Economic evaluation of antimicrobial resistance in curable sexually transmitted infections; a systematic review and a case study.
To provide a summary of the economic and methodological evidence on capturing antimicrobial resistance (AMR) associated costs for curable sexually transmitted infections (STIs). To explore approaches for incorporating the cost of AMR within an economic model evaluating different treatment strategies for gonorrhoea, as a case study. A systematic review protocol was registered on PROSPERO (CRD42022298232). MEDLINE, EMBASE, CINAHL, Cochrane Library, International Health Technology Assessment Database, National Health Service Economic Evaluation Database, and EconLit databases were searched up to August 2022. Included studies were analysed, quality assessed and findings synthesised narratively. Additionally, an economic evaluation which incorporated AMR was undertaken using a decision tree model and primary data from a randomised clinical trial comparing gentamicin therapy with standard treatment (ceftriaxone). AMR was incorporated into the evaluation using three approaches-integrating the additional costs of treating resistant infections, conducting a threshold analysis, and accounting for the societal cost of resistance for the antibiotic consumed. Twelve studies were included in the systematic review with the majority focussed on AMR in gonorrhoea. The cost of ceftriaxone resistant gonorrhoea and the cost of ceftriaxone sparing strategies were significant and related to the direct medical costs from persistent gonorrhoea infections, sequelae of untreated infections, gonorrhoea attributable-HIV transmission and AMR testing. However, AMR definition, the collection and incorporation of AMR associated costs, and the perspectives adopted were inconsistent or limited. Using the review findings, different approaches were explored for incorporating AMR into an economic evaluation comparing gentamicin to ceftriaxone for gonorrhoea treatment. Although the initial analysis showed that ceftriaxone was the cheaper treatment, gentamicin became cost-neutral if the clinical efficacy of ceftriaxone reduced from 98% to 92%. By incorporating societal costs of antibiotic use, gentamicin became cost-neutral if the cost of ceftriaxone treatment increased from £4.60 to £8.44 per patient. Inclusion of AMR into economic evaluations may substantially influence estimates of cost-effectiveness and affect subsequent treatment recommendations for gonorrhoea and other STIs. However, robust data on the cost of AMR and a standardised approach for conducting economic evaluations for STI treatment which incorporate AMR are lacking, and requires further developmental research.


[Depression post stroke in Africa: myth or reality?].
Depression is a complication occurring frequently after a stroke. It negatively affects the physical, cognitive and social recovery. Authors report the results of a casecontrol study section was performed in neurology of the friendship hospital and psychiatry of the general hospital in Bangui, from January to August 2012 to ascertain the existence of a link between stroke and depression in hospitalized patients and to identify factors limiting taken into efficient load. On one hundred five subjects included, thirty five were stroke victims matched with seventy witnesses. The prevalence of post stroke depression was 88.6% (31/35) versus (20/70) 28.5% in controls (p <0.001). This post stroke depression occurred in 58% of men with a sex ratio of 1.4. The mean age of subjects with post stroke depression was 49.1 years, with extremes ranging from 33 to 76 years of age. Most (64.5%) subjects with post stroke depression was no occupation; 71.5% of them had a stroke dating back more than six weeks, and 92% had a motor deficit with a Barthel Index <100. Subjects with stroke suffered mostly moderate depression (48.1%) whereas the controls usually had mild depression (80.4%). This depression was not correlated with motor deficit, or the laterality of the lesion, or cognitive disorder. But, some Central African specificities could explain this phenomenon. These results demonstrate the reality of post stroke depression in Africa, hence the need to think in support of any subject with stroke topic. Moreover, questions about the tools used to evaluate the post stroke depression and the time interval between stroke onset and the onset of depressive symptoms remain and require further consideration.


Adrenergic modulation of melanocortin pathway by hunger signals.
Norepinephrine (NE) is a well-known appetite regulator, and the nor/adrenergic system is targeted by several anti-obesity drugs. To better understand the circuitry underlying adrenergic appetite control, here we investigated the paraventricular hypothalamic nucleus (PVN), a key brain region that integrates energy signals and receives dense nor/adrenergic input, using a mouse model. We found that PVN NE level increases with signals of energy deficit and decreases with food access. This pattern is recapitulated by the innervating catecholaminergic axon terminals originating from NTSTH-neurons. Optogenetic activation of rostral-NTSTH → PVN projection elicited strong motivation to eat comparable to overnight fasting whereas its inhibition attenuated both fasting-induced & hypoglycemic feeding. We found that NTSTH-axons functionally targeted PVNMC4R-neurons by predominantly inhibiting them, in part, through α1-AR mediated potentiation of GABA release from ARCAgRP presynaptic terminals. Furthermore, glucoprivation suppressed PVNMC4R activity, which was required for hypoglycemic feeding response. These results define an ascending nor/adrenergic circuit, NTSTH → PVNMC4R, that conveys peripheral hunger signals to melanocortin pathway.


Long-term clinical manifestations of retained bullet fragments within the intervertebral disk space.
A retrospective review of 12 patients who were victims of penetrating trauma with a bullet or bullet fragments lodged within the intervertebral disk space was conducted. The objective of the review was to evaluate the potential systemic effects of lead resorption at long-term follow-up. Literature regarding the potential for lead toxicity due to retained bullet fragments within the intervertebral disk space is lacking. Between January 1969 and June 1993, a total of 238 patients with a gunshot wound to the spine were identified. Twelve of the 238 were found to have a bullet or bullet fragments within the intervertebral disk space. All patients were fully screened for evidence of plumbism. The average age at time of gunshot injury was 35.8 years; the average time for follow-up was 7.8 years. One of the 12 patients showed clinical evidence of plumbism. The patient subsequently underwent a partial laminectomy and diskectomy with excision of the bullet fragments. The patient's complaints, specific for plumbism, resolved 2 months postoperatively. We conclude that patients with retained lead-based bullet fragments in the intervertebral disk should be educated about the rare potential for plumbism due to partial bullet fragment resorption and that long-term observation for this disorder is recommended.


Fast Gamma Rhythms in the Hippocampus Promote Encoding of Novel Object-Place Pairings.
Hippocampal gamma rhythms increase during mnemonic operations (Johnson and Redish, 2007; Montgomery and Buzsáki, 2007; Sederberg et al., 2007; Jutras et al., 2009; Trimper et al., 2014) and may affect memory encoding by coordinating activity of neurons that code related information (Jensen and Lisman, 2005). Here, a hippocampal-dependent, object-place association task (Clark et al., 2000; Broadbent et al., 2004; Eacott and Norman, 2004; Lee et al., 2005; Winters et al., 2008; Barker and Warburton, 2011) was used in rats to investigate how slow and fast gamma rhythms in the hippocampus relate to encoding of memories for novel object-place associations. In novel object tasks, the degree of hippocampal dependence has been reported to vary depending on the type of novelty (Eichenbaum et al., 2007; Winters et al., 2008). Therefore, gamma activity was examined during three novelty conditions: a novel object presented in a location where a familiar object had been (NO), a familiar object presented in a location where no object had been (NL), and a novel object presented in a location where no object had been (NO+NL). The strongest and most consistent effects were observed for fast gamma rhythms during the NO+NL condition. Fast gamma power, CA3-CA1 phase synchrony, and phase-locking of place cell spikes increased during exploration of novel, compared to familiar, object-place associations. Additionally, place cell spiking during exploration of novel object-place pairings was increased when fast gamma rhythms were present. These results suggest that fast gamma rhythms promote encoding of memories for novel object-place associations.


Synaptotagmin-1 and -7 Are Redundantly Essential for Maintaining the Capacity of the Readily-Releasable Pool of Synaptic Vesicles.
In forebrain neurons, Ca(2+) triggers exocytosis of readily releasable vesicles by binding to synaptotagmin-1 and -7, thereby inducing fast and slow vesicle exocytosis, respectively. Loss-of-function of synaptotagmin-1 or -7 selectively impairs the fast and slow phase of release, respectively, but does not change the size of the readily-releasable pool (RRP) of vesicles as measured by stimulation of release with hypertonic sucrose, or alter the rate of vesicle priming into the RRP. Here we show, however, that simultaneous loss-of-function of both synaptotagmin-1 and -7 dramatically decreased the capacity of the RRP, again without altering the rate of vesicle priming into the RRP. Either synaptotagmin-1 or -7 was sufficient to rescue the RRP size in neurons lacking both synaptotagmin-1 and -7. Although maintenance of RRP size was Ca(2+)-independent, mutations in Ca(2+)-binding sequences of synaptotagmin-1 or synaptotagmin-7--which are contained in flexible top-loop sequences of their C2 domains--blocked the ability of these synaptotagmins to maintain the RRP size. Both synaptotagmins bound to SNARE complexes; SNARE complex binding was reduced by the top-loop mutations that impaired RRP maintenance. Thus, synaptotagmin-1 and -7 perform redundant functions in maintaining the capacity of the RRP in addition to nonredundant functions in the Ca(2+) triggering of different phases of release.


