Rtp1p is a karyopherin-like protein required for RNA polymerase II biogenesis.
The assembly and nuclear transport of RNA polymerase II (RNA pol II) are processes that require the participation of many auxiliary factors. In a yeast genetic screen, we identified a previously uncharacterized gene, YMR185w (renamed RTP1), which encodes a protein required for the nuclear import of RNA pol II. Using protein affinity purification coupled to mass spectrometry, we identified interactions between Rtp1p and members of the R2TP complex. Rtp1p also interacts, to a different extent, with several RNA pol II subunits. The pattern of interactions is compatible with a role for Rtp1p as an assembly factor that participates in the formation of the Rpb2/Rpb3 subassembly complex and its binding to the Rpb1p-containing subcomplex. Besides, Rtp1p has a molecular architecture characteristic of karyopherins, composed of HEAT repeats, and is able to interact with phenylalanine-glycine-containing nucleoporins. Our results define Rtp1p as a new component of the RNA pol II biogenesis machinery that plays roles in subunit assembly and likely in transport through the nuclear pore complex.


Quantitative biparametric analysis of hybrid 18F-FET PET/MR-neuroimaging for differentiation between treatment response and recurrent glioma.
We investigated the diagnostic potential of simultaneous 18F-FET PET/MR-imaging for differentiation between recurrent glioma and post-treatment related effects (PTRE) using quantitative volumetric (3D-VOI) lesion analysis. In this retrospective study, a total of 42 patients including 32 patients with histologically proven glioma relapse and 10 patients with PTRE (histopathologic follow-up, n = 4, serial imaging follow-up, n = 6) were evaluated regarding recurrence. PET/MR-imaging was semi-automatically analysed based on FET tracer uptake using conservative SUV thresholding (isocontour 80%) with emphasis on the metabolically most active regions. Mean (relative) apparent diffusion coefficient (ADCmean, rADCmean), standardised-uptake-value (SUV) including target-to-background (TBR) ratio were determined. Glioma relapse presented higher ADCmean (MD ± SE, 284 ± 91, p = 0.003) and TBRmax (MD ± SE, 1.10 ± 0.45, p = 0.02) values than treatment-related changes. Both ADCmean (AUC ± SE = 0.82 ± 0.07, p-value < 0.001) and TBRmax (AUC ± SE = 0.81 ± 0.08, p-value < 0.001) achieved reliable diagnostic performance in differentiating glioma recurrence from PTRE. Bivariate analysis based on a combination of ADCmean and TBRmax demonstrated highest diagnostic accuracy (AUC ± SE = 0.90 ± 0.05, p-value < 0.001), improving clinical (false negative and false positive) classification. In conclusion, biparametric analysis using DWI and FET PET, both providing distinct information regarding the underlying pathophysiology, presented best diagnostic accuracy and clinical benefit in differentiating recurrent glioma from treatment-related changes.


Visual evaluation and differentiation of renal oncocytomas from renal cell carcinomas by means of 99mTc-sestamibi SPECT/CT.
Despite the progress in the quality of multiphasic CT and MRI scans, it is still difficult to fully characterize a solid kidney lesion. Approximately 10% of all solid renal tumours turn out to be oncocytomas. In actual clinical practice, this is verified only following unnecessary surgery or a renal biopsy/ablation. The objective of our pilot study examines whether 99mTc-sestamibi SPECT/CT can play a crucial role in the characterization of solid renal neoplasms and the differentiation of oncocytomas from renal cell carcinomas. The study included 27 patients identified with 31 solid renal lesions. All patients were discussed in a multidisciplinary conference, and a decision for surgery or biopsy was taken. Prior to invasive procedures, patients underwent a SPECT/CT with 99mTc-sestamibi. Visual evaluation was performed, and any focal 99mTc-sestamibi uptake detected on SPECT in the localisation of tumour was considered as positive. Eleven out of 12 oncocytomas (91.6%) displayed positive uptake of 99mTc-sestamibi. Three hybrid tumours (mixed-type oncocytoma and chromophobe renal cancer) were positive on SPECT/CT. One papillary renal cell carcinoma had a slight uptake of 99mTc-sestamibi. The remaining 11 renal cell carcinomas were sestamibi negative. Differentiation of benign renal oncocytomas from renal cell carcinomas seems very promising on 99mTc-sestamibi SPECT/CT examination. Additional supplement to visual evaluation, i.e. quantitative tools, should be sought for an accurate estimate of biological behaviour and hence a secure diagnosis.


A study of degradation resistance and cytocompatibility of super-hydrophobic coating on magnesium.
Calcium stearate based super-hydrophobic coating was deposited on plasma electrolytic oxidation (PEO) pre-treated magnesium substrate. The pre-treated magnesium and super-hydrophobic coating covered sample were characterized by scanning electron microscopy, X-ray diffraction and electrochemical corrosion measurements. The cytocompatibility and degradation resistance of magnesium, pre-treated magnesium and super-hydrophobic coating were analysed in terms of cell adhesion and osteoblast differentiation. The results indicate that the calcium stearate top coating shows super-hydrophobicity and that the surface is composed of micro/nanostructure. The super-hydrophobic coating covered sample shows higher barrier properties compared with the PEO pre-treated magnesium and bare magnesium. Human osteoblast proliferation, but not differentiation is enhanced by the PEO coating. Contrary, the super-hydrophobic coating reduces proliferation, but enhances differentiation of osteoblast, observable by the formation of hydroxyapatite. The combination of corrosion protection and cell reaction indicates that this system could be interesting for biomedical applications.


The role of arsenic in obesity and diabetes.
As many individuals worlwide are exposed to arsenic, it is necessary to unravel the role of arsenic in the risk of obesity and diabetes. Therefore, the present study reviewed the effects of arsenic exposure on the risk and potential etiologic mechanisms of obesity and diabetes. It has been suggested that inflammation, oxidative stress, and apoptosis contribute to the pathogenesis of arsenic-induced diabetes and obesity. Though arsenic is known to cause diabetes through different mechanisms, the role of adipose tissue in diabetes is still unclear. This review exhibited the effects of arsenic on the metabolism and signaling pathways within adipose tissue (such as sirtuin 3 [SIRT3]- forkhead box O3 [FOXO3a], mitogen-activated protein kinase [MAPK], phosphoinositide-dependant kinase-1 [PDK-1], unfolded protein response, and C/EBP homologous protein [CHOP10]). Different types of adipokines involved in arsenic-induced diabetes are yet to be elucidated. Arsenic exerts negative effects on the white adipose tissue by decreasing adipogenesis and enhancing lipolysis. Some epidemiological studies have shown that arsenic can promote obesity. Nevertheless, few studies have indicated that arsenic may induce lipodystrophy. Arsenic multifactorial effects include accelerating birth and postnatal weight gains, elevated body fat content, glucose intolerance, insulin resistance, and increased serum lipid profile. Arsenic also elevated cord blood and placental, as well as postnatal serum leptin levels. The data from human studies indicate an association between inorganic arsenic exposure and the risk of diabetes and obesity. However, the currently available evidence is insufficient to conclude that low-moderate dose arsenic is associated with diabetes or obesity development. Therefore, more investigations are needed to determine biological mechanisms linking arsenic exposure to obesity and diabetes.


Prevention of PPROM: current and future strategies.
Our understanding of the pathophysiologic processes leading to preterm premature rupture of membranes (PPROM) has grown tremendously in recent years. Evidence suggests that there may be a genetic susceptibility to PPROM and that genetic and environmental elements are important cofactors in its development. A number of risk-based protocols have been proposed in an attempt to identify those women at highest risk for PPROM. While we have made advances in the area of predicting PPROM, treatments based on current risk-based systems have failed to distinguish a specific, effective preventive therapy for PPROM. The concept that genetic factors increase susceptibility or decrease resistance to disease has stimulated new work in the field of PPROM. Several maternal and fetal gene polymorphisms have been identified that are associated with an increased risk for PPROM. Patients with 'susceptible' genotypes may also have clinical risk factors for PPROM resulting in a synergistic increase in the risk for PPROM, a so-called gene-environment interaction. The concept that these gene-environment interactions represent new targets for our efforts to prevent PPROM is explored.


[Extended resection for a huge retroperitoneal malignant paraganglioma-a case report].
A 74-year-old man was transferred to our institute because of a huge abdominal tumor in April 2012. Computed tomography (CT) showed the presence of a huge retroperitoneal tumor, 20 cm in diameter. The tumor directly infiltrated the right kidney, the liver, and the inferior vena cava. Obstruction of the hepatic hilum and right hydronephrosis in the near future was predicted, and therefore, immediate surgical intervention was selected. Extracorporeal circulation was essential for complete tumor removal. The tumor was removed en bloc together with the right lobe of the liver, the right kidney, the ileocecal portion, and the retrohepatic vena cava. Histopathological examination indicated a diagnosis of paraganglioma. Two months after surgery, CT showed a recurrent lesion at the resected surface of the pelvic cavity. Additional radiotherapy was ineffective, and the patient died 6 months after surgery.


Epileptic Spasms in Patients With Down Syndrome: Experiences From Caregivers.
Epileptic spasms are the most common type of seizure in infants with Down syndrome; however, the scope of current literature is largely limited to treatment options. We performed a chart review of patients seen at a Down syndrome specialty clinic to identify potential developmental sequelae of Down syndrome and epileptic spasms. We further interviewed parents of the children with Down syndrome and epileptic spasms to identify areas for improvement in counseling, diagnosis, and follow-up. Persistent developmental delays and autism spectrum disorder were highly prevalent in our patients. Caregivers attributed delays in treatment to insufficient counseling and awareness of epileptic spasms. They also identified inadequate emotional support after the diagnosis of the spasms. When counseling parents of infants with Down syndrome, pediatricians should educate about epileptic spasms. If spasms are diagnosed, providing emotional support with frequent follow-up is important. Furthermore, clinicians should monitor for signs of epilepsy and autism spectrum disorder.


Postnatal development of the circadian rhythm of circulating blood cells in rats.
In the present study the variations in the leukocyte and erythrocyte counts were investigated in the peripheral blood within the light and darkness periods during the postnatal development of rats. The animals were kept under an artificial illumination regime (12 hours light, 12 hours darkness), and examined at the ages of 7, 14, 21, 28, 35 and 45 days, and in maturity (56 days). Erythrocyte counts exhibited no light-dark rhythm. The circadian rhythm of leukocyte counts developed in male and female laboratory rats in the fourth week of age.


