower than those on the traditional noble metals. This opens a new avenue to fabricate low cost and high activity boron nitride-based metal-free catalysts.


Fascicular nerve graft using an empty perineurial tube: an experimental study in the rabbit.
An experimental model of a free, empty perineurial tube for use as a nerve graft is presented as an alternative to existing methods. The technique is described and the model compared with conventional nerve graft in the sciatic nerve of a rabbit. Results are evaluated with EMG studies, angiography, and histology. The experimental model compared favorably with the standard graft. Further avenues of investigation and clinical use are suggested.


A mesomelic skeletal dysplasia, Kantaputra-like, not related to HOXD cluster region, and with phenotypic gender differences.
Mesomelic skeletal dysplasia is a heterogeneous group of skeletal disorders that has grown since the molecular basis of these conditions is in the process of research and discovery. Here, we report a Brazilian family with eight affected members over three generations with a phenotype similar to mesomelic Kantaputra dysplasia. This family presents marked shortening of the upper limbs with hypotrophy of the lower limbs and clubfeet without synostosis. Array-based CNV analysis and exome sequencing of four family members failed to show any region or gene candidate. Interestingly, males were more severely affected than females in this family, suggesting that gender differences could play a role in the phenotypic expressivity of this condition.


Research progress of lens zonules.
The lens zonule, a circumferential system of fibres connecting the ciliary body to the lens, is responsible for centration of the lens. The structural, functional, and positional abnormalities of the zonular apparatus can lead to the abnormality of the intraocular structure, presenting a significant challenge to cataract surgery. The lens zonule is the elaborate system of extracellular fibers, which not only centers the lens in the eye but also plays an important role in accommodation and lens immunity, maintains the shape of the lens, and corrects spherical aberration. The zonules may directly participate in the formation of cataract via the immune mechanism. Abnormal zonular fibers that affect the position and shape of the lens may play an important role in the pathogenesis of angle closure disease and increase the complexity of the surgery. Capsular tension rings and related endocapsular devices are used to provide sufficient capsular bag stabilization and ensure the safety of cataract surgery procedures. Better preoperative and intraoperative evaluation methods for zonules are needed for clinicians. The microstructure, biomechanical properties, and physiological functions of the lens zonules help us to better understand the pathogenesis of cataract and glaucoma, facilitating the development of safer surgical procedures for cataract. Further studies are needed to carefully analyze the structure-function relationship of the zonular apparatus to explore new treatment strategies for cataract and glaucoma.


Role of Arabidopsis ARGONAUTE4 in RNA-directed DNA methylation triggered by inverted repeats.
In a number of organisms, transgenes containing transcribed inverted repeats (IRs) that produce hairpin RNA can trigger RNA-mediated silencing, which is associated with 21-24 nucleotide small interfering RNAs (siRNAs). In plants, IR-driven RNA silencing also causes extensive cytosine methylation of homologous DNA in both the transgene "trigger" and any other homologous DNA sequences--"targets". Endogenous genomic sequences, including transposable elements and repeated elements, are also subject to RNA-mediated silencing. The RNA silencing gene ARGONAUTE4 (AGO4) is required for maintenance of DNA methylation at several endogenous loci and for the establishment of methylation at the FWA gene. Here, we show that mutation of AGO4 substantially reduces the maintenance of DNA methylation triggered by IR transgenes, but AGO4 loss-of-function does not block the initiation of DNA methylation by IRs. AGO4 primarily affects non-CG methylation of the target sequences, while the IR trigger sequences lose methylation in all sequence contexts. Finally, we find that AGO4 and the DRM methyltransferase genes are required for maintenance of siRNAs at a subset of endogenous sequences, but AGO4 is not required for the accumulation of IR-induced siRNAs or a number of endogenous siRNAs, suggesting that AGO4 may function downstream of siRNA production.