Genetic variation in populations from central Argentina based on mitochondrial and Y chromosome DNA evidence.
We present new data and analysis on the genetic variation of contemporary inhabitants of central Argentina, including a total of 812 unrelated individuals from 20 populations. Our goal was to bring new elements for understanding micro-evolutionary and historical processes that generated the genetic diversity of the region, using molecular markers of uniparental inheritance (mitochondrial DNA and Y chromosome). Almost 76% of the individuals show mitochondrial lineages of American origin. The Native American haplogroups predominate in all surveyed localities, except in one. The larger presence of Eurasian maternal lineages were observed in the plains (Pampas) of the southeast, whereas the African lineages are more frequent in northern Córdoba. On the other hand, the analysis of 258 male samples reveals that 92% of them present Eurasian paternal lineages, 7% carry Native American haplogroups, and only 1% of the males show African lineages. The maternal lineages have high genetic diversity homogeneously distributed throughout central Argentina, probably as result of a recent common origin and sustained gene flow. Migratory events that occurred in colonial and recent times should have contributed to hiding any traces of differentiation that might have existed in the past. The analysis of paternal lineages showed also homogeneous distribution of the variation together with a drastic reduction of the native male population.


Premenstrual syndrome.
Premenstrual syndrome is characterized by an array of somatic, cognitive, affective and behavioral disturbances that recur in cyclic fashion during the luteal phase of the menstrual cycle. The goal of management is to control symptoms well enough that the patient can function appropriately at all stages of the menstrual cycle. Both the patient and the physician must acknowledge that premenstrual syndrome is a complex reproductive disorder with a large number of possible manifestations; therefore, they must be willing to consider more than one strategy, and they must allow sufficient time to seek out successful therapeutic options. The patient must play an active role in all stages of management. Although no specific cure for premenstrual syndrome currently exists, most patients experience significant reduction of symptoms and improvement of quality of life when a rational individualized approach is used. Management may involve pharmacologic, nutritional and psychosocial interventions.


Sidemode suppression for coupled optoelectronic oscillator by optical pulse power feedforward.
Multiple sidemodes have been observed in a coupled optoelectronic oscillator (COEO) when the contained actively mode-locked fiber ring laser employs erbium-doped fiber (EDF). We propose that such sidemodes can be suppressed significantly by an optical pulse power feedforward scheme, through which the mode-locked optical pulse is reversely intensity-modulated by itself, resulting in a fast power limiting. Experimentally we show that sidemodes are suppressed as much as 40 dB in a 10-GHz COEO. The additional noise induced by the power feedforward technique is analyzed numerically. We show that for a COEO with a typical cavity length, the feedforward contribution to final single-side band (SSB) noise is minor and neglectable.


Implication of molecular vascular smooth muscle cell heterogeneity among arterial beds in arterial calcification.
Vascular calcification is a strong and independent predictive factor for cardiovascular complications and mortality. Our previous work identified important discrepancies in plaque composition and calcification types between carotid and femoral arteries. The objective of this study is to further characterize and understand the heterogeneity in vascular calcification among vascular beds, and to identify molecular mechanisms underlying this process. We established ECLAGEN biocollection that encompasses human atherosclerotic lesions and healthy arteries from different locations (abdominal, thoracic aorta, carotid, femoral, and infrapopliteal arteries) for histological, cell isolation, and transcriptomic analysis. Our results show that lesion composition differs between these locations. Femoral arteries are the most calcified arteries overall. They develop denser calcifications (sheet-like, nodule), and are highly susceptible to osteoid metaplasia. These discrepancies may derive from intrinsic differences between SMCs originating from these locations, as microarray analysis showed specific transcriptomic profiles between primary SMCs isolated from each arterial bed. These molecular differences translated into functional disparities. SMC from femoral arteries showed the highest propensity to mineralize due to an increase in basal TGFβ signaling. Our results suggest that biological heterogeneity of resident vascular cells between arterial beds, reflected by our transcriptomic analysis, is critical in understanding plaque biology and calcification, and may have strong implications in vascular therapeutic approaches.


Down-regulation of protein kinase C protects cerebellar granule neurons in primary culture from glutamate-induced neuronal death.
Exposing primary cultures of cerebellar granule neurons to 100 nM phorbol 12-myristate 13-acetate (PMA) for 24 hr decreases the Ca2+/phosphatidylserine/diolein-dependent protein kinase C (PKC; ATP:protein phosphotransferase, EC 126.96.36.199) by approximately 90% in the 100,000 x g supernatant and pellet fractions of neuronal culture homogenates. Immunoblot analysis of the homogenates with polyclonal antibodies raised against either the beta-type PKC peptide or total rat brain PKC reveals a virtual loss of 78-kDa PKC immunoreactivity in the supernatant and a marked decrease of PKC immunoreactivity in the pellet. Exposure of the cultures to 50 microM glutamate for 15 min (no Mg2+) induces the translocation of supernatant PKC immunoreactivity to the pellet. Such translocation persists after glutamate withdrawal and is followed by a progressive increase in neuronal death, which begins 2 hr later. Neuronal death approaches completion in about 24 hr. PMA-induced down-regulation of PKC decreases glutamate-elicited neurotoxicity. Yet, the culture exposure to 100 nM PMA fails to decrease the high-affinity binding of [3H]glutamate to neuronal membranes and does not reduce glutamate-induced activation of ionotropic or metabolotropic receptors (assayed as total membrane current measured in whole-cell voltage-clamped neurons, 45Ca2+ uptake in intact monolayers, inositolphospholipid hydrolysis, and transcriptional activation and translation of c-fos mRNA). Moreover, the immediate cell-body swelling and activation of spectrin proteolysis elicited by glutamate remain unchanged. On the other hand, PMA-induced PKC down-regulation reduces any increase in 45Ca2+ uptake or Ca2(+)-dependent proteolysis (measured as spectrin degradation) after glutamate withdrawal. These results support the view that PKC translocation is operative in glutamate-induced destabilization of cytosolic ionized Ca2+ homeostasis and neuronal death.


Pedogenetic processes in anthrosols with pretic horizon (Amazonian Dark Earth) in Central Amazon, Brazil.
Anthrosols known as Amazonian Dark Earth (ADE) have borne witness to the intensification of sedentary patterns and the demographic increase in Central Amazon. As a result, a recurring pattern has been observed of mounds with ADE arising from domestic activities and the disposal of waste. The objective of this research was to demonstrate the relationship of these anthropic activities with pedogenetic formation processes of ADE in the municipality of Iranduba, Brazil. Disturbed and undisturbed soil samples were taken from two areas of ADE (pretic horizon) and from a non-anthropic pedon. Physical, chemical, micromorphological and SEM-EDS analyses were performed. The coarse material of the pretic horizons consisted predominantly of quartz, iron nodules, ceramics and charcoal fragments, and the fine material is organo-mineral. There was a direct relationship between the color of pretic horizons and the number of charcoal fragments. The thickness of the ADE results from the redistribution of charcoal at depth through bioturbation, transforming subsurface horizons into anthropic horizons. ADE presents granular microaggregates of geochemical and zoogenetic origin. Degradation of iron nodules is intensified in pretic horizons, promoting a reverse pedogenic process contributing to the xanthization process. Surprisingly the anthropic activities also favor clay dispersion and argilluviation; clay coatings on the ceramic fragments and in the pores demonstrate that this is a current process. Processes identified as contributing to ADE genesis included: i) addition of organic residues and ceramic artifacts (cumulization) with the use of fire; ii) mechanical action of humans, roots and macrofauna (bioturbation); iii) melanization of deeper horizons as a result of bioturbation; iv) argilluviation and degradation of iron nodules. This study offers new support to archaeological research in respect to ADE formation processes in Central Amazon and confirmed the hypothesis that ancient anthropic activities may trigger and/or accelerate pedogenetic processes previously credited only to natural causes.


A novel dual-channel immunochromatographic strip using up-conversion nanoparticles for simultaneous detection of AFB1 and ZEN in maize.
Due to universal contamination and synergistic toxicity of multiple mycotoxins in foodstuff, reliable and high-throughput detection methods for multiple mycotoxins are urgently needed in corn products. In this study, a novel dual-channel immunochromatographic assay (ICA) based on improved up-conversion nanoparticles (IUCNPs) was developed for rapidly detecting aflatoxin B1 (AFB1) and zearalenone (ZEN). The synthesized IUCNPs doped by 30% Lu3+ showed a larger size, more regular structure, and brighter fluorescence intensity than conventional UCNPs. The limits of detection (LODs) of single-channel ICA test strips for AFB1 and ZEN detection were 0.01 and 0.1 ng/mL, respectively. After the optimization, the dual-channel ICA of AFB1 and ZEN in 10 min was conducted, resulting in low detection limits of 0.025 and 0.1 ng/mL, respectively. Moreover, the built assay was revealed to be highly specific for six other food-contaminated mycotoxins, and exhibited excellent accuracy, with corresponding R2 of 0.9931 and 0.9982 in calibration curves, respectively. Long-term storage experiments indicated that the dual-channel test strips had superior stability and precision. The LODs of AFB1 and ZEN in spiked maize were 0.025 and 0.25 μg/kg, demonstrating great sensitivity and matrix tolerance. Furthermore, the IUNCP-ICA was validated by high-performance liquid chromatography (HPLC) analyses, and a satisfactory consistency was obtained in 15 natural maize samples. Thus, the IUCNPs-ICA proposed in this work realized rapid and sensitive detection of AFB1 and ZEN, providing broad application potential in on-site screening for multiple mycotoxins in agricultural products.