Soybean Whey Bio-Processed Using Weissella hellenica D1501 Protects Neuronal PC12 Cells Against Oxidative Damage.
Soybean whey, as a byproduct of soybean industry, has caused considerable concern recently because of its abundant nutrients. To further utilize soybean whey, it was fermented with Weissella hellenica D1501, and the neuroprotective potency of this beverage was studied in the present work. The phenolic profile and antioxidant capacity of fermented soybean whey (FSBW) were analyzed. The neuroprotective effects were evaluated based on the hydrogen peroxide-stimulated oxidative damage model in a neural-like cell (PC12). Results demonstrated that soybean whey's phenolic contents and antioxidant activities were markedly improved after fermentation. Glycoside isoflavones were efficiently converted into aglycones by W. hellenica D1501. FSBW extract apparently increased cell viability, decreased reactive oxide species levels, and protected antioxidant enzymes in oxidative damage. Furthermore, FSBW effectively reduced apoptosis rate by inhibiting Bax protein and improving Bcl-2 and Bcl-xL proteins. FSBW ameliorated the cell cycle through the decrease of p21 protein and an increase of cyclin A protein. The findings of this study thus suggested that W. hellenica D1501-fermented soybean whey could potentially protect nerve cells against oxidative damage.


Cancer Incidence after In Utero Exposure to Ionizing Radiation in Techa River Residents.
Health effects of in utero exposure to ionizing radiation, especially among adults, are still unclear. The aim of this study was to analyze cancer risk in a cohort of subjects exposed in utero due to releases of nuclear waste into the Techa River in the Southern Urals, taking into account additional postnatal exposure. Analysis for solid cancer was based on 242 cases among 10,482 cohort members, accumulating 381,948 person-years at risk, with follow-up from 1956-2009, while analysis for hematological malignancies was based on 26 cases among 11,070 persons, with 423,502 person-years at risk, with follow-up from 1953-2009. Mean doses accumulated in soft tissues and in red bone marrow during the prenatal period were 4 mGy and 30 mGy, respectively. Additional respective mean postnatal doses received by cohort members were 11 and 84 mGy. Poisson regression analysis was used to estimate the excess relative risk (ERR) of cancer incidence related to in utero and postnatal doses. No association was observed for in utero exposure with solid cancer risk [ERR per 10 mGy: -0.007; 95% confidence interval (CI): <-0.107; 0.148] or with hematological malignancy risk (ERR/10 mGy: -0.011; 95% CI: <-0.015; 0.099). However, ERR of solid cancer increased significantly with increasing postnatal dose (ERR/10 mGy: 0.11; 95% CI: 0.04; 0.22). The very wide confidence intervals in these ERR results are similar to those of studies performed on the LSS cohort and the offspring of the Mayak Female Worker Cohort, as well as case-control studies of effects after in utero medical exposure. There were limitations of this study, with decreased statistical power, due to the low prenatal doses received by most of the cohort members, the small number of cancer cases and the absence of cohort members over the age of 59 years (living cohort members had reached 49-59 years of age). Further aging of the cohort and extension of the follow-up period will enhance the statistical power of this study in the future. There is a shortage of cohort studies reporting on the effects of prenatal radiation exposure, as well as information on chronic exposure during the prenatal period. Therefore, further research of this unique cohort will be a useful addition to the published literature on this subject, and a valuable means of elucidating the long-term effects of low-dose radiation exposure in the fetus.


[Acute liver failure--medical viewpoints].
Acute liver failure is a rare disease that can cause death in the majority of untreated cases. Sudden loss of liver function in the absence of a preexisting liver disease is considered the true form and has to be distinguished from impaired function following exacerbation of an underlying liver disease (acute or chronic failure). Common causes include acute viral hepatitis, drug induced liver injury (DILI) and toxins. The loss of the excretory and synthetic function of the liver marks the clinical presentation and results in icterus, coagulopathy and encephalopathy. Additionally impairment of renal function and sepsis occur and contribute to the high mortality of this disease. The activation of cell death mechanisms (apoptosis) leading to a reductio of viable, functional liver tissue is considered to be an important pathophysiologic mechanism. Curative therapy of this disease includes liver transplantation that has been performed in Germany for the first time in 1969. In the year 2004 a total of 91 liver transplantation were performed for acute liver failure (10.3% of all transplants) in German transplant centers.


Many human genes are transcribed from the antisense promoter of L1 retrotransposon.
Human L1 retrotransposon has two transcription-regulatory regions: an internal or sense promoter driving transcription of the full-length L1, and an antisense promoter (ASP) driving transcription in the opposite direction into adjacent cellular sequences yielding chimeric transcripts. Both promoters are located in the 5'-untranslated region (5'-UTR) of L1. Chimeric transcripts derived from the L1 ASP are highly represented in expressed-sequence tag (EST) databases. Using a bioinformatics approach, we have characterized 10 chimeric ESTs (cESTs) derived from the EST division of GenBank. These cESTs contained 3' regions similar or identical to known cellular mRNA sequences. They were accurately spliced and preferentially expressed in tumor cell lines. Analysis of the hundreds of cESTs suggests that the L1 ASP-driven transcription is a common phenomenon not only for tumor cells but also for normal ones and may involve transcriptional interference or epigenetic control of different cellular genes.


Electrochemical synthesis of cobalt hydroxide films with tunable interlayer spacings.
An electrochemical synthetic condition is developed to produce cobalt hydroxide films with significantly increased basal spacings (d(001)>or= 25.0 A) by incorporating anionic surfactants (i.e. sodium dodecyl sulfate and 1-hexadecanesulfonate) into the interlayer regions via electrodeposition.


Lower-Limb Ischemia at Birth Because of Spontaneous Arterial Thrombosis: A Case Report.
A full-term neonate presented with right lower extremity ischemia at birth because of spontaneous thrombosis of the right common iliac artery. He was initially managed with supportive treatment, anticoagulation, and dressings; however, advanced gangrenous changes precluded salvage of the ischemic limb. A guillotine amputation was performed at day 15 of life, and the stump went on to heal well by secondary intention. Thromboembolic events occurring in infancy are well-recognized phenomena; however, it is far rarer to encounter a neonate born with "congenital gangrene". We discuss the etiology, approach to diagnosis, and treatment of this rare but devastating condition.


Calcium channel blocker azelnidipine reduces glucose intolerance in diabetic mice via different mechanism than angiotensin receptor blocker olmesartan.
The potential combined effect and mechanism of calcium channel blockers (CCB) and angiotensin II type 1 receptor blockers (ARB) to improve insulin resistance were investigated in type 2 diabetic KK-Ay mice, focusing on their antioxidative action. Treatment of KK-Ay mice with a CCB, azelnidipine (3 mg/kg/day), or with an ARB, olmesartan (3 mg/kg/day), for 2 weeks lowered the plasma concentrations of glucose and insulin in the fed state, attenuated the increase in plasma glucose in the oral glucose tolerance test (OGTT), and increased 2-[(3)H]deoxy-d-glucose (2-[(3)H]DG) uptake into skeletal muscle with the increase in translocation of glucose transporter 4 (GLUT4) to the plasma membrane. Both blockers also decreased the in situ superoxide production in skeletal muscle. The decrease in plasma concentrations of glucose and insulin in the fed state and superoxide production in skeletal muscle, as well as GLUT4 translocation to the plasma membrane, after azelnidipine administration was not significantly affected by coadministration of an antioxidant, 2,2,6,6-tetramethyl-1-piperidinyloxy (tempol). However, those changes caused by olmesartan were further improved by tempol. Moreover, olmesartan enhanced the insulin-induced tyrosine phosphorylation of insulin receptor substrate-1 induced in skeletal muscle, whereas azelnidipine did not change it. Coadministration of azelnidipine and olmesartan further decreased the plasma concentrations of glucose and insulin, improved OGTT, and increased 2-[(3)H]DG uptake in skeletal muscle. These results suggest that azelnidipine improved glucose intolerance mainly through inhibition of oxidative stress and enhanced the inhibitory effects of olmesartan on glucose intolerance, as well as the clinical possibility that the combination of CCB and ARB could be more effective than monotherapy in the treatment of insulin resistance.


Does orthostatic stress influence the neuroendocrine response to subsequent hypoglycemia in humans?
Neuroendocrine response to stress stimuli is influenced by previous stimuli of different nature. The aim of the study was to test whether antecedent orthostatic stress may affect the neuroendocrine response to subsequent hypoglycemia. A group of 12 (6 men, 6 women) nonobese, healthy volunteers aged 19 to 27 y (mean 24 +/- 0.8) participated in the study in two sessions: controlled insulin-induced hypoglycemia to 2.7 mmol/L for 15 min either with or without antecedent orthostatic stress (30 min of 60 degrees head-up tilt before insulin administration). Orthostatic stress caused a significant decrease in plasma volume (-9.6%; P < 0.001) and a significant increase in plasma renin activity, aldosterone, norepinephrine (P < 0.01), and adrenocorticotropic hormone (ACTH) concentrations (P < 0.05) in all subjects. Growth hormone response to hypoglycemia was diminished in women (P < 0.01). The epinephrine response to hypoglycemia was diminished in women in comparison to men (P < 0.001), but was unaffected by antecedent orthostatic stress. Hypoglycemia failed to induce the ACTH release after its elevation during orthostatic stress. ACTH response to moderate hypoglycemia without previous orthostatic stress was evident only in men in comparison to women (P < 0.05). We conclude that the epinephrine, growth hormone, and ACTH responses to hypoglycemia were diminished in women. Except ACTH, the neuroendocrine response to mild hypoglycemia was not affected by previous orthostatic stress in healthy subjects. In the case of ACTH, the first stress stimulus is consequential for the subsequent response of this hormone, probably due to short-loop negative feedback effects.


Myoelectric stimulation on peroneal muscles with electrodes of the muscle belly size attached to the upper shank gives the best effect in resisting simulated ankle sprain motion.
Ankle sprain is a common sports related injury that may be caused by incorrect positioning of the foot prior to and at initial contact during landing from a jump or gait. Furthermore a delayed reaction of the peroneal muscle may also contribute to the injury mechanism. A recent study demonstrated that myoelectric stimulation of the peroneal muscles within 15 ms of a simulated inversion event would significantly resist an ankle spraining motion. This study further investigated its effect with three different electrode sizes and three different lateral shank attachment positions. Twelve male subjects with healthy ankles performed simulated ankle supination spraining motion on a pair of mechanical sprain simulators. A pair of electrodes of one of the three sizes (large, medium, small) was attached to one of the three positions (upper 1/4, middle, lower 1/4) along the lateral shank to deliver an electrical signal of 130 V for 0.5s when the sprain simulator started. Ankle kinematics data were collected by a tri-axial gyroscope motion sensor and the peak inward heel tilting velocity was obtained to represent the effect in resisting the simulated ankle spraining motion. Repeated measures one-way analysis of variance was performed and showed a significant drop from 273.3 (control, no stimulation) to 215.8 deg/s (21%) when small electrodes were attached to the upper 1/4 position. Decrease was found in all other conditions but the drops (11-18%) were not statistically significant. The small electrodes used in this study fitted the width of the peroneal muscle belly at the upper 1/4 position, so the electrical current may have well flowed to the motor points of the muscles to initiate quick contraction.