[Two Cases of Colon Metastasis of Gastric Cancer by Different Metastasis Pathway].
We treated 2 cases ofcolon metastasis ofgastric cancer considered to be caused by different pathway. Case 1 was a 55- year-old male with gastric cancer associated with metastases for lymph node, gallbladder, and liver. Curative surgical treatment of distal gastrectomy, partial hepatectomy, cholecystectomy and lymph node dissection was performed. The final find- ing was, L, Less, Type 3, pT4b(GB), tub2, pN3a(10/20), sP0, CY0, pH1, pM1, Stage IV , R0. Ten months after, ileocecal resection was performed, as a tumor was detected in the cecum. It was a submucosal tumor of well to moderately differentiated adenocarcinoma, and diagnosed as a metastasis ofgastric cancer. Case 2 was a 59-year-old male who received total gastrectomy. The final finding was UE, Less, Type 4, tub2-por2, pT4a, pN2(5/19), cM0, sP0, CY0, Stage III B, R1. One year and 10 months later, unevenness and redness in the mucosal membrane ofthe transverse colon occurred. Signet-ring cells were observed by the endoscopic biopsy, and colon metastasis ofstomach cancer was diagnosed. Consequently, transverse colectomy was performed. Diffused invasion of cancer cells was observed in all layers of the wall, which was considered as metastasis via gastrocolic ligament. Although colon metastasis ofstomach cancer is rare, its pathway varies, such as infiltration, direct invasion, hematogenous, and lymphogenous. Form oflesion also varies. For diagnosis ofcolon lesion occurring during follow-up after gastric cancer, these points should be noted.


Single-Particle Detection of Transcription following Rotavirus Entry.
Infectious rotavirus particles are triple-layered, icosahedral assemblies. The outer layer proteins, VP4 (cleaved to VP8* and VP5*) and VP7, surround a transcriptionally competent, double-layer particle (DLP), which they deliver into the cytosol. During entry of rhesus rotavirus, VP8* interacts with cell surface gangliosides, allowing engulfment into a membrane vesicle by a clathrin-independent process. Escape into the cytosol and outer-layer shedding depend on interaction of a hydrophobic surface on VP5* with the membrane bilayer and on a large-scale conformational change. We report here experiments that detect the fate of released DLPs and their efficiency in initiating RNA synthesis. By replacing the outer layer with fluorescently tagged, recombinant proteins and also tagging the DLP, we distinguished particles that have lost their outer layer and entered the cytosol (uncoated) from those still within membrane vesicles. We used fluorescent in situ hybridization with probes for nascent transcripts to determine how soon after uncoating transcription began and what fraction of the uncoated particles were active in initiating RNA synthesis. We detected RNA synthesis by uncoated particles as early as 15 min after adding virus. The uncoating efficiency was 20 to 50%; of the uncoated particles, about 10 to 15% synthesized detectable RNA. In the format of our experiments, about 10% of the added particles attached to the cell surface, giving an overall ratio of added particles to RNA-synthesizing particles of between 250:1 and 500:1, in good agreement with the ratio of particles to focus-forming units determined by infectivity assays. Thus, RNA synthesis by even a single, uncoated particle can initiate infection in a cell.IMPORTANCE The pathways by which a virus enters a cell transform its packaged genome into an active one. Contemporary fluorescence microscopy can detect individual virus particles as they enter cells, allowing us to map their multistep entry pathways. Rotaviruses, like most viruses that lack membranes of their own, disrupt or perforate the intracellular, membrane-enclosed compartment into which they become engulfed following attachment to a cell surface, in order to gain access to the cell interior. The properties of rotavirus particles make it possible to determine molecular mechanisms for these entry steps. In the work described here, we have asked the following question: what fraction of the rotavirus particles that penetrate into the cell make new viral RNA? We find that of the cell-attached particles, between 20 and 50% ultimately penetrate, and of these, about 10% make RNA. RNA synthesis by even a single virus particle can initiate a productive infection.


Prevalence and diagnosis of hemotrophic mycoplasma infection in research sheep and its effects on hematology variables and erythrocyte membrane fragility.
Hemotrophic mycoplasma (hemoplasma) infection in research sheep can confound experimental results and contribute to morbidity and mortality. Prevalence and clinicopathologic studies historically relied on blood-smear diagnosis, but systematic studies using current molecular techniques are warranted. Here we sought to report the prevalence of subclinical infection in our study population, compare diagnostic sensitivity and specificity between blood smears and a PCR assay, and determine the effects of infection on CBC variables and erythrocyte membrane fragility. We collected whole-blood samples from 111 convenience-sampled research sheep. All samples were tested for hemoplasmas by using a PCR assay, blood smears were evaluated for visual presence of hemoplasmas, and CBC and osmotic fragility assays were performed. Subclinical prevalence, according to PCR diagnosis, was 14.1% (14 of 99) in our study population. Relative to the PCR assay, blood-smear diagnosis was 8.3% sensitive and 100% specific for hemoplasma detection. Subclinical infection was associated with changes in MCV, MCHC, RBC distribution width, and absolute monocyte count. Acute infection was associated with changes in RBC mass, Hgb concentration, MCV, MCH, MCHC, and absolute lymphocyte and monocyte counts. Acute infection was associated with increased mean erythrocyte fragility compared with that in uninfected control and treated sheep. We demonstrated that hemoplasma infection is common in our study population, blood-smear evaluation is insensitive at detecting infection, and infection is associated with changes in CBC variables and increased erythrocyte membrane fragility. These findings raise concerns regarding the suitability of hemoplasma-infected sheep for biomedical research.


CXC195 induces apoptosis and endoplastic reticulum stress in human hepatocellular carcinoma cells by inhibiting the PI3K/Akt/mTOR signaling pathway.
CXC195 exhibits strong protective effects against neuronal apoptosis by exerting antioxidant activity. However, the pharmacological function of CXC195 in cancer remains to be elucidated. The present study demonstrated that CXC195 exhibited significant cytotoxic effects, and induced cell cycle arrest and apoptosis in HepG2 human hepatocellular carcinoma (HCC) cell lines. Following treatment of HepG2 cells with 150 µΜ CXC195 for 24 , cell viability and the apoptotic rate were assessed using an MTT assay and Annexin V/propidium iodide staining followed by flow cytometric analysis. Molecular markers of the cell cycle, apoptosis, mitochondrial function and endoplasmic reticulum (ER) stress were analyzed by western blot or polymerase chain reaction analysis. Caspase activation, cytochrome c and apoptosis‑inducing factor release, and analysis of the B cell lymphoma 2 (Bcl‑2)‑associated X protein/Bcl‑2 ratio demonstrated that the anticancer effects of CXC195 in HepG2 cells were mediated by caspase and mitochondria‑dependent apoptosis. CXC195 also induced the expression of ER stress‑associated proteins, including CCAAT‑enhancer‑binding protein homologous protein, and glucose‑regulated proteins 94 and 78, and led to the activation of multiple branches of ER stress transducers, including inositol‑requiring enzyme 1α‑apoptosis signal‑regulating kinase‑p38/c‑Jun N‑terminal kinase, and protein kinase R‑like endoplasmic reticulum kinase‑eukaryotic translation initiation factor 2α‑activating transcription factor (ATF)4 and ATF6, in the HepG2 cells. In addition, CXC195 inhibited the phosphorylation of phosphoinositide 3‑kinase (PI3K), Akt and mammalian target of rapamycin (mTOR) in the HepG2 cells. These effects were enhanced following treatment with selected inhibitors of PI3K (LY294002), Akt (SH‑6) and mTOR (rapamycin). Furthermore, these inhibitors enhanced the pro‑apoptotic effects of CXC195 in the HepG2 cells. In conclusion, the results of the present study indicated that CXC195 induced apoptosis and ER stress in HepG2 cells through the inhibition of the PI3K/Akt/mTOR signaling pathway.