Accuracy of clinical diagnosis and malaria rapid diagnostic test and its influence on the management of children with fever under reduced malaria burden in Misungwi district, Mwanza Tanzania.
Malaria diagnosis is known to be non-specific because of the overlap of symptoms of malaria with other infectious diseases that is made worse with declining malaria burden. Though the use of malaria rapid diagnostic test (mRDT) for malaria confirmation has universally been adopted, malaria decline may alter performance of mRDT. This study examined accuracy of clinical diagnosis and mRDT and its influence on prescription for febrile underfives. A cross-sectional study of 600 underfives was carried out in 6 randomly selected health facilities in Misungwi district, Mwanza; from November - December 2014. Consecutive underfives with a fever consultation were recruited: for each fever and the clinical diagnosis entertained were recorded. Parasitological confirmation of malaria was done by mRDT and microscopic examination of finger prick blood samples. Treatment was based on mRDT results, drugs prescribed recorded. Accuracy of clinical diagnosis and mRDT in predicting malaria was assessed by performance indices against microscopy. Antimalarial and antibiotics prescriptions were assessed against parasitological findings. Clinically, 37.2% had malaria; 32.8% were mRDTpositive and 17.0% microscopically positive. Sensitivity of clinical diagnosis was very high (97.0% [95%CI: 91.0-99.2]); specificity 66.7% [95%CI: 62.3-70.8], and positive predictive value 37.4% (95%CI: 31.6-43.5). Sensitivity of mRDTwas very high (99.0% [95%CI: 93.9-99.9]), specificity (80.7% [95%CI: 76.9-84.0]), positive predictive value 51.3% [95% CI: 44.1-58.4]) and negative predictive 99.75% [95%CI: 99.4-100.0]. Those receiving antimalarial prescription, 75.0% were mRDT positive; 39.4% microscopically positive. Those receiving antibiotic, 78.8% were mRDT negative; 90.1% microscopically negative. Decline in malaria lowered specificity of mRDT to < 95% against WHO recommendation. Though adherence to mRDT results was high, there was over prescription of antibiotics.


Glutathiolation regulates tumor necrosis factor-alpha-induced caspase-3 cleavage and apoptosis: key role for glutaredoxin in the death pathway.
Caspase-3 cleavage and activation are known to play central roles in apoptosis. However, the mechanisms that regulate caspase-3 cleavage remain elusive. Glutaredoxin (Grx) is a ubiquitous redox molecule that is unique in its ability to regulate S-glutathiolation (glutathiolation) of proteins. Here we show the essential role of Grx in caspase-3 cleavage via regulation of caspase-3 glutathiolation. Grx activity was significantly upregulated by tumor necrosis factor-alpha in endothelial cells. Small interference RNA knock down of Grx significantly inhibited tumor necrosis factor-alpha-induced endothelial cell death because of attenuated caspase-3 cleavage concomitant with increased caspase-3 glutathiolation. Enhanced caspase-3 cleavage by wild-type Grx overexpression was reversed by catalytically inactive Grx (C22S), demonstrating a requirement for thioltransferase activity. Cysteine-to-serine mutations (C163S, C184S, and C220S) of caspase-3 that were predicted to prevent glutathiolation showed increased cleavage compared with wild-type caspase-3. This inverse correlation between caspase-3 glutathiolation and cleavage was further confirmed by the observation that in vitro glutathiolation of caspase-3 inhibited its cleavage with recombinant caspase-8. Furthermore, Grx association with caspase-3 was decreased by tumor necrosis factor-alpha. These findings demonstrate a novel mechanism of caspase-3 regulation by Grx in tumor necrosis factor-alpha-induced apoptosis.


[Contemplating a university clinical department].
University clinics combine teaching, research and patient care. Some think that no single person (head of department) can perform all three tasks. Also, the head has to have the political skills necessary to manage the faculty society. The guidelines for university clinics, and for their heads in particular, are: (a) conscious pursuit of optimal quality, (b) giving the highest priority to training house staff and teaching students, (c) providing patient care and (d) ensuring that clinical research should serve the purpose of inspiring scientific attitudes in house staff. The 'product' of a university clinic is neither the sum of its publications nor the cured patient, but the medical specialist delivered to society.


Modulation of the local SR Ca2+ release by intracellular Mg2+ in cardiac myocytes.
In cardiac muscle, Ca(2+)-induced Ca(2+) release (CICR) from the sarcoplasmic reticulum (SR) defines the amplitude and time course of the Ca(2+) transient. The global elevation of the intracellular Ca(2+) concentration arises from the spatial and temporal summation of elementary Ca(2+) release events, Ca(2+) sparks. Ca(2+) sparks represent the concerted opening of a group of ryanodine receptors (RYRs), which are under the control of several modulatory proteins and diffusible cytoplasmic factors (e.g., Ca(2+), Mg(2+), and ATP). Here, we examined by which mechanism the free intracellular Mg(2+) ([Mg(2+)](free)) affects various Ca(2+) spark parameters in permeabilized mouse ventricular myocytes, such as spark frequency, duration, rise time, and full width, at half magnitude and half maximal duration. Varying the levels of free ATP and Mg(2+) in specifically designed solutions allowed us to separate the inhibition of RYRs by Mg(2+) from the possible activation by ATP and Mg(2+)-ATP via the adenine binding site of the channel. Changes in [Mg(2+)](free) generally led to biphasic alterations of the Ca(2+) spark frequency. For example, lowering [Mg(2+)](free) resulted in an abrupt increase of spark frequency, which slowly recovered toward the initial level, presumably as a result of SR Ca(2+) depletion. Fitting the Ca(2+) spark inhibition by [Mg(2+)](free) with a Hill equation revealed a K(i) of 0.1 mM. In conclusion, our results support the notion that local Ca(2+) release and Ca(2+) sparks are modulated by Mg(2+) in the intracellular environment. This seems to occur predominantly by hindering Ca(2+)-dependent activation of the RYRs through competitive Mg(2+) occupancy of the high-affinity activation site of the channels. These findings help to characterize CICR in cardiac muscle under normal and pathological conditions, where the levels of Mg(2+) and ATP can change.


Large nest building and high marble-burying: Two compulsive-like phenotypes expressed by deer mice (Peromyscus maniculatus bairdii) and their unique response to serotoninergic and dopamine modulating intervention.
This study aimed to further dissect the deer mouse (Peromyscus maniculatus bairdii) model of compulsive-like behavior with respect to two persistent-like behavioral phenotypes viz. large nest building (LNB) and high marble-burying (HMB), which may be relevant to understanding the neurobiology of different symptom dimensions in obsessive-compulsive and related disorders. Since LNB is sensitive to chronic, high dose escitalopram intervention but HMB is not, we assessed whether the two behaviors could be further distinguished based on their response to 4 weeks of uninterrupted serotoninergic intervention (i.e. escitalopram; ESC; 50 mg/kg/day), dopaminergic antagonism, i.e. flupentixol; FLU; 0.9 mg/kg/day), dopaminergic potentiation (i.e. rasagiline; RAS; 5 mg/kg/day), and their respective combinations with escitalopram (ESC/FLU and ESC/RAS). Here we show LNB to be equally responsive to chronic ESC and ESC/FLU. HMB was insensitive to either of these interventions but was responsive to ESC/RAS. Additionally, we report that scoring preoccupied interaction with marbles over several trials is an appropriate measure of compulsive-like behavioral persistence in addition to the standard marble burying test. Taken together, these data provide further evidence that LNB and HMB in deer mice have distinctive neurobiological underpinnings. Thus, the naturally occurring compulsive-like behaviors expressed by deer mice may be useful in providing a platform to test unique treatment targets for different symptom dimensions of OCD and related disorders.


Knockdown of RhoGDIα induces apoptosis and increases lung cancer cell chemosensitivity to paclitaxel.
This study aimed to investigate the effects of RhoGDIα knockdown on apoptosis and the chemosensitivity of lung cancer cells to paclitaxel. The signaling proteins involved were also assessed. RhoGDIα expression was assessed by RT-PCR, Western blotting and immunohistochemistry. Apoptosis was determined by flow cytometric assessment, and cell viability was measured with the MTT assay. Phosphorylation levels of signaling proteins, ERK, JNK, Akt, Bad and IκBα were tested by Western blotting and immunohistochemistry. Positivity for RhoGDIα in lung cancer tissues was significantly higher than in paracancerous tissues. Downregulation of RhoGDIα was associated with significantly increased apoptosis and repressed cell viability. This effect could be due to the consequent upregulation of p-JNK, as well as decreased levels of p-ERK, p-Bad and p-IκBα. Knockdown of RhoGDIα strengthened the effect on apoptosis and inhibition of cell viability induced by paclitaxel treatment. This chemosensitization effect could be a result of the intensification of pro-apoptotic JNK activation, and repression of anti-apoptotic p-ERK, p-Bad and p-IκBα expression stimulated by paclitaxel. In summary, our study indicated that RhoGDIα could be a promising therapeutic target, and the combination of RhoGDIα siRNA and paclitaxel might be a valuable potential therapy for lung cancer treatment.


Plasma kininogen during the oestrous cycle, early pregnancy and pseudopregnancy in the rat.
1. Changes in the plasma kinin precursor, kininogen, occur following treatment with oestrogens and progestogens. This work was undertaken to attempt to relate plasma kininogen values to hormonal changes in various reproductive states. 2. During the oestrous cycle kininogen concentrations follow a nychthemeral rhythm, kininogen depletion occurring during the increase in general activity of the rat. 3. Superimposed on the nychthemeral changes in kininogen concentration are changes which may be related to the hormonal events of the oestrous cycle. 4. During early pregnancy and pseudopregnancy the kininogen level rises; this increase may be due to changes in the circulating levels of oestrogens and progestogens. 5. It is suggested that the changes in kininogen concentration may result from utilization of kinin which could be of functional significance.