Interaction of reelin and stress on immobility in the forced swim test but not dopamine-mediated locomotor hyperactivity or prepulse inhibition disruption: Relevance to psychotic and mood disorders.
Psychotic disorders, such as schizophrenia, as well as some mood disorders, such as bipolar disorder, have been suggested to share common biological risk factors. One such factor is reelin, a large extracellular matrix glycoprotein that regulates neuronal migration during development as well as numerous activity-dependent processes in the adult brain. The current study sought to evaluate whether a history of stress exposure interacts with endogenous reelin levels to modify behavioural endophenotypes of relevance to psychotic and mood disorders. Heterozygous Reeler Mice (HRM) and wildtype (WT) controls were treated with 50mg/L of corticosterone (CORT) in their drinking water from 6 to 9weeks of age, before undergoing behavioural testing in adulthood. We assessed methamphetamine-induced locomotor hyperactivity, prepulse inhibition (PPI) of acoustic startle, short-term spatial memory in the Y-maze, and depression-like behaviour in the Forced-Swim Test (FST). HRM genotype or CORT treatment did not affect methamphetamine-induced locomotor hyperactivity, a model of psychosis-like behaviour. At baseline, HRM showed decreased PPI at the commonly used 100msec interstimulus interval (ISI), but not at the 30msec ISI or following challenge with apomorphine. A history of CORT exposure potentiated immobility in the FST amongst HRM, but not WT mice. In the Y-maze, chronic CORT treatment decreased novel arm preference amongst HRM, reflecting reduced short-term spatial memory. These data confirm a significant role of endogenous reelin levels on stress-related behaviour, supporting a possible role in both bipolar disorder and schizophrenia. However, an interaction of reelin deficiency with dopaminergic regulation of psychosis-like behaviour remains unclear.


Management of Pediatric Chronic Spontaneous Urticaria: A Review of Current Evidence and Guidelines.
Chronic urticaria (CU) is associated with debilitating symptoms such as pruritic wheals and/or angioedema, which can significantly affect patients' sleep, productivity and quality of life. Chronic spontaneous urticaria (CSU) is defined in cases in which no triggering factor is identified. Various guidelines directing the optimal management of CU in the adult population were published and updated over the recent years with the most accepted and widely used being the EAACI/GA2LEN/EDF/WAO 2017 guidelines. Meanwhile, guidelines specific to the pediatric population are scarce, mainly due to the fact that high quality evidence is lacking for many treatment options in this age group. The objective of this article is to review and synthesize the existing literature regarding the management of pediatric CSU. Our review highlights evidence supporting the EAACI/GA2LEN/EDF/WAO 2017 treatment guidelines with non-sedating second-generation antihistamines (sgAHs) as the mainstay of treatment for pediatric CSU, considering their demonstrated efficacy and reassuring safety profile. Additionally, the use of omalizumab in adolescents is well supported by the current literature. There is limited data available regarding the updosing of sgAHs, omalizumab in children with CSU under 12 years of age and the treatment with cyclosporine and leukotriene receptor antagonists (LTRAs) in pediatric patients of all ages. However, the results from currently available case series and case reports are promising for omalizumab and cyclosporine use in children with CSU, although large and well-designed randomized control trials (RCTs) assessing these treatment options are needed in order to formulate strong recommendations for their use. First-generation antihistamines (fgAHs) remain commonly used in pediatric CSU treatment despite a lack of studies assessing their efficacy and safety in the pediatric population and their widely known inferior safety profile compared to sgAHs.


Grifolin, neogrifolin and confluentin from the terricolous polypore Albatrellus flettii suppress KRAS expression in human colon cancer cells.
In our search for bioactive mushrooms native to British Columbia, we determined that the ethanol extracts from fruiting bodies of the terrestrial polypore Albatrellus flettii had potent anti-cell viability activity. Using bioassay-guided fractionation, mass spectrometry and nuclear magnetic resonance, we successfully isolated three known compounds (grifolin, neogrifolin and confluentin). These compounds represent the major anti-cell viability components from the ethanol extracts of A. flettii. We also identified a novel biological activity for these compounds, specifically in down-regulating KRAS expression in two human colon cancer cell lines. Relatively little is known about the anti-cell viability activity and mechanism of action of confluentin. For the first time, we show the ability of confluentin to induce apoptosis and arrest the cell cycle at the G2/M phase in SW480 human colon cancer cells. The oncogenic insulin-like growth factor 2 mRNA-binding protein 1 (IMP1) has been previously shown to regulate KRAS mRNA expression in colon cancer cells, possibly through its ability to bind to the KRAS transcript. Using a fluorescence polarization assay, we show that confluentin dose-dependently inhibits the physical interaction between KRAS RNA and full-length IMP1. The inhibition also occurs with truncated IMP1 containing the KH1 to KH4 domain (KH1to4 IMP1), but not with the di-domain KH3 and KH4 (KH3&4 IMP1). In addition, unlike the control antibiotic neomycin, grifolin, neogrifolin and confluentin do not bind to KRAS RNA. These results suggest that confluentin inhibits IMP1-KRAS RNA interaction by binding to the KH1&2 di-domains of IMP1. Since the molecular interaction between IMP1 and its target RNAs is a pre-requisite for the oncogenic function of IMP1, confluentin should be further explored as a potential inhibitor of IMP1 in vivo.


Hypervalent Iodine-Mediated Oxidative Rearrangement of N-H Ketimines: An Umpolung Approach to Amides.
An umpolung approach to amides via hypervalent iodine-mediated oxidative rearrangement of N-H ketimines under mild reaction conditions is described. This strategy provides target amides with excellent selectivity in good yields. In addition, preliminary mechanistic studies demonstrated that the migration preference depends on both steric and electronic effects of the migrating groups.


Construct validity of the canadian occupational performance measure in participants with tendon injury and Dupuytren disease.
In patient-centered practice, instruments need to assess outcomes that are meaningful to patients with hand conditions. It is unclear which assessment tools address these subjective perspectives best. The aim of this study was to establish the construct validity of the Canadian Occupational Performance Measure (COPM) in relation to the Disabilities of Arm, Shoulder, and Hand (DASH) questionnaire and the Michigan Hand Outcomes Questionnaire (MHQ) in people with hand conditions. It was hypothesized that COPM scores would correlate with DASH and MHQ total scores only to a moderate degree and that the COPM, DASH questionnaire, and MHQ would all correlate weakly with measures of hand impairments. This was a validation study. The COPM, DASH questionnaire, and MHQ were scored, and then hand impairments were measured (pain [numerical rating scale], active range of motion [goniometer], grip strength [dynamometer], and pinch grip strength [pinch meter]). People who had received postsurgery rehabilitation for flexor tendon injuries, extensor tendon injuries, or Dupuytren disease were eligible. Seventy-two participants were included. For all diagnosis groups, the Pearson coefficient of correlation between the DASH questionnaire and the MHQ was higher than .60, whereas the correlation between the performance scale of the COPM and either the DASH questionnaire or the MHQ was lower than .51. Correlations of these assessment tools with measures of hand impairments were lower than .46. The small sample sizes may limit the generalization of the results. The results supported the hypotheses and, thus, the construct validity of the COPM after surgery in people with hand conditions.


Comparison of two methods for tumour-targeting peptide modification of liposomes.
Liposomes decorated with tumour-targeting cell-penetrating peptides can enhance specific drug delivery at the tumour site. The TR peptide, c(RGDfK)-AGYLLGHINLHHLAHL(Aib)HHIL, is pH-sensitive and actively targets tumour cells that overexpress integrin receptor αvβ3, such as B16F10 melanoma cells. Liposomes can be modified with the TR peptide by two different methods: utilization of the cysteine residue on TR to link DSPE-PEG2000-Mal contained in the liposome formula (LIPTR) or decoration of TR with a C18 stearyl chain (C18-TR) for direct insertion into the liposomal phospholipid bilayer through electrostatic and hydrophobic interactions (LIPC18-TR). We found that both TR and C18-TR effectively reversed the surface charge of the liposomes when the systems encountered the low pH of the tumour microenvironment, but LIPC18-TR exhibited a greater increase in the charge, which led to higher cellular uptake efficiency. Correspondingly, the IC50 values of PTX-LIPTR and PTX-LIPC18-TR in B16F10 cells in vitro were 2.1-fold and 2.5-fold lower than that of the unmodified PTX-loaded liposomes (PTX-LIP), respectively, in an acidic microenvironment (pH 6.3). In B16F10 tumour-bearing mice, intravenous administration of PTX-LIPTR and PTX-LIPC18-TR (8 mg/kg PTX every other day for a total of 4 injections) caused tumour reduction ratios of 39.4% and 56.1%, respectively, compared to 20.8% after PTX-LIP administration. Thus, we demonstrated that TR peptide modification could improve the antitumour efficiency of liposomal delivery systems, with C18-TR presenting significantly better results. After investigating different modification methods, our data show that selecting an adequate method is vital even when the same molecule is used for decoration.


A Drosophila model for toxicogenomics: Genetic variation in susceptibility to heavy metal exposure.
The genetic factors that give rise to variation in susceptibility to environmental toxins remain largely unexplored. Studies on genetic variation in susceptibility to environmental toxins are challenging in human populations, due to the variety of clinical symptoms and difficulty in determining which symptoms causally result from toxic exposure; uncontrolled environments, often with exposure to multiple toxicants; and difficulty in relating phenotypic effect size to toxic dose, especially when symptoms become manifest with a substantial time lag. Drosophila melanogaster is a powerful model that enables genome-wide studies for the identification of allelic variants that contribute to variation in susceptibility to environmental toxins, since the genetic background, environmental rearing conditions and toxic exposure can be precisely controlled. Here, we used extreme QTL mapping in an outbred population derived from the D. melanogaster Genetic Reference Panel to identify alleles associated with resistance to lead and/or cadmium, two ubiquitous environmental toxins that present serious health risks. We identified single nucleotide polymorphisms (SNPs) associated with variation in resistance to both heavy metals as well as SNPs associated with resistance specific to each of them. The effects of these SNPs were largely sex-specific. We applied mutational and RNAi analyses to 33 candidate genes and functionally validated 28 of them. We constructed networks of candidate genes as blueprints for orthologous networks of human genes. The latter not only provided functional contexts for known human targets of heavy metal toxicity, but also implicated novel candidate susceptibility genes. These studies validate Drosophila as a translational toxicogenomics gene discovery system.


The superiority of bioimpedance vs. echocardiography and pitting edema in predicting automated office blood pressure in continuous ambulatory peritoneal dialysis patients.
To achieve optimal blood pressure control in continuous ambulatory peritoneal dialysis (CAPD) patients, identifying methods of volume assessment with the strongest correlation with blood pressure is essential. In this cross-sectional study, 52 CAPD patients were assigned to automated office blood pressure (AOBP) measurement, assessment of pedal pitting edema, bioimpedance analysis (BIA), and inferior vena cava collapsibility index (IVCCI%) measurement. Data were analyzed using STATA ver.17, and the significance level was p < 0.05. Fifty-two patients were divided based on their AOBP readings. 29 (55.8%) of patients had uncontrolled AOBP. Overhydration (OH) and the grade of pitting edema were significantly higher in the uncontrolled AOBP group. OH was identified as the best variable for predicting blood pressure (p ≤ 0.001) and detecting uncontrolled blood pressure (AUC = 0.832) using multivariate linear regression and ROC analysis, respectively. BIA-derived OH was the best variable for predicting systolic and diastolic AOBP, outperforming IVCCI% and pitting edema.


Solid-state tautomeric structure and invariom refinement of a novel and potent HIV integrase inhibitor.
The conformation and tautomeric structure of (Z)-4-[5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl]-4-hydroxy-2-oxo-N-(2-oxopyrrolidin-1-yl)but-3-enamide, C27H22F3N3O5, in the solid state has been resolved by single-crystal X-ray crystallography. The electron distribution in the molecule was evaluated by refinements with invarioms, aspherical scattering factors by the method of Dittrich et al. [Acta Cryst. (2005), A61, 314-320] that are based on the Hansen-Coppens multipole model [Hansen & Coppens (1978). Acta Cryst. A34, 909-921]. The β-diketo portion of the molecule exists in the enol form. The enol -OH hydrogen forms a strong asymmetric hydrogen bond with the carbonyl O atom on the β-C atom of the chain. Weak intramolecular hydrogen bonds exist between the weakly acidic α-CH hydrogen of the keto-enol group and the pyridinone carbonyl O atom, and also between the hydrazine N-H group and the carbonyl group in the β-position from the hydrazine N-H group. The electrostatic properties of the molecule were derived from the molecular charge density. The molecule is in a lengthened conformation and the rings of the two benzyl groups are nearly orthogonal. Results from a high-field (1)H and (13)C NMR correlation spectroscopy study confirm that the same tautomer exists in solution as in the solid state.


Cell-based imaging of sodium iodide symporter activity with the yellow fluorescent protein variant YFP-H148Q/I152L.
The sodium iodide symporter (NIS) mediates iodide (I(-)) transport in the thyroid gland and other tissues and is of increasing importance as a therapeutic target and nuclear imaging reporter. NIS activity in vitro is currently measured with radiotracers and electrophysiological techniques. We report on the development of a novel live cell imaging assay of NIS activity using the I(-)-sensitive and genetically encodable yellow fluorescent protein (YFP) variant YFP-H148Q/I152L. In FRTL-5 thyrocytes stably expressing YFP-H148Q/I152L, I(-) induced a rapid and reversible decrease in cellular fluorescence characterized by 1) high affinity for extracellular I(-) (35 muM), 2) inhibition by the NIS inhibitor perchlorate, 3) extracellular Na(+) dependence, and 4) TSH dependence, suggesting that fluorescence changes are due to I(-) influx via NIS. Individual cells within a population of FRTL-5 cells exhibited a 3.5-fold variation in the rate of NIS-mediated I(-) influx, illustrating the utility of YFP-H148Q/I152L to detect cell-to-cell difference in NIS activity. I(-) also caused a perchlorate-sensitive decrease in YFP-H148Q/I152L fluorescence in COS-7 cells expressing NIS but not in cells lacking NIS. These results demonstrate that YFP-H148Q/I152L is a sensitive biosensor of NIS-mediated I(-) uptake in thyroid cells and in nonthyroidal cells following gene transfer and suggest that fluorescence detection of cellular I(-) may be a useful tool by which to study the pathophysiology and pharmacology of NIS.


Design strategies of biodegradable scaffolds for tissue regeneration.
There are numerous available biodegradable materials that can be used as scaffolds in regenerative medicine. Currently, there is a huge emphasis on the designing phase of the scaffolds. Materials can be designed to have different properties in order to match the specific application. Modifying scaffolds enhances their bioactivity and improves the regeneration capacity. Modifications of the scaffolds can be later characterized using several tissue engineering tools. In addition to the material, cell source is an important component of the regeneration process. Modified materials must be able to support survival and growth of different cell types. Together, cells and modified biomaterials contribute to the remodeling of the engineered tissue, which affects its performance. This review focuses on the recent advancements in the designs of the scaffolds including the physical and chemical modifications. The last part of this review also discusses designing processes that involve viability of cells.


Metacercarial proteins interacting with WD40-repeat protein of Clonorchis sinensis.
The WD40-repeat proteins serve as a platform coordinating partner proteins and are involved in a range of regulatory cellular functions. A WD40-repeat protein (CsWD1) of Clonorchis sinensis previously cloned is expressed stage-specifically in the tegumental syncytium of C. sinensis metacercariae. In the present study, interacting proteins with the CsWD1 protein was purified by immunoprecipitation and 2 dimension gel electrophoresis from the C. sinensis metacercaria soluble extract, and tryptic peptides were analyzed by LC/ESI-MS. Putative partner proteins were annotated to be actin-2, glyceraldehyde-3-phosphate dehydrogenase, and hypothetical and unmanned proteins. The CsWD1 protein was predicted to contain 3 conserved actin-interacting residues on its functional surface. With these results, the CsWD1 protein is suggested to be an actin-interacting protein of C. sinensis.


Should histologic variants alter definitive treatment of bladder cancer?
The clinical significance of variant histology is controversial and diagnosis is challenging. If variant architecture truly identifies high-risk patients, or those with a differential response to therapy, than treatment algorithms should be altered. This review outlines the current evidence and determines whether histologic variants should indeed alter definitive treatment. For patients with pure squamous cell, adenocarcinoma, or small cell carcinoma, there is clear evidence to alter treatment paradigms. In adenocarcinoma or squamous cell carcinoma, there is a focus on local control and multimodal therapy with radiation. In small cell carcinoma all stages should be treated with primary chemotherapy followed by surgical extirpation. For patients with other variants of urothelial differentiation (i.e., micropapillary, sarcomatoid, squamous/glandular differentiation, etc.), management guidelines are less clear and radical cystectomy remains the mainstay of treatment at this time. The management of variant histology is challenging as it not only depends on accurate diagnosis and staging, but on assumptions regarding sensitivity to multimodal therapy (i.e., chemotherapy, radiation, intravesical agents) based on a handful of retrospective case series. This will need to be the focus of future studies and collaborative efforts in order to make significant advancements in the field.


Therapeutic doses of cyproheptadine do not inhibit monoamine oxidase in man.
Cypro, a serotonin and histamine antagonist, has been shown to be a moderately potent reversible inhibitor of tissue monoamine oxidase (MAO) obtained from hamsters and rabbits. In the present study, Cypro inhibits MAO obtained from human platelets with the same potency as harmine (Ki = 5 x 10(-5) M). However, when ten normal volunteers received conventional therapeutic doses of Cypro (16 mg/day) for two days, there was no alteration in their urinary excretion of tryptamine, 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxymandelic acid, epinephrine, or norepinephrine. We conclude that, when used in conventional clinical doses, Cypro does not inhibit MAO in man.


[Compartment syndrome].
The compartment syndrome is a common and severe clinical condition within the scope of peripheral vascular surgery and it is accompanied by a high risk of a limb loss or even the patients' death. Its etiology is linked to the acute limb ischemia or trauma and its management consists essentially in the descompressive fasciotomies, associated to diverse pharmacological agents with doubtful efficacy. The main features of this clinical entity and the criteria for therapeutic interventions are subjected to analysis and discussion.