Oblique incisions in hamstring tendon harvesting reduce iatrogenic injuries to the infrapatellar branch of the saphenous nerve.
Iatrogenic injury to the infrapatellar branch of the saphenous nerve (IPBSN) is associated with many surgical interventions to the medial aspect of the knee, such as anterior cruciate ligament (ACL) reconstruction. Different types of surgical incisions during hamstring tendon harvesting for ACL reconstruction are related to a variable risk of IPBSN injury. This study aimed to evaluate the risk of iatrogenic IPBSN injury during hamstring tendon harvesting for ACL reconstruction with different incision techniques over the pes anserinus. This study was performed on 100 cadavers. Vertical, horizontal, or oblique incisions were simulated on each cadaveric limb to determine the incidence of iatrogenic IPBSN injury. The vertical incision caused the IPBSN injury during hamstring tendon harvesting in 101 (64.7%), the horizontal incision in 78 (50.0%), and the oblique incision in 43 (27.6%) examined lower limbs. The calculated odds ratios (OR) for risk of injury in vertical versus horizontal and horizontal versus oblique incisions were 2.4 (95% CI 1.5-3.6) and 1.8 (95% 1.2-2.8), respectively. The vertical incision technique over the pes anserinus should be avoided during hamstring tendon harvesting for ACL reconstruction. The adoption of an oblique incision, with the shortest possible length, will allow for the safest procedure possible, thus minimizing the risk of iatrogenic IPBSN injury, and improving patient outcomes and postoperative quality-of-life.


The association of cytopenias and weight loss with hepatitis C virus virologic response in HIV/HCV-coinfected patients treated with PEG-IFN and RBV.
Pegylated interferon (PEG-IFN)/ribavirin (RBV)-related cytopenias have been associated with improved virological outcomes among hepatitis C virus (HCV)-monoinfected patients. This analysis evaluated PEG-IFN/RBV-related cytopenias with virological responses among HIV/HCV-coinfected patients. Pooled data from PARADIGM and AIDS Pegasys Ribavirin International CO-infection Trial (APRICOT) trials of HIV/HCV-infected patients treated with PEG-IFN/RBV. Virologic response was categorized as HCV RNA detectable (end of treatment nonresponders [ET-NR]) or nondetectable (end of treatment responders [ETR]). Declines in hemoglobin (Hgb), platelets, neutrophils, lymphocytes, and weight between the groups were compared via analysis of covariance and Cochran-Mantel-Haenszel test. A total of 474 patients, 291 ET-NR and 183 ETR (67 relapsers, 116 with sustained virologic response), 81% male, 52% Caucasian, 88% noncirrhotic, and 67% nondetectable HIV. The ETR experienced greater Hgb declines (≥3.0 g/dL) from baseline (73.8% versus 55.0%; P < .0001), neutrophils ≤1 and ≤ 0.5 × 10(9)/L (66.1% versus 56.4%; P = .0334 and 42.6% versus 33.3%; P = .0312, respectively), and lymphocytes ≤1.5 and ≤0.5 × 10(9)/L (99.5% versus 87.6%; P < .0001 and 24.6% versus 14.9%; P =.0079, respectively). The HIV/HCV-coinfected patients with ETR experienced greater declines in Hgb, neutrophils, and lymphocytes than the ET-NR patients.


Nutrient intake in heart failure patients.
Approximately 50% of heart failure (HF) patients are thought to be malnourished, and macronutrient and micronutrient deficiencies may potentially aggravate HF symptoms. Thus, concerns have been raised about the overall nutrient composition of diets in HF populations. The purpose of this study was to examine the macronutrient and micronutrient intake by caloric adequacy among community-dwelling adults with HF. A secondary analysis of baseline data of participants in an HF lifestyle intervention study was conducted. Participants (n = 45) were predominantly male (55.6%), white, and non-Hispanic (64.4%); had a mean age of 61 years (SD, 11 years) and mean body mass index of 31.2 kg/m (SD, 7.3 kg/m); were of New York Heart Association functional classes II and III (77.8%); and had a mean ejection fraction of 31.9% (SD, 13.2%); and 69% had a college or higher level of education. The Block Food Habits Questionnaire was used to assess the intake of macronutrients and micronutrients. Analysis included descriptive statistics and Mann-Whitney U tests. Individuals reporting inadequate daily caloric intake reported a lower intake of macronutrients and micronutrients as well as other differences in dietary patterns compared with individuals reporting adequate daily caloric intake. More than half of the individuals reporting adequate caloric intake did not meet the recommended dietary allowance for magnesium and vitamin E. Interventions aimed at increasing overall intake and nutrient density are suggested. Further research is needed to better understand the relationship between dietary factors and outcomes in HF.


PECAM-1 (CD31) cloning and relation to adhesion molecules of the immunoglobulin gene superfamily.
An antibody to a platelet integral membrane glycoprotein was found to cross-react with the previously identified CD31 myelomonocytic differentiation antigen and with hec7, an endothelial cell protein that is enriched at intercellular junctions. This antibody identified a complementary DNA clone from an endothelial cell library. The 130-kilodalton translated sequence contained six extracellular immunoglobulin (Ig)-like domains and was most similar to the cell adhesion molecule (CAM) subgroup of the Ig superfamily. This is the only known member of the CAM family on platelets. Its cell surface distribution suggests participation in cellular recognition events.


[A shop for caretakers: how to improve the quality of life for the caretaker and for the patient].
The authors narrate five years editions (2004-2007) at a caretakers shop which developed out of collaboration between the Gaudi Basic Health Area and the Sagrada Familia Social Services Center. This experience was innovative since it developed due to the coordination and collaboration between two entities in the same neighborhood as well as in regards to methodology employed because the self-esteem of the caretaker and the caretaker-patient relationships with medical professionals in the zone are dealt with in a transversal manner. This shop evaluation rates the overload placed on caretakers and the frequency of visits to the different services to show that the well-being of the former is proportional to patient improvement and that when this occurs, an adequate use of services available takes place.


The intrusive nature of the Châtelperronian in the Iberian Peninsula.
Multiple factors have been proposed to explain the disappearance of Neandertals between ca. 50 and 40 kyr BP. Central to these discussions has been the identification of new techno-cultural complexes that overlap with the period of Neandertal demise in Europe. One such complex is the Châtelperronian, which extends from the Paris Basin to the Northern Iberian Peninsula between 43,760-39,220 BP. In this study we present the first open-air Châtelperronian site in the Northern Iberian Peninsula, Aranbaltza II. The technological features of its stone tool assemblage show no links with previous Middle Paleolithic technology in the region, and chronological modeling reveals a gap between the latest Middle Paleolithic and the Châtelperronian in this area. We interpret this as evidence of local Neandertal extinction and replacement by other Neandertal groups coming from southern France, illustrating how local extinction episodes could have played a role in the process of disappearance of Neandertals.


Localization of the calreticulin gene mRNA in unpollinated and pollinated styles of Petunia hybrida Hort.
The objective of our research on Petunia hybrida is to understand the role of calreticulin in the growth of pollen tubes in the pistil. The aim of this study was the first step: finding out whether CRT gene expression takes place in unpollinated and pollinated styles. It was revealed by in situ hybridization that the transcription of the calreticulin gene takes place in the transmitting cells of unpollinated and pollinated styles and in pollen tubes growing in vivo. The mRNA transcripts of the CRT gene were localized mainly on the surface of endoplasmic reticulum (ER) membranes, both in transmitting cells and in the tip cytoplasm of pollen tubes. The results of this study show that calreticulin can be involved in pollen - pistil interaction in vivo.


High Primary Antibiotic Resistance of Helicobacter pylori Strains Isolated from Pediatric and Adult Patients in Poland during 2016-2018.
Monitoring the antibiotic resistance of H. pylori is an important step in the effective treatment of this bacterium, thus the aim of the present study was to assess the prevalence of antimicrobial resistance of H. pylori strains isolated from pediatric and adult patients with primary infections in 2016-2018. Antral biopsies from 334 treatment-naïve patients (126 children and 208 adults) were obtained. A total of 71 clinical H. pylori strains (22 from children and 49 from adults) were isolated and examined for amoxicillin (AMX), clarithromycin (CLR), metronidazole (MTZ), tetracycline (TET), and levofloxacin (LEV) susceptibility. The activity of the antibiotics was measured by E-tests. Strains were considered as resistant to antibiotics with minimum inhibitory concentrations (MICs) equal to ≥0.125 μg/mL (AMX), ≥0.5 μg/mL (CLR), ≥8 μg/mL (MTZ), and ≥1 μg/mL (TET and LEV). The highest prevalence of antibiotic resistance in H. pylori strains was observed for CLR and MTZ, at frequencies of 54.5% and 31.8% vs. 30.6% and 46.9% for children and adults, respectively. A much lower frequency of isolation of resistant strains was demonstrated for LEV and TET, this being 9.1% and 4.5% vs. 18.4% and 4.1% for pediatric and adult patients, respectively. The presence of AMX-resistant strains was not observed. The H. pylori strains isolated from Polish patients with primary infections showed a high level of antibiotic resistance to CLR and MTZ (>30%).


Effects of High-Pressure Hydrogen Annealing (HPHA) on Reliability Characteristics of RRAM.
Reliability characteristics (retention and endurance) of RRAM are critical for its practical realization and need to be improved. In this work, we confirmed the trade-off between retention and endurance by using various top electrode thickness conditions. The trade-off between retention and endurance characteristics was mainly due to the different amount of oxygen in scavenging layer (Ta) and the amount of oxygen vacancy in switching layer (HfO2). The amount of the oxygen in scavenging layer (Ta) and the amount of the oxygen vacancy in switching layer (HfO2) will be increased with the increase of Ta thickness. Therefore, the thicker Ta cells have worse retention because the large amount of oxygen in scavenging layer (Ta) can diffuse back into switching layer (HfO2) and recombine with oxygen vacancies in the filament. However, it has longer endurance because the large amount of oxygen vacancy in switching layer (HfO2) can be a source of the filament. Hence, there exists a trade-off relation between retention and endurance under the various Ta thickness conditions. To improve both retention and endurance characteristics, we proposed a new method by using high-pressure hydrogen annealing (HPHA). The thin Ta cells have longer retention and worse endurance because it has small amount of both oxygen in scavenging layer (Ta) and oxygen vacancy in switching layer (HfO2). Therefore, to generate more oxygen vacancies in switching layer (HfO2) maintaining small amount of oxygen in scavenging layer (Ta), we treated the samples by HPHA before Ta deposition. Finally, we obtained both improved retention and endurance characteristics in HfO2 based RRAM devices after high-pressure hydrogen annealing treatment.


Smoking and loneliness in older adults: a population-based study in Campinas, São Paulo State, Brazil.
This study aims to analyze the relationship between social isolation and loneliness with smoking in older adults. This is a cross-sectional, population-based study performed with 986 individuals aged 60 years or older. Data were collected from the Health Survey of the Municipality of Campinas (ISACamp 2014/2015), state of São Paulo, Brazil. We estimated the prevalence of smoking and smoking cessation according to independent variables and tested the associations using the chi-square test, considering a 5% significance level. Adjusted prevalence ratios were calculated using simple and multiple Poisson regression. Smoking and smoking cessation were not associated with most variables that indicate objective social isolation. "Often or always" loneliness was related to a higher prevalence of smoking (PR = 2.25; 95%CI: 1.38-3.66) whereas loneliness accompanied of self-reported emotional problems or common mental disorders was strongly associated with smoking and with lower smoking cessation (PR = 6.24; 95%CI: 1.37-28.47 and PR = 0.46; 95%CI: 0.28-0.77, respectively). These findings indicate that loneliness is a psychosocial aspect related to tobacco use which hinders smoking cessation in older adults, emphasizing the importance of emotional problems in this association.