Tropomyosin isoform expression in normal and neoplastic astrocytes.
Changes of tropomyosin isoforms have previously been found accompanying morphologic alterations such as those associated with neoplastic transformations in mammalian cells. To determine whether an isoform change is associated with the malignancy of brain tumors, we employed both polyclonal antibodies specific to high and low molecular weight tropomyosin isoforms. We found, by using immunocytochemistry and immunoblotting, that an alteration of tropomyosin isoforms is associated with human astrocytomas. Differential staining patterns were seen for normal, reactive, and neoplastic astrocytes. Characterization of the antibodies revealed an increase in the higher molecular weight tropomyosin in more anaplastic astrocytomas than in those that were well differentiated. We also observed that the different isoforms have specific subcellular localizations. These findings suggest that neoplastic transformation is associated with alteration of tropomyosin isoforms in astrocytomas. We speculate that this change may be related to morphologic transformation in which microfilament functions, such as cell shape, interaction, and recognition are altered.


Association analysis between the polymorphisms of HSD17B5 and HSD17B6 and risk of polycystic ovary syndrome in Chinese population.
To assess whether single nucleotide polymorphisms of HSD17B5 (AKR1C3) (rs1937845 and rs12529) and HSD17B6 (rs898611) are associated with polycystic ovary syndrome (PCOS) in a Chinese population. A case-control study was conducted to investigate the relation between HSD17B5 and HSD17B6 polymorphisms and PCOS. In this study, 335 patients with PCOS and 354 controls were recruited. The genotypes of HSD17B5 (rs1937845 and rs12529) and HSD17B6 (rs898611) were detected by the TaqMan method. We found that the genotypic frequencies of the rs1937845 polymorphism were different in subjects with PCOS compared with control, with the CT genotype being more commonly found in patients with PCOS than in controls (P=0.005). We observed a significantly 1.74-fold higher risk of CT genotype in the polymorphism rs1937845 in women with PCOS vs the control group (adjusted odds ratio (OR), 1.74; 95% CI=1.19-2.54; P=0.005). A similar, significant 1.47-fold higher risk (adjusted OR, 1.47; 95% CI=1.07-2.03; P=0.018) was demonstrated for T allele of polymorphism rs1937845 associated with PCOS. In patients with PCOS, the rs12529 (G>C) and rs1937845 (C>T) polymorphisms were strongly associated with the high level of testosterone. The TT carriers of polymorphism rs1937845 had a significantly increased homeostatic model assessment-B% (HOMA-B%) (P=0.045) and that might be associated with the high risk of insulin resistance. However, no significant difference was found in genotype or allele distributions of the polymorphisms rs12529 of HSD17B5 and rs898611 of HSD17B6 between patients with PCOS and controls. Additionally, the two polymorphisms of HSD17B5 are associated with hyperandrogenemia in patients with PCOS. In conclusion, our findings showed a significant statistical association between HSD17B5 rs1937845 and PCOS risk in Chinese women. The CT genotype and T allele frequency are influenced significantly to a higher extent in patients with PCOS than controls. Further studies are needed to confirm the results and find out the exact molecular mechanism of the polymorphism on the risk of hyperandrogenemia and PCOS.


Thickness and Microdomain Orientation of Asymmetric PS-b-PMMA Block Copolymer Films Inside Periodic Gratings.
The ordering process of asymmetric PS-b-PMMA block copolymers (BCPs) is investigated on flat SiO2 surfaces and on topographically patterned substrates. The topographic patterns consist of periodic gratings of 10 trenches defined by conventional top-down approaches and subsequently neutralized using a P(S-r-MMA) random copolymer (RCP). When the ordering process is accomplished on a flat surface at a temperature ranging between 180 and 230 °C, cylindrical microdomains perpendicularly oriented with respect to the substrate are observed irrespective of annealing temperature. In contrast, when the ordering process occurs on topographically patterned substrates, different phenomena have to be considered. The simultaneous effect of the flow around the gratings and the BCP flux from the zone located between adjacent trenches (mesa) into the inner part of the trenches results in significant thickness variations of the confined BCP film. Therefore, the amount of BCP inside the trenches depends on the width of the mesa region, which acts as a BCP reservoir. Moreover, within each trench group, the BCP thickness progressively decreases from the external to the central trenches composing the periodic grating. The thickness variation of the BCP film within the trenches strongly affects the ordering process, ultimately leading to different orientations of the microdomains within the trenches. In particular, when the annealing temperature is 190 °C a precise confinement of the BCP within the trenches featuring a perpendicular cylinder morphology is observed. At higher temperatures, mixed or parallel orientations of the microdomains are obtained depending on the width of the trenches in the periodic grating.


Optimization low-fat and low cholesterol mayonnaise production by central composite design.
In this study, the optimized process variables for mayonnaise low in cholestrol and fat, which contained soy milk as a yolk substitute with different levels of Xanthan gum, Zodo gum, and oil, were determined by response surface methodology using a central composite design. Polynomial equation was fitted with an insignificant lack of fit factor in order to study the relationship between variables and responses including apparent viscosity, consistency coefficient, flow index, firmness, and stability of mayonnaise sauces. Results showed that increased amounts of Xanthan gum, Zodo gum and oil led to an increase in the apparent viscosity, the consistency coefficient, the firmness/emulsion stability of the mayonnaise, while the mayonnaise flow index was reduced. The interaction effects between Xanthan gum and Zodo gum, and between Xanthan gum and oil were significant on apparent viscosity. Optimum conditions of variables were obtained due to response ranges of commercial mayonnaise as following ingredients: 0.25% Xanthan gum, 3.84% Zodo gum, 37.50% oil, and with the replacement of 63.61% soy milk. Yolk, however, was replaced with soy milk without emulsion fracture up to 100%. This study showed good potential for Zodo gum native mixed with Xanthan gum and soy milk to be used as a fat and yolk substitute in mayonnaise, respectively.


Microcylinders within mitochondrial cristae in the rat pinealocyte.
A minute cylindrical structure with a dense core, designated as "microcylinder," has been observed within enlarged spaces of mitochondrial cristae in pinealocytes of some adult rats (osmium tetroxide fixed, methacrylate embedded). The microcylinders are 270 to 330 A in diameter and of indeterminate length. Their wall is found to be made up of slender filamentous subunits, probably 6 in number, and surrounds a central filament. The microcylinders are arranged parallel to one another, forming monolayered or, more frequently, multilayered aggregates. Their number within a crista varies considerably. Packets of microcylinders may be seen located in the outer mitochondrial chamber, but are never found in the mitochondrial matrix. They have been observed neither in other cell types of the pineal gland nor in neurons, ependymal, and glial cells of the nearby epithalamic tissue. The origin and nature of the microcylinders are unknown. Glycogen-like particles have been encountered, though very infrequently, accompanying bundles of microcylinders within mitochondrial cristae.


[Susceptibility genes for Kawasaki disease].
More than 45 years have passed since Kawasaki disease(KD) was firstly described. Although the infectious agent possibly triggering the disease has not been identified, a total of 6 susceptibility genes/loci for KD have been identified through genome-wide studies. Although association of these loci are robust and has been confirmed in multiple populations, these can explain only a part of genetic background of the disease. Further investigation of genetic factors including unidentified common and rare variants as well as personal mutations contributing to individuals' susceptibility to the disease and risk for severer manifestation should be warranted and multicenter collaboration of collecting patients' subjects and information is essential for current and future genetic study of KD.


Cholesterol-induced modulated phase in phospholipid membranes.
We report the observation of a cholesterol-induced modulated phase (Pbeta) in dipalmitoyl phosphatidylcholine bilayers. It occurs below the main transition of the lipid at cholesterol concentrations of around 15 to 20 mol % and is distinct from the ripple (Pbeta') phase found in between the main and pretransitions at lower cholesterol concentrations. An electron density map of this phase, constructed from x-ray diffraction data from oriented multilayers, shows that the bilayers in this phase have a one-dimensional periodic height modulation with an amplitude of about 2.5 A. A partial phase diagram of the system deduced from diffraction data is in broad agreement with earlier studies.


[Cloning and expression of rat alpha-fetoprotein cDNA in Escherichia coli].
AFP is a major serum protein during ontogeny and is synthesized mainly by the mammalian fetal liver and yolk sac. Its synthesis ceases early in postnatal life and its reappearance in the serum in adult is a sign of hepatoma or yolk sac tumor, since these tumors produce AFP. This paper describes the cloning of rat AFP cDNA spanning complete coding region, its expression in E. coli and characterization of this recombinant AFP. The determination of the nucleotide sequence and cell-free translation of purified AFPmRNA suggested that rat AFP was synthesized as a precursor with a signal peptide of 24 amino acids followed by mature AFP of 587 amino acids. An expression vector was constructed with the cDNA and the introduction of the plasmid into E. coli resulted in the production of immunologically reactive AFP with a molecular weight of 65,000. The recombinant AFP was highly purified by immunoaffinity chromatography followed by SDS-PAGE. Analysis of the amino acids sequence indicated that the product was AFP lacking N-terminal 53 amino acid residues of preAFP.


HMG CoA reductase inhibition modulates VEGF-induced endothelial cell hyperpermeability by preventing RhoA activation and myosin regulatory light chain phosphorylation.
The beneficial effects of statins are usually assumed to stem from their ability to reduce cholesterol biosynthesis. However, because statins are potent inhibitors of the mevalonate, which governs diverse cell signaling pathways, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase may also result in pleiotropic effects. The present study describes a novel pleiotropic effect of statins on vascular endothelial growth factor (VEGF)-induced glomerular endothelial cell (GEnC) hyperpermeability. Using live cell imaging with green fluorescent protein-tagged myosin regulatory light chain (MLC) and correlative biochemical analyses, we investigated 1) VEGF signaling pathway leading to GEnC hyperpermeability and 2) the modulatory effects of statins on VEGF signaling. Our findings indicate that VEGF stimulation elicits a robust increase in GEnC permeability. The signaling pathway that mediates VEGF-induced GEnC hyperpermeability involves RhoA activation leading to actin cytoskeletal remodeling, MLC diphosphorylation, and enhanced paracellular gap formation. Remarkably, cotreatment of endothelial cells with simvastatin, a hydrophobic statin, reversed VEGF-induced GEnC hyperpermeability by preventing MLC diphosphorylation, and cytoskeletal remodeling. In summary, this study identifies RhoA and MLC phosphorylation as key mediators of VEGF-induced endothelial cell hyperpermeability and demonstrates the modulatory effects of statins on VEGF signaling pathway.


[Clinical experiences of minimally invasive direct coronary artery bypass (MIDCAB)].
From Jan. to Oct. in 1997, we performed 18 minimally invasive direct coronary artery bypass (MIDCAB), aged from 45 to 86 years (the mean age of 69 years). They had single LAD disease post PTCA failure in 2 patients, and multiple vessel disease in 16 patients including left main stenosis in 2 patients. Sixteen patients had associated risk factors for using cardiopulmonary bypass, such as cerebrovascular disease in 9 patients, calcification of ascending aorta in 5 patients, renal failure in 2 patients, old age over 80 years in 4 patients and cancer in one patient. Single bypass grafting of left internal thoracic artery (LITA) to left anterior descending artery (LAD) underwent through left anterior small thoracotomy in 9 patients, double bypass grafting of gastroepiploic artery or right ITA to right coronary artery with LITA to LAD in 9 patients through subxiphoid small incision or right anterior small thoracotomy. The mean number of distal anastomosis was 1.5/patient. All patients are alive and asymptomatic, and postoperative angiography demonstrated the patency rate of 96.2% (26/27). MIDCAB is considered as a justified and safe technique for the patients who are ineligible for standard coronary artery bypass grafting.


Gravity's effect on biology.
Gravity is a fundamental interaction that permeates throughout our Universe. On Earth, gravity gives weight to physical objects, and has been a constant presence throughout terrestrial biological evolution. Thus, gravity has shaped all biological functions, some examples include the growth of plants (e.g., gravitropism), the structure and morphology of biological parts in multicellular organisms, to its effects on our physiological function when humans travel into space. Moreover, from an evolutionary perspective, gravity has been a constant force on biology, and life, to our understanding, should have no reason to not experience the effects of gravity. Interestingly, there appear to be specific biological mechanisms that activate in the absence of gravity, with the space environment the only location to study the effects of a lack of gravity on biological systems. Thus, in this perspective piece, biological adaptations from the cellular to the whole organism levels to the presence and absence of gravity will be organized and described, as well as outlining future areas of research for gravitational biological investigations to address. Up to now, we have observed and shown how gravity effects biology at different levels, with a few examples including genetic (e.g., cell cycle, metabolism, signal transduction associated pathways, etc.), biochemically (e.g., cytoskeleton, NADPH oxidase, Yes-associated protein, etc.), and functionally (e.g., astronauts experiencing musculoskeletal and cardiovascular deconditioning, immune dysfunction, etc., when traveling into space). Based from these observations, there appear to be gravity-sensitive and specific pathways across biological organisms, though knowledge gaps of the effects of gravity on biology remain, such as similarities and differences across species, reproduction, development, and evolutionary adaptations, sex-differences, etc. Thus, here an overview of the literature is provided for context of gravitational biology research to-date and consideration for future studies, as we prepare for long-term occupation of low-Earth Orbit and cis-Lunar space, and missions to the Moon and Mars, experiencing the effects of Lunar and Martian gravity on biology, respectively, through our Artemis program.


Antifungal triazole derivative triadimefon induces ectopic maxillary cartilage by altering the morphogenesis of the first branchial arch.
The triazole derivative, triadimefon (FON), induces branchial arch abnormalities in post-implantation rat embryos cultured in vitro, and cranio-facial malformations in mouse fetuses. Ectopic maxillary cartilage has been also described as a typical FON-related malformation. This work studies the morphogenesis of the ectopic cartilage in rat embryos and fetuses exposed in vivo to FON during the early postimplantation period. Pregnant rats were treated with 0, 250, and 500 mg/kg FON on Day 9.5 of pregnancy (D9.5) and sacrificed at term (D20), during the early fetal period (D17) or at different embryogenetic periods (D10, D11, D12). The skeleton was examined after stain of bone and cartilage or of cartilage alone respectively at term or at D17. The neural crest cell (NCC) migration and compaction was investigated at D10 and D11 and the cranial nerve organization described at D12. Triadimefon is teratogenic in rats under the chosen experimental conditions. The malformations were at the level of the cranio-facial and axial skeleton at term and of the hindbrain nerves in embryos. A NCC abnormal migration and compaction was observed at the level of the first branchial arch: in FON-exposed embryos NCC were detected at the level of both maxillary and mandibular processes, whereas control embryos showed the immunostained tissue only at the level of the mandibular bud. The pathogenic pathway, proposed to explain the ectopic cartilage, is the displacement of part of the NCC-derived tissues at the maxillary region of the first branchial arch.


Effect of Implant Angulation on the Rotational Displacement of a 3-Unit Bridge after Digital Impression.
This study aimed to assess the effect of implant angulation on the rotational displacement of a 3-unit bridge following a digital impression. This in vitro experimental study evaluated 3 master models of the maxilla with Kennedy's class III partial edentulism and bilateral three-unit implant-supported fixed partial dentures. Two implants were placed with 0° (first model), 15° (second model), and 30° (third model) interimplant angles. The implants were placed bilaterally at the sites of first premolars and first molars from the posterior towards the anterior region and coded A (posterior) and B (anterior) in the left, and C (posterior) and D (anterior) in the right side. Next, their position was recorded using a coordinate measuring machine to serve as a reference. The models were then scanned by both 3Shape and Sirona digital scanners (12 times by each scanner). The obtained data were compared with the reference data three-dimensionally using GOM Inspect software to determine the rotational displacement of the implants. Data were analyzed by repeated-measures ANOVA, one-way ANOVA, paired sample t-test, and independent sample t-test (P < 0.05). Since repeated-measures ANOVA showed that the interaction effect was significant (P = 0.010), the data were analyzed by subgroup analysis. The 3Shape scanner showed significantly higher accuracy for C-D region in model 2 (P = 0.001), and A-B region in model 1 (P ≤ 0.01). In the use of the 3Shape scanner, model 3 showed a lower error rate in the A-B region, compared with models 1 and 2. Model 1 showed higher error rate than models 2 and 3 in the C-D region (P ≤ 0.01). In the use of the Sirona scanner, model 1 showed a higher error rate than models 2 (P = 0.031) and 3 (P = 0.004) in the C-D region. In digital impressions of angulated implants in 3-unit bridges by using 3Shape and Sirona scanners, the rotational error decreases as the interimplant angle increases.


EWMA Document: Negative Pressure Wound Therapy.
1. Introduction Since its introduction in clinical practice in the early 1990's negative pressure wounds therapy (NPWT) has become widely used in the management of complex wounds in both inpatient and outpatient care.1 NPWT has been described as a effective treatment for wounds of many different aetiologies2,3 and suggested as a gold standard for treatment of wounds such as open abdominal wounds,4-6 dehisced sternal wounds following cardiac surgery7,8 and as a valuable agent in complex non-healing wounds.9,10 Increasingly, NPWT is being applied in the primary and home-care setting, where it is described as having the potential to improve the efficacy of wound management and help reduce the reliance on hospital-based care.11 While the potential of NPWT is promising and the clinical use of the treatment is widespread, highlevel evidence of its effectiveness and economic benefits remain sparse.12-14 The ongoing controversy regarding high-level evidence in wound care in general is well known. There is a consensus that clinical practice should be evidence-based, which can be difficult to achieve due to confusion about the value of the various approaches to wound management; however, we have to rely on the best available evidence. The need to review wound strategies and treatments in order to reduce the burden of care in an efficient way is urgent. If patients at risk of delayed wound healing are identified earlier and aggressive interventions are taken before the wound deteriorates and complications occur, both patient morbidity and health-care costs can be significantly reduced. There is further a fundamental confusion over the best way to evaluate the effectiveness of interventions in this complex patient population. This is illustrated by reviews of the value of various treatment strategies for non-healing wounds, which have highlighted methodological inconsistencies in primary research. This situation is confounded by differences in the advice given by regulatory and reimbursement bodies in various countries regarding both study design and the ways in which results are interpreted. In response to this confusion, the European Wound Management Association (EWMA) has been publishing a number of interdisciplinary documents15-19 with the intention of highlighting: The nature and extent of the problem for wound management: from the clinical perspective as well as that of care givers and the patients Evidence-based practice as an integration of clinical expertise with the best available clinical evidence from systematic research The nature and extent of the problem for wound management: from the policy maker and healthcare system perspectives The controversy regarding the value of various approaches to wound management and care is illustrated by the case of NPWT, synonymous with topical negative pressure or vacuum therapy and cited as branded VAC (vacuum-assisted closure) therapy. This is a mode of therapy used to encourage wound healing. It is used as a primary treatment of chronic wounds, in complex acute wounds and as an adjunct for temporary closure and wound bed preparation preceding surgical procedures such as skin grafts and flap surgery. Aim An increasing number of papers on the effect of NPWT are being published. However, due to the low evidence level the treatment remains controversial from the policy maker and health-care system's points of view-particularly with regard to evidence-based medicine. In response EWMA has established an interdisciplinary working group to describe the present knowledge with regard to NPWT and provide overview of its implications for organisation of care, documentation, communication, patient safety, and health economic aspects. These goals will be achieved by the following: Present the rational and scientific support for each delivered statement Uncover controversies and issues related to the use of NPWT in wound management Implications of implementing NPWT as a treatment strategy in the health-care system Provide information and offer perspectives of NPWT from the viewpoints of health-care staff, policy makers, politicians, industry, patients and hospital administrators who are indirectly or directly involved in wound management.