Evolution of the Rhodococcus equi vap pathogenicity island seen through comparison of host-associated vapA and vapB virulence plasmids.
The pathogenic actinomycete Rhodococcus equi harbors different types of virulence plasmids associated with specific nonhuman hosts. We determined the complete DNA sequence of a vapB(+) plasmid, typically associated with pig isolates, and compared it with that of the horse-specific vapA(+) plasmid type. pVAPB1593, a circular 79,251-bp element, had the same housekeeping backbone as the vapA(+) plasmid but differed over an approximately 22-kb region. This variable region encompassed the vap pathogenicity island (PAI), was clearly subject to selective pressures different from those affecting the backbone, and showed major genetic rearrangements involving the vap genes. The pVAPB1593 PAI harbored five different vap genes (vapB and vapJ to -M, with vapK present in two copies), which encoded products differing by 24 to 84% in amino acid sequence from the six full-length vapA(+) plasmid-encoded Vap proteins, consistent with a role for the specific vap gene complement in R. equi host tropism. Sequence analyses, including interpolated variable-order motifs for detection of alien DNA and reconstruction of Vap family phylogenetic relationships, suggested that the vap PAI was acquired by an ancestor plasmid via lateral gene transfer, subsequently evolving by vap gene duplication and sequence diversification to give different (host-adapted) plasmids. The R. equi virulence plasmids belong to a new family of actinobacterial circular replicons characterized by an ancient conjugative backbone and a horizontally acquired niche-adaptive plasticity region.


Supporting learning in practice in the EBL curriculum: pre-registration students' access to learning resources in the placement setting.
This paper explores access to learning resources for nursing students when on placement. It also examines, in parallel, the impact of the move to enquiry based learning has on learning resources use by nursing students. The increased time spent learning in the clinical setting means that a deeper understanding of the use of learning resources by nursing students is necessary. A questionnaire survey was completed by 247 nursing students at Northumbria University around their use of learning resources on placement. This corresponded with focus groups being run with University and NHS providers of learning resources to establish the impact of enquiry based learning. It was found that effective collaboration between different stakeholders was especially important. Nursing students are also becoming increasingly sophisticated in their use of electronic learning resources. The nature of support for effective learning resources use by nursing students whilst on placement in the NHS has also been identified as key. The work has shown that it is very difficult to establish the impact of enquiry based learning on learning resources, as there are so many other variables.


Influence of solvent, anion and presence of nitrogen in the ring structure on the mechanism of complexation of alkali metal cations with crown ethers.
The mechanism of complexation of alkali metal cations with macrocyclic ligands such as the simple crown ethers and the role of desolvation vs. ligand rearrangement are discussed. The unique role of water solvent in the rate-determining step of complexations in aqueous solutions is brought into focus. The competitive role of the anion, which becomes of paramount importance in solvents of low permittivity, is reiterated. Monoazo crown ethers are shown to possess isomeric equilibria in methanol solvent. The rate-determining process for the first step of complexation of these macrocycles with Na+ in methanol appears to be the rearrangement of the ligand through inversion to an exo position of the nitrogen lone electron pair. The rate-determining step of the overall complexation is the entrance of the Na+ into the ring with (possibly) concomitant rotation of the lone electron of the nitrogen to an endo configuration.


Yawn, yawn, yawn, yawn; yawn, yawn, yawn! The social, evolutionary and neuroscientific facets of contagious yawning.
Contagious yawning is a common phenomenon affecting upwards of 60% of healthy humans. It has also been observed, at a lesser rate, in great apes and other primates. Here I summarize the suggestion that contagious yawning is a primitive expression of social cognition, namely empathy. Susceptibility to contagious yawning is correlated with the speed in recognizing one's own face, theory of mind processing, and is also associated with activation in regions of the brain that have been associated with social cognitive processes. This suggests that contagious yawning may be an evolutionarily old process that begot a higher level of social cognition in certain species.


A Population Pharmacokinetic Model of Gentamicin in Pediatric Oncology Patients To Facilitate Personalized Dosing.
To ensure the safe and effective dosing of gentamicin in children, therapeutic drug monitoring (TDM) is recommended. TDM utilizing Bayesian forecasting software is recommended but is unavailable, as no population model that describes the pharmacokinetics of gentamicin in pediatric oncology patients exists. This study aimed to develop and externally evaluate a population pharmacokinetic model of gentamicin to support personalized dosing in pediatric oncology patients. A nonlinear mixed-effect population pharmacokinetic model was developed from retrospective data. Data were collected from 423 patients for model building and a further 52 patients for external evaluation. A two-compartment model with first-order elimination best described the gentamicin disposition. The final model included renal function (described by fat-free mass and postmenstrual age) and the serum creatinine concentration as covariates influencing gentamicin clearance (CL). Final parameter estimates were as follow CL, 5.77 liters/h/70 kg; central volume of distribution, 21.6 liters/70 kg; peripheral volume of distribution, 13.8 liters/70 kg; and intercompartmental clearance, 0.62 liter/h/70 kg. External evaluation suggested that current models developed in other pediatric cohorts may not be suitable for use in pediatric oncology patients, as they showed a tendency to overpredict the observations in this population. The final model developed in this study displayed good predictive performance during external evaluation (root mean square error, 46.0%; mean relative prediction error, -3.40%) and may therefore be useful for the personalization of gentamicin dosing in this cohort. Further investigations should focus on evaluating the clinical application of this model.


The adoption of technology in higher/nursing education.
This is a review article on the adoption of technology in higher education. Higher education in general is looked at. Nursing Education is also higher education and therefore it will not be addressed separately, but mentioned in some instances. The article presents a look into how students and lecturers experience change, as well as barriers they perceive in the integration and adoption of technology. Some suggestions are made to the adoption process as well as the necessity for personnel development in information technology. The role that Information Technology personnel play in the adoption and integration process of technology is also discussed.


Ozurdex for the Treatment of a Patient with Birdshot Chorioretinopathy.
We report a 57-year-old patient with birdshot chorioretinopathy (BCR) who was treated with bilateral Ozurdex injections. The patient's vitritis resolved, and visual acuity improved following this treatment. This is only the second case report focused on the treatment of BCR with Ozurdex and the first to report its use for treating vitritis. A concise review of the literature on the use of intravitreal steroids for this disease is provided. This case serves to report the clinical usefulness of Ozurdex in treating posterior vitritis associated with BCR even in the absence of macular edema.


Recognizing and addressing unique vulnerabilities of suicidal patients: Suicide research at The Menninger Clinic.
Suicide risk is an inescapable presence in the treatment of people with psychiatric disorders, a fact that applies especially in inpatient psychiatric settings. This article summarizes a several-year research initiative at The Menninger Clinic aimed at better understanding psychological contributors to suicidality and developing more effective clinical interventions. Two areas of research are described, an outcomes arm focused on assessing the feasibility and effectiveness of a suicide-specific intervention (The Collaborative Assessment and Management of Suicidality) and an exploratory arm whose objective is to learn about psychological vulnerabilities that distinguish suicidal from nonsuicidal patients, with an eye toward developing interventions that address such vulnerabilities. The author concludes that, combined with other developments in the field, this body of work strongly supports the view that suicidal patients should be treated with interventions that specifically target vulnerabilities that seem to set the stage for suicidal episodes.


Pharmacoeconomic outcomes for pregabalin: a systematic review in neuropathic pain, generalized anxiety disorder, and epilepsy from a Spanish perspective.
Pregabalin is an anticonvulsant approved in Europe for the treatment of neuropathic pain, as an adjunct therapy for epileptic seizures, and recently for generalized anxiety disorder. The aim of this study was to conduct a systematic review to evaluate the cost-effectiveness of pregabalin associated with the treatment of its labeled indications from a societal perspective in Spain. Data from the MEDLINE database were searched using algorithms to identify relevant economic evaluations published in English or Spanish on pregabalin for the management of neuropathic pain, generalized anxiety disorder (GAD), and epilepsy in Spanish patients over the last 10 years. In total, 52 potentially relevant abstracts were identified from the MEDLINE database. Twenty manuscripts met the inclusion criteria. The majority of the selected papers (14/20) evaluated pregabalin for neuropathic pain from a societal perspective in Spain (5 economic models of pregabalin vs. gabapentin, 4 economic analyses of pregabalin in comparison with usual care, 4 economic evaluations comparing pregabalin monotherapy with add-on strategies, and one that evaluated different times of initiating pregabalin therapy). Five studies analyzed the use of pregabalin in Spain for the management of GAD (one cost-effectiveness model that compared pregabalin with venlafaxine, 2 secondary analyses in benzodiazepine-refractory patients, and 2 studies evaluating pregabalin vs. usual care in patients refractory to standard regimens). The last manuscript described a cost-effectiveness model that compared pregabalin versus levetiracetam use for the treatment of refractory partial epilepsy. The majority of published evidence supports the possibility that pregabalin could be a cost-effective and/or cost-saving alternative for the treatment of refractory epilepsy, GAD, and neuropathic pain, in both treatment-naïve patients and in those who have demonstrated inadequate response or intolerance to previous therapy.


CT characteristics of recurrent acute pancreatitis and acute pancreatitis in different stages-a retrospective cross-sectional study.
Acute pancreatitis (AP), recurrent acute pancreatitis (RAP), and chronic pancreatitis (CP) are a continuum of the same disease. The course of RAP and AP is a dynamic process. Previous studies are contradictory regarding the severity of RAP and AP. We conducted this study to investigate the computed tomography (CT) characteristics of RAP and AP in the early and late stages; respectively. Patients who underwent contrast-enhanced computed tomography for symptoms during RAP or AP episodes were retrospectively collected from three tertiary hospitals in Sichuan Province, China from January 2015 to December 2019. The patients were categorized into RAP and AP groups based on recurrence and initial events. Both the RAP and AP groups were divided into early (first week) and late stages (after the first week) based on the 2012 revised Atlanta classification (RAC). Patient demographic data, RAC, CT findings, CT severity index (CTSI) scores, and extrapancreatic inflammation on CT scores in the early and late phases were analyzed between the two groups. The Wilcoxon signed-rank test, χ2 test, and Fisher's exact test were used to compare continuous and categorical variables between the two groups respectively. In 683 RAP and 1,829 AP patients, the most common etiologies were hypertriglyceridemia and cholelithiasis, respectively. The RAP group had lower extrapancreatic inflammation on CT scores and Acute Physiology and Chronic Health Evaluation II scores than the AP group in the early stage (both P<0.001). The RAP group had higher CTSI scores than the AP group in the late stage (P=0.022). Compared with AP patients, the most common cause of RAP patients was hypertriglyceridemia in China, and the severity of RAP was lower than that of initial AP in the early stage and higher than that of initial AP in the late stage.


[Treatment sequence using newly developed agents for men with castration resistant prostate cancer].
Abiraterone acetate(AA), enzalutamide (EZL) and cabazitaxel (CBZ) are becoming available in Japan. Clinical trials demonstrated the benefit of these agents in men with castration resistant prostate cancer (CRPC). However, data on sequence therapy using these agents are very limited. Based on the mechanisms of agents and clinical data, AA and EZL may be indicated in early stage and CBZ may be indicated in late stage of CRPC. Prostate cancer is significantly heterogeneous between individuals and useful biomarkers for deciding the best treatment are unavailable yet. Therefore, it is hard to establish a standard sequence of the treatments. Until clinical trials demonstrate the best treatment sequence, individualized therapy is required for each patient based on patient and disease characteristics.


[Stereoselective synthesis of polyhydroxylated amines using (S)-pyroglutamic acid derivatives].
Naturally occurring polyhydroxylated amines such as (+)-1-deoxynojirimycin, polyoxamic acid, anisomycin, (-)swainsonine, and alexine stereoisomers, which have interesting biological activities including glucosidase- and mannosidase-inhibitory activity, immunoregulatory activity, and antibacterial effects, were synthesized stereoselectively starting from (S)-pyroglutamic acid derivatives. α,β-Unsaturated lactams ((S)-5-hydroxymethyl-2-oxo-3-pyrroline derivatives), α,β-unsaturated δ-lactone ((S)-4-amino-2-penten-5-olide derivative), and E-olefin ((S,E)-methyl-4-amino-5-hydroxypent-2-enoate derivative) from (S)-pyroglutamic acid derivatives were dihydroxylated using OsO4 in the presence of N-methyl morpholine N-oxide (NMO) to afford various chiral building blocks with different configurations. The stereoselectivity of cis-dihydroxylation for α,β-unsaturated lactams and α,β-unsaturated δ-lactone was very high, while the stereoselectivity was low for E-olefin. Therefore, the double asymmetric induction of E-olefin using K2OsO4 with chiral ligands was successively applied to yield high stereoselectivity. (2R,3S)-2-Hydroxymethyl-3-hydroxypyrrolidine and Gaissman-Weiss lactone, important intermediates for the preparation of pyrrolizidine alkaloids, were synthesized from a (3R,4R,5R)-3,4-dihydroxy-5-hydroxymethyl-2-pyrrolidinone derivative derived from α,β-unsatulated lactam. (+)-1-Deoxynojirimycin was synthesized from a (2S,3R,4R)-methyl 4-amino-2,3,5-trihydroxypentanoate derivative of E-olefin. (-)-Swainsonine and its stereoisomers were synthesized from (2R,3S,4R)- or (2R,3R,4R)-2-hydroxymethyl-3,4-dihydroxypyrrolidine derivatives of α,β-unsaturated δ-lactone or α,β-unsaturated lactam. The key reaction was diastereoselective allylation of the aldehyde derived from the corresponding 2-hydroxymethylpyrrolidine derivatives with various allylation reagents. The high diastereoselectivity could be explained by cyclic chelate formation between metals and the α-aminocarbonyl group or β-alkoxycarbonyl group, in which the nucleophile approaches from the less hindered face. Four alexine stereoisomers were synthesized from (2R,3R,4S,5R)- and (2R,3R,4S,5S)-2,3-dihydroxymethyl-3,4-dihydroxyl pyrrolidine derivatives of α,β-unsaturated lactam.


Expanding research on the role of alcohol consumption and related risks in the prevention and treatment of HIV/AIDS.
This article is a review of some of the major epidemiological, behavioral, biological, and integrative prevention research issues and priorities in the area of HIV/AIDS and alcohol consumption. Drinking alcohol increases both the risk for infection with HIV and related illnesses and the morbidity and mortality of patients who progress to AIDS. New and improved measurement procedures have helped in assessment of the complex patterns of alcohol use, identification of intervening explanatory mechanisms for risk behaviors and contexts, and determination of intervention outcomes. Both the direct and indirect effects of alcohol misuse appear to be major contributors to both the risk for infection with HIV and the transmission of HIV/AIDS at the individual and population levels. There is increasing evidence that perhaps no level of alcohol consumption is "safe" for those who are HIV infected and receiving antiretroviral treatment. Interdisciplinary basic behavioral and biomedical research is needed to develop comprehensive culturally appropriate strategies for programs that can be effectively delivered in community contexts in the United States and abroad and that focus on the integration of our understanding of individual behaviors, high-risk group membership, biological mechanisms, and the social and physical environments that place individuals at risk for HIV infection. High-priority topics include improving adherence to antiretroviral medications, prevention of infection in young minority women in the United States, and treatment of HIV+ pregnant women who are alcohol abusers to prevent adverse fetal outcomes, which is an international focus in under-resourced settings in Africa.


Human Lymphatic Architecture and Dynamic Transport Imaged Using Near-infrared Fluorescence.
Although the importance of lymphatic function is well recognized, the lack of real-time imaging modalities limits our understanding of its role in many diseases. In a phase 0 exploratory study, we used dynamic, near-infrared (NIR) fluorescence imaging to assess the extremes of lymphatic architecture and transport in healthy human subjects and in subjects clinically diagnosed with unilateral lymphedema (LE), a disease that can be prevalent in cancer survivors. Active lymphatic propulsion was imaged after intradermal injections of 25 µg of indocyanine green (total maximum dose ≤400 µg) bilaterally in the arms or legs of control and subjects. Images show well-defined lymphatic structures with propulsive dye transport in limbs of healthy subjects. In LE subjects, we observed extravascular dye accumulation, networks of fluorescent lymphatic capillaries, and/or tortuous lymphatic vessels in all symptomatic and some asymptomatic limbs. Statistical models indicate that disease status and/or limb significantly affect parameters of apparent lymph propagation velocity and contractile frequency. These clinical research studies demonstrate the potential of NIR fluorescence imaging as a diagnostic measure of functional lymphatics and as a new tool in translational research studies to decipher the role of the lymphatic system in cancer and other diseases.


Phylogeny and phylogeography of the genus Luciobarbus (Haeckel, 1843) in Algeria inferred from mitochondrial DNA sequence variation.
Phylogenetic relationships and biogeographical patterns of the genus Luciobarbus in Algeria were investigated by analysing the complete cytochrome b sequence variation. With regard to species of the Maghreb Province and the Iberian Peninsula, phylogenetic analysis resulted in five strongly supported clades and a non-monophyletic origin for the Algerian populations. The present study supports the existence of two distinct lineages of L. setivimensis which could have diverged posterior to the emplacement of the Kabylides onto the African margin. Analysis of the 48 haplotypes detected within populations showed a clear phylogeographic structure strongly correlated with species' geographical distribution. Two haplotypes were found to be shared between different species attesting the possibility that an introgression would have occurred within the genus Luciobarbus in Algeria. The divergence time estimate suggests a rapid radiation of the genus Luciobarbus in Algeria and a pattern of distribution of populations shaped under paleogeographic conditions such as the tectonic dynamics which have led to the change in the geographic configuration of North Africa at the end of Miocene, the formation of the current fluvial basins' net in the Pliocene as well as the end of the Tell System building in the Pleistocene which seems to have played an important role in the speciation of this genus.


New Frontiers in Prostate Cancer Treatment: Are We Ready for Drug Combinations with Novel Agents?
Medical treatment for metastatic castration-resistant prostate cancer (mCRPC) patients has progressively been evolving from a nonspecific clinical approach to genomics-oriented therapies. The scientific community is in fact increasingly focusing on developing DNA damage repair (DDR) defect-driven novel molecules, both as single-agent therapy and in combined treatment strategies. Accordingly, research is under way into combined drug therapies targeting different pathways, e.g. androgen receptor signaling (ARS) and poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) enzymes, immune checkpoint (IC) and PARP, IC, and ARS, and prostate-specific membrane antigen (PSMA). In an attempt to formulate evolving treatment paradigms in mCRPC patients, here we selected clinical research into patients undergoing therapies with emerging molecules, with particular emphasis towards PARP-, IC-, and PSMA-inhibitors. In order to focus on those molecules and drug combinations most likely to be translated into routine clinical care in the near future, we selected only those clinical studies currently recruiting patients. A PubMed search focusing on the keywords "prostate cancer", "metastatic castration-resistant prostate cancer", "DDR pathways", "ARS inhibitors", "PARP inhibitors", "IC inhibitors", "PSMA-targeting agents", and "drug combinations" was performed.


Complaint handling in healthcare: expectation gaps between physicians and the public; results of a survey study.
Patients who submit complaints about the healthcare they have received are often dissatisfied with the response to their complaints. This is usually attributed to the failure of physicians to respond adequately to what complainants want, e.g. an apology or an explanation. However, expectations of complaint handling among the public may colour how they evaluate the way their own complaint is handled. This descriptive study assesses expectations of complaint handling in healthcare among the public and physicians. Negative public expectations and the gap between these expectations and those of physicians may explain patients' dissatisfaction with complaints procedures. We held two surveys; one among physicians, using a panel of 3366 physicians (response rate 57 %, containing all kinds of physicians like GP's, medical specialist and physicians working in a nursing home) and one among the public, using the Dutch Healthcare Consumer Panel (n = 1422, response rate 68 %). We asked both panels identical questions about their expectations of how complaints are handled in healthcare. Differences in expectation scores between the public and the physicians were tested using non-parametric tests. The public have negative expectations about how complaints are handled. Physician's expectations are far more positive, demonstrating large expectation gaps between physicians and the public. The large expectation gap between the public and physicians means that when they meet because of complaint, they are likely to start off with opposite expectations of the situation. This is no favourable condition for a positive outcome of a complaints procedure. The negative public preconceptions about the way their complaint will be handled will prove hard to change during the process of complaints handling. People tend to see what they thought would happen, almost inevitably leading to a negative judgement about how their complaint was handled.


Teaching an old drug new tricks: metformin as a targeted therapy for lung cancer.
Identifying novel drugs for treatment of lung cancer remains of utmost importance, and, in recent years, targeted therapies have been acknowledged as particularly attractive. Metformin, a commonly prescribed oral hypoglycemic agent, has known effects on the mammalian target of rapamycin pathway, ultimately resulting in downstream inhibition of cellular growth and proliferation. In a recent article (Memmott RM, Mercado JR, Maier CR, et al: Metformin prevents tobacco carcinogen-induced lung tumorigenesis. Cancer Prev Res (Phila) 3:1066-1076, 2010), Memmott et al assessed the utility of metformin in an in vivo model of tobacco carcinogen-induced lung cancer. The authors show that tumor burden is decreased in animals administered metformin, suggesting that this drug may have promising potential for the treatment and chemoprevention of lung cancer.


Doxorubicin pretreatment enhances FAPα/survivin co-targeting DNA vaccine anti-tumor activity primarily through decreasing peripheral MDSCs in the 4T1 murine breast cancer model.
The tumor microenvironment (TME) provides necessary nutrition for tumor growth and recruits immunosuppressive factors including regulatory T cells and myeloid-derived suppressor cells (MDSCs) to inhibit the anti-tumor immune response induced by immunotherapy. As a main TME component, cancer associated fibroblasts (CAFs) can restrain T cell infiltration and activity through extracellular matrix remodeling. Vaccines targeting fibroblast-activating protein α (FAPα), which is mainly expressed on the CAF surface, can eliminate CAFs in tumors and regulate the TME, enhancing the potency of T cell-mediated anti-tumor effects. However, the anti-tumor effects were not fully realized as the tumor induces a large number of peripheral MDSCs during its growth, rendering the body of mice in an immunosuppressive state and preventing the vaccine from inducing effective anti-tumor immune responses. Here, we developed a dual-targeted DNA vaccine OsFS, targeting tumor matrix antigen FAPα and tumor cell antigen survivin simultaneously, exhibited enhanced antineoplastic effects in an established breast cancer model. Moreover, doxorubicin (Dox) pretreatment to remove the peripheral MDSCs induced to regulate the peripheral immune environment could further facilitate the anti-tumor activity of the vaccine. These results indicated that combination treatment of the tumor cells and the TME dual-targeting vaccine plus Dox could effectively realize the anti-tumor activity of the vaccine by decreasing immunosuppressive factors and inducing more tumor-infiltrating lymphocytes, which may offer important guidance for clinical research regarding the combination of the DNA vaccine with low-dose Dox.


A rare case of cutaneous myxoma with trichofolliculoma-like features.
Carney complex is a rare genetic disorder associated with a number of cutaneous lesions, especially cutaneous myxomas. We present a rare case of cutaneous myxoma (superficial angiomyxoma) with trichofolliculoma-like features in a patient with Carney complex, and explore how the associated histopathology provides critical context for elucidating the etiology of this benign neoplasm.


Three-year outcomes of alcohol delamination of corneal epithelium for recurrent corneal erosions of traumatic etiology.
Alcohol delamination of the corneal epithelium (ADCE) is a therapeutic option for patients with recurrent corneal erosion (RCE) who do not respond to nonsurgical management of lubricants and extended wear contact lens. The aim of the study is to report on three-year efficacy and safety of ADCE for RCE of traumatic etiology. This is a retrospective review of consecutive patients who underwent ADCE for traumatic RCE in a local hospital between January 2010 and January 2020. The outcomes at a 3-year follow-up review are included. Nonsurgical therapy used; intra- and postoperative complications were recorded. ADCE was only offered to those who remained symptomatic despite maximum topical lubrications and/or extended wear contact lens. Success was defined as the absence of recurrence of corneal erosion. Twenty-six eyes of 26 patients with RCE caused by trauma underwent ADCE. The mean age of patients was 39 years. The follow-up period was a minimum of 36 months. Three eyes (11.5%) had recurrence of corneal erosion after ADCE at the 3-year follow-up. Recurrence was noted at months 2, 23, and 36 postoperatively in these patients. All patients reported significant improvement in symptoms associated with recurrent erosion. Ten eyes (38.5%) stopped all topical lubricants postoperatively. No intra- or postoperative complications were noted in our study. This study documents the long-term safety and efficacy of alcohol delamination of corneal epithelium at 3 years for patients with RCE of traumatic origin.


Clinical significance of CSF glutamate concentrations following severe traumatic brain injury in humans.
Glutamate excitotoxicity is a putative mechanism of secondary damage after traumatic brain injury (TBI). No relationship between glutamate release and clinical status has been shown in humans, however. We hypothesize a dose-response relationship between CSF glutamate concentrations and severity of injury, electrophysiological deterioration as measured by somatosensory evoked potential amplitudes, and clinical outcome. From August 1991 to March 1996, intensive monitoring of 55 patients with severe TBI (GCS < or = 8 after resuscitation) included twice daily CSF glutamate levels and hourly somatosensory evoked potentials (SSEPs) for an average of 5 days. Clinical outcomes were survival/nonsurvival and Glasgow outcome score (GOS) at 3 months or more post-injury. Glutamate levels were not associated with severity of injury, electrophysiological deterioration, or clinical outcome. Neither peak nor mean glutamate levels significantly improved a simple logistic regression model which used only age and presence of bilaterally unreactive pupils to predict survival. Using this methodology CSF glutamate concentrations did not display a dose-response relationship to severity of injury, electrophysiological deterioration, or predict clinical outcomes following TBI in a group of 55 patients. An early effect of glutamate, an effect dependent on time of exposure to glutamate or other modulating effects cannot be ruled out.


Post-lumbar-puncture headache: the significance of body posture. A controlled study of 300 patients.
In this single-blind, randomized study of post-lumbar-puncture headache (PPH) in 300 neurologic inpatients the significance of body posture after lumbar puncture (LP) was evaluated. Immediate mobilization was compared with bed rest for 6 h (3 h prone followed by 3 h supine posture). Contrary to the widely held belief, this investigation did not show significant differences between recumbent and ambulant patients as to frequency of PPH in the total material (39% versus 35%) or when men (31% versus 29%) and women (48% versus 41%) were evaluated separately. Headache associated with nausea was significantly more frequent in the recumbent than in the ambulant patients both in the total material (23% versus 13%) and in women (35% versus 16%). Thus, immediate mobilization seems to be preferable after LP.


Biotinylated Bioluminescent Probe for Long Lasting Targeted in Vivo Imaging of Xenografted Brain Tumors in Mice.
Bioluminescence is a useful tool for imaging of cancer in in vivo animal models that endogenously express luciferase, an enzyme that requires a substrate for visual readout. Current bioluminescence imaging, using commonly available luciferin substrates, only lasts a short time (15-20 min). To avoid repeated administration of luciferase substrate during cancer detection and surgery, a long lasting bioluminescence imaging substrate or system is needed. A novel water-soluble biotinylated luciferase probe, B-YL (1), was synthesized. A receptor-targeted complex of B-YL with streptavidin (SA) together with a biotinylated epidermal growth factor short peptide (B-EGF) (SA/B-YL/B-EGF = 1:3:1, molar ratio) was then prepared to demonstrate selective targeting. The complex was incubated with brain cancer cell lines overexpressing the EGF receptor (EGFR) and transfected with the luciferase gene. Results show that the complex specifically detects cancer cells by bioluminescence. The complex was further used to image xenograft brain tumors transfected with a luciferase gene in mice. The complex detects the tumor immediately, and bioluminescence lasts for 5 days. Thus, the complex generates a long lasting bioluminescence for cancer detection in mice. The complex with selective targeting may be used in noninvasive cancer diagnosis and accurate surgery in cancer treatment in clinics in the future.


Evolution of Brain Volume Loss Rates in Early Stages of Multiple Sclerosis.
To describe the dynamics of brain volume loss (BVL) at different stages of relapsing-remitting multiple sclerosis (RRMS), to describe the association between BVL and clinical measures, and to investigate an effect of treatment escalation on the rate of BVL. Together, 1903 patients predominantly with RRMS from the Avonex-Steroids-Azathioprine cohort (N = 166), the study of early IFN-β1a treatment cohort (N = 180), and the quantitative MRI cohort (N = 1,557) with ≥2 MRI scans and ≥1-year of follow-up were included. Brain MRI scans (N = 7,203) were performed using a single 1.5-T machine. Relationships between age or disease duration and global and tissue-specific BVL rates were analyzed using mixed models. Age was not associated with the rate of BVL (β = -0.003; Cohen f2 = 0.0005; adjusted p = 0.39). Although disease duration was associated with the rate of BVL, its effect on the BVL rate was minimal (β = -0.012; Cohen f2 = 0.004; adjusted p = 4 × 10-5). Analysis of association between tissue-specific brain volume changes and age (β = -0.019 to -0.011; adjusted p = 0.028-1.00) or disease duration (β = -0.028 to -0.008; adjusted p = 0.16-0.96) confirmed these results. Although increase in the relapse rate (β = 0.10; adjusted p = 9 × 10-9), Expanded Disability Status Scale (EDSS; β = 0.17; adjusted p = 8 × 10-5), and EDSS change (β = 0.15; adjusted p = 2 × 10-5) were associated with accelerated rate of BVL, their effect on the rate of BVL was minimal (all Cohen f2 ≤ 0.007). In 94 patients who escalated therapy, the rate of BVL decreased following treatment escalation by 0.29% (β = -0.29; Cohen f2 = 0.133; p = 5.5 × 10-8). The rate of BVL is relatively stable throughout the course of RRMS. The accelerated BVL is weakly associated with concurrent higher disease activity, and timely escalation to high-efficacy immunotherapy helps decrease the rate of BVL.


Phenotypic and genotypic identification of streptococci and related bacteria isolated from bovine intramammary infections.
Streptococcus spp. and other Gram-positive, catalase-negative cocci (PNC) form a large group of microorganisms which can be found in the milk of cows with intramammary infection. The most frequently observed PNC mastitis pathogens (major pathogens) are Streptococcus uberis, Strep. dysgalactiae, and Strep. agalactiae. The remaining PNC include a few minor pathogens and a large nonpathogenic group. Improved methods are needed for the accurate identification and differentiation of PNC. A total of 151 PNC were collected from cows with intramammary infection and conclusively identified by 16S rRNA sequencing as reference method. Nine phenotypic microbiological tests (alpha-hemolysis, CAMP reaction, esculin hydrolysis, growth on kanamycin esculin azide agar and on sodium chloride agar, inulin fermentation, hippurate hydrolysis, leucine aminopeptidase and pyrrolidonyl peptidase activity), multiplex PCR for the three major pathogens (target genes for Strep. uberis, Strep. dysgalactiae and Strep. agalactiae: pauA, 16S rRNA, and sklA3, respectively), and mass spectroscopy using the matrix-assisted laser desorption ionization-time of flight (MALDI-TOF MS) were evaluated for the diagnosis and discrimination of the three clinically most relevant PNC. The probability that a strain of Strep. uberis, Strep. dysgalactiae and Strep. agalactiae was correctly identified by combining the results of the 9 phenotypic tests was 92%, 90%, and 100%, respectively. Applying the multiplex PCR, all strains of the three major pathogens were correctly identified and no false positive results occurred. Correct identification was observed for all strains of Strep. uberis and Strep. agalactiae using MALDI-TOF MS. In the case of Strep. dysgalactiae, some variability was observed at the subspecies level, but all strains were allocated to one single cluster. The results of the present study show that reliable identification of the clinically most relevant PNC (Strep. uberis, Strep. agalactiae and Strep. dysgalactiae) can be obtained by use of a combination of colony morphology, hemolysis type and catalase reaction, and a multiplex PCR with specific primers restricted to these 3 pathogens. The MALDI-TOF MS is a fast method that shows promising results, although identification of Strep. dysgalactiae at the subspecies level is not yet satisfactory.


[Antitumor effect of docetaxel against human endometrial tumor cell lines].
The antitumor effect of docetaxel against human endometrial tumor cell lines was investigated in vitro and in vivo. In the in vitro study,docetaxel showed concentration-dependent inhibition of the growth of 4 tumor cell lines having different degrees of differentiation (AN3 CA, KLE, HEC-1-A and HEC-1-B), with IC(50) values ranging from 2.48 to 82.40 ng/ml. These values represent ca. 1/900-1/30 of the mean maximum plasma concentration of 2.27 microg/ml attained when the recommended dose of 70 mg/m(2) for patients with endometrial cancer was administered to patients with various types of cancer in phase I trial. In addition, the activity was nearly equal to paclitaxel, and much more potent than fluorouracil, cisplatin and doxorubicin. Docetaxel also showed strong antitumor activity against xenografts of the AN3 CA human endometrial adenocarcinoma cell line in nude mice. In the docetaxel treated group at its MTD (33 mg/kg/dose, q 6 d x 3, iv), all of the animals were tumor-free survivors on Day 62 after xenografting. The antitumor effect in the MTD-administered group was the strongest of all of the tested anticancer drug groups (cyclophosphamide, mitomycin C, fluorouracil, cisplatin, doxorubicin). Even at two docetaxel dosages below its MTD (20.5 and 12.5 mg/kg/day), the drug showed a marked cytotoxic activity. These results demonstrated that docetaxel shows potent antitumor efficacy against human endometrial tumor cell lines, leading to the expectation that it will be useful as a therapeutic agent for endometrial cancer.


Percutaneous Tricuspid Valve Regurgitation Repair With the MitraClip Device Using an Edge-to-Edge Bicuspidization Technique.
Patients who present with both severe mitral and tricuspid regurgitation who are symptomatic despite optimal medical therapy and at prohibitive risk for surgery pose a significant therapeutic challenge. The MitraClip device (Abbott Vascular) is approved for percutaneous mitral valve repair in high-risk and non-operative patients, and has also been used for tricuspid valve repair. Imaging support for percutaneous edge-to-edge tricuspid valve repair has not been reported and is a vital part of the procedure. Here, we present a periprocedural imaging strategy for percutaneous tricuspid valve repair with the MitraClip device using a bicuspidization technique.


Profiling of sperm proteins and association of sperm PDC-109 with bull fertility.
The composition of sperm proteins influences the fertilizing ability of sperm and hence the present study was conducted (i) to profile sperm proteins expression patterns in bulls of differing fertility index and (ii) to identify and relate the abundant sperm proteins with bull fertility. The semen samples were collected from Holstein-Friesian bulls (n = 12) varying in conception rate (CR) (high/low). The frozen semen straws (three ejaculates, from each bull) were used to study (a) sperm kinetic parameters, (b) plasmalemma integrity, (c) mitochondrial membrane potential, and (d) chromatin distribution. Three bulls were randomly selected from each group (n = 3) and the neat sperm pellets were subjected to percoll purification, followed by protein isolation using 0.1% Triton X100. The sperm kinetic parameters, plasmalemma integrity, mitochondrial membrane potential, and the chromatin distribution did not differ significantly between groups. The number of acidic (pI; 3.1-5.6, 37%) and basic (pI; 7.9-10.0, 27%) proteins and their pattern of expression varied significantly (p < 0.05) between high and low fertile bulls. The abundant sperm protein spots in 2D-gel electrophoresis (2DE) were identified as seminal plasma protein PDC-109 (i.e., protein with N-terminus aspartic acid, D and carboxy terminus cystine, having 109 amino acids) and its isoform and spermadhesin-1 (SPADH1). The western blot analysis confirmed the presence of PDC-109 isoform proteins at 15.4 kDa (pI 5.3 and 5.5). The seminal plasma protein PDC-109 was abundant in the low fertile when compared to the high fertile group (p < 0.05). This study suggests that the imbalance in acidic and basic sperm proteins may influence sperm fertility and sperm PDC-109 levels above a certain threshold affects bull fertility.


Synthesis of a Hexagonal Phase ZnS Photocatalyst for High CO Selectivity in CO2 Reduction Reactions.
ZnS materials exhibit very negative potential of the conduction band, which is promising in photocatalytic reduction reactions. Unfortunately, previously reported ZnS materials for photocatalysis are mainly in the cubic phase, which produce high activity for H2 evolutions and low activity toward CO2 reductions. Herein, a hexagonal phase ZnS photocatalyst is fabricated for highly efficient CO2 reduction reactions. The hexagonal ZnS nanoplates with the pure phase and well crystallization are synthesized via three-step solvothermal methods. In photocatalytic CO2 reduction reactions under an aqueous solution environment, the hexagonal ZnS produces a CO selectivity of 21%, which is distinctly higher than that of 0.2% for commonly used cubic ZnS. The energy band study suggests that hexagonal ZnS possesses a slightly more negative conduction band and wider bandgap than cubic ZnS. Theoretical calculations reveal that the hexagonal ZnS possesses increased electron density around Zn atoms as that of cubic ZnS. Furthermore, hexagonal ZnS exhibits relatively reduced absorption energy of CO2 reduction intermediates and increased absorption energy of H* as cubic ZnS, which result in better selectivity toward CO2 reduction reactions. This study offers deep insights into the synthesis and electronic structure of hexagonal ZnS for CO2 reduction reactions, which inspire the design of highly active photocatalysts for artificial photosynthesis.


[Cost-effectiveness and affordability of strategy for preventing mother-to-child transmission of hepatitis B in China].
Objective: To evaluate the cost effectiveness of nationwide prevention of mother to child transmission (PMTCT) strategy for hepatitis B, and estimate the willing to pay and budget impacts on the PMTCT. Methods: The decision analytic Markov model for the PMTCT was constructed and a birth cohort of Chinese infants born in 2013 was used to calculate the cost-effectiveness of the PMTCT among them compared with those receiving no intervention. The parameters in the model were obtained from literatures of national surveys or Meta-analysis. The costs, cases of HBV-related diseases and quality-adjusted life-years (QALYs) were obtained from the societal and payer perspectives, respectively. The incremental cost-effectiveness ratio (ICER) was used as measures of strategy optimization. One-way and probability sensitivity analysis were performed to explore the uncertainty of the primary results. In addition, cost-effectiveness acceptability curve and cost-effectiveness affordability curves were drawn to illustrate the cost effectiveness threshold and financial budget of the PMTCT strategy. Results: The lifetime cost for PMTCT strategy was 4 063.5 yuan (RMB) per carrier, which was 37 829.7 yuan (RMB) lower compared with those receiving no intervention. Due to the strategy, a total of 24.516 1 QALYs per person would be gained, which was higher than that in those receiving no intervention. From societal perspective, the ICER was -59 136.6 yuan (RMB) per additional QALYs gained, indicating that the PMTCT is cost effective. The results were reliable indicated by one-way, multi-way and probability sensitivity analyses. By the CEAC, the willing to pay was much lower than the cost-effectiveness threshold. From the affordability curve of the PMTCT strategy, the annual budget ranged from 590.4 million yuan (RMB) to 688.8 million yuan (RMB), which was lower than the financial ability. Based on the results of cost-effectiveness affordability curves, the higher annual budget was determined, the higher probability of affordability for the PMTCT would be obtained under the same willing to pay state. Only when the annual budget reaches 688.8 million yuan (RMB), the goal of PMTCT would be fully realized. Conclusions: The PMTCT strategy in China was cost effective, and the cost is not beyond the financial budget needed and the willing to pay. The strategy, which is consistent with the global hepatitis B elimination efforts, should be conducted widely in China.


[Effects of acute hypoxia on the blood pressure heart rate, microvessels response and free radical in rabbit].
To study the effects of different acute hypoxia on blood pressure, heart rate and microvessels and free radical in rabbits. The experiment model was carried out with acute hypoxia on two groups of rabbits, using artificial inspiration 12.5% O2 and 87.5% N2, 8.5% O2 and 91.5% N2 (equivalent to altitudes of some 4 000 m and 6 500 m) keeping hypoxia for 5, 10, 15, 20 min. During the course of it, the changes of blood pressure, heart rate and microvessels response, superoxide dismutase (SOD), malondialdehyde (MDA) were recorded accordingly. (1) systolic pressure was slightly up, then down in 5 mins. Diastolic pressure was significantly down (P < 0.05) in 20 min. (2) Heart rate showed reduced and prolonged, particularly in 8.5% hypoxia group (P < 0.05). (3) Vas bores of microvessle expanded (P < 0.05) and the blood stream became slow gradually (P < 0.05, P < 0.01) in following acute hypoxia time. (4) SOD was significantly down (P < 0.05), MDA was significantly increased (P < 0.05) in 20 mins. Acute hypoxia could cause the blood pressure and heart rate to decrease, vas bore of microvessle to expand, the blood circulation to slow down and free radicals would increase.


Tumor-infiltrating CD39+γδTregs are novel immunosuppressive T cells in human colorectal cancer.
Tumor microenvironment (TME) promotes immune suppression through recruiting and expanding suppressive immune cells such as regulatory T cells (Tregs) to facilitate cancer progression. In this study, we identify a novel CD39+ γδTreg in human colorectal cancer (CRC). CD39+ γδTregs are the predominant regulatory T cells and have more potent immunosuppressive activity than CD4+ or CD8+ Tregs via the adenosine-mediated pathway but independent of TGF-β or IL-10. They also secrete cytokines including IL-17A and GM-CSF, which may chemoattract myeloid-derived suppressive cells (MDSCs), thus establishing an immunosuppressive network. We further demonstrate that tumor-derived TGF-β1 induces CD39+ γδT cells from paired normal colon tissues to produce more adenosine and become potent immunosuppressive T cells. Moreover, CD39+ γδTreg infiltration is positively correlated with TNM stage and other unfavorable clinicopathological features, implicating that CD39+ γδTregs are one of the key players in establishment of immunosuppressive TME in human CRC that may be critical for tumor immunotherapy.