The distribution of a specific HLA-B27-associated cell surface component on the tissues of patients with ankylosing spondylitis.
In this paper, we report the presence on Epstein-Barr virus-transformed lymphoblastoid cell lines on platelets and on fibroblasts of an HLA-B27-associated cell surface complex (antigenically related to some antigens of Klebsiella K43 and K21) which is identical to or cross-reactive with the determinant present on the peripheral blood lymphocytes (PBL) of B27-positive patients with ankylosing spondylitis (AS). By contrast, no Klebsiella K43 markers could be demonstrated on the spermatozoa of B27+ AS+ individuals even though these cells expressed the HLA-B27 alloantigen. No B27-associated K43 antigen was detected on the erythrocytes of patients or of normal controls. The B27-associated membrane marker is still detectable on lymphoblastoid cell lines after 20 generations and on fibroblasts after about 10 generations. This finding implies that the continued expression of Klebsiella-modified B27 structure is generally determined and does not require the repeated exposure of the cell surface to Klebsiella antigen. These data suggest that certain non-lymphoid as well as lymphoid cells may be involved in the complex sequence of events leading to the clinical manifestation of AS.


Effects of contact lens wearing on keratoconus: a confocal microscopy observation.
To evaluate the corneal cell morphology of new keratoconus patients wearing two different types of rigid gas-permeable (RGP) contact lenses for 1y. Thirty nine eyes of 39 new keratoconus patients were selected and randomly fitted with two types of RGP contact lenses. Group 1 had 21 eyes with regular rigid gas-permeable (RRGP) contact lens and rest 18 eyes were in group 2 with specially designed rigid gas-permeable (SRGP) contact lens. Corneal cell morphology was evaluated using a slit scanning confocal microscope at no-lens wear and after 1y of contact lens wearing. After 1y of contact lens wearing in group 1, the mean anterior and posterior stromal keratocyte density were significantly less (P=0.006 and P=0.001, respectively) compared to no-lens wear. The mean cell area of anterior and posterior stromal keratocyte were also significantly different (P=0.005 and P=0.001) from no-lens wear. The anterior and posterior stromal haze increased by 18.74% and 23.81%, respectively after 1y of contact lens wearing. Whereas in group 2, statistically significant changes were observed only in cell density & area of anterior stroma (P=0.001 and P=0.001, respectively) after 1y. While, level of anterior and posterior stromal haze increased by 16.67% and 11.11% after 1y of contact lens wearing. Polymegathism and pleomorphism also increased after 1y of contact lens wearing in both the contact lens groups. Confocal microscopy observation shows the significant alterations in corneal cell morphology of keratoconic corneas wearing contact lenses especially in group 1. The type of contact lens must be carefully selected to minimize changes in corneal cell morphology.


AngII-induced glomerular mesangial cell proliferation inhibited by losartan via changes in intracellular calcium ion concentration.
This study investigated the changes in intracellular [Ca(2+)](i) (intracellular calcium ion concentration) and TRPC6 (transient receptor potential channel 6) expression during angiotensin II (AngII)-induced glomerular mesangial cell (GMC) proliferation, as well as the inhibitory effect of losartan. GMC cultures were split into four groups treated for 24 h: Group N (blank control group), Group A (10(-7 )mol/L AngII), Group LT (10(-7 )mol/L AngII and 10(-5 )mol/L losartan), and Group Pred (10(-7 )mol/L AngII and 10(-5 )mol/L prednisone). GMCs proliferation was measured by the MTT and trypan blue assays. The distribution of TRPC6 was monitored by immunofluorescence, the expression of TRPC6 was detected by RT-PCR and Western blotting, and [Ca(2+)](i) was measured by laser scanning confocal microscopy. The results showed that the maximal proliferation of GMCs was induced by treatment with 10(-7 )mol/L AngII for 24 h. In Group A, the distribution of TRPC6 was not uniform in the cell membrane, there was increased accumulation of this protein within the cytoplasm, and the increased expression of TRPC6 and [Ca(2+)](i) was consistent with the proliferation of cells. In Group LT, losartan inhibited the proliferation of GMCs significantly, the levels of TRPC6 and [Ca(2+)](i) were diminished, and the distribution of TRPC6 was improved. Prednisone also significantly inhibited the proliferation of GMCs and had no effects on the expression of TRPC6 and [Ca(2+)](i) in Group Pred. These findings suggested that AngII could enhance the expression of TRPC6, increase [Ca(2+)](i,) and demonstrate a time-dose-response relationship with the proliferation of GMCs, while losartan reversed the effect of AngII on GMC proliferation.


Structure and anomalous underscreening in ethylammonium nitrate solutions confined between two mica surfaces.
The observation of long-range interactions across ionic liquids and highly concentrated electrolytes, extending far beyond the Debye-Hückel prediction and beyond the range predicted in liquid state theory, has been called 'anomalous underscreening'. A number of theoretical and experimental works have explored this phenomenon over recent years, although its origin is not yet fully understood. Most of the experimental studies of anomalous underscreening until now involved aprotic ionic liquids, and so it is of interest to explore interactions in protic ionic liquids where the distribution of charge in the fluid is different in nature. Here we present direct measurements of the interaction force as a function of separation distance, measured using a surface force balance, across solutions of a protic ionic liquid ethylammonium nitrate (EAN) and its mixtures with water over a range of volume fractions from 10 vol% to 100 vol% EAN. The results reveal intricate details about near-surface ordering and dynamics at the EAN-mica interface as well as anomalous underscreening consistent with that observed in the past with aprotic ionic liquids.


[Induction of nuclear envelope formation around individual chromosomes under impact of hypotonic shock].
In the present work we have studied the distribution of some proteins participating in the nuclear envelope assembly (lamins A/C, B and LAP2 alpha) in mitotic cells and after hypotonic treatment with 15% Hank's solution. In untreated cells, these proteins are localized in the nuclei of interphase cells migrate to the cytoplasm during mitosis. Hypotonic treatment of interphase, prophase and telophase cells does not lead to considerable relocalization of lamins A/C and B. However, unlike normal mitosis, in prometaphase and metaphase cells their chromosomes acquire affinity to lamins and LAP2 alpha. Comparative analysis of lamins and LAP2 alpha distribution have revealed that chromosomes have special sites for binding with different proteins.


Multiple reflections enhanced fiber-optic photoacoustic sensor for gas micro-leakage.
A multiple reflections-enhanced fiber-optic photoacoustic (PA) gas sensor for gas micro-leakage is introduced. Multiple reflections of the excitation laser occur on the inner surface of a reflective ring to enhance the PA signal. The PA signal is obtained by measuring the deflection of the gold-coated poly (phenylene sulfide) (PPS) diaphragm with a Fabry-Perot interferometer (FPI). The second harmonic wavelength modulation spectrum (2f-WMS) technology can essentially eliminate the fundamental frequency noise generated by the wavelength-independent absorption of the reflective ring. Experimental results show that the PA signal can be effectively enhanced 11.7 times by the multiple reflections optical path compare with the double-pass optical path. The minimum detection limit of the system is achieved to be 23.6 ppb. The designed PA gas sensor is suited for remote detection of gas micro-leakage.


Replication of transformation-defective mutants of the Prague strain of Rous sarcoma virus and isolation of a td mutant from duck-adapted PR-RSV-C.
The replication of transformation-defective mutants of the Prague strain of Rous sarcoma virus subgroup C was studied using roller cultures. Under such conditions, 10(5)--10(6) infectous units of virus per 0.2 ml were produced, as revealed in both the reverse transcriptase and 16Q complementation tests. A new td daPR-RSV-C mutant was isolated from duck-adapted PR-RSV-C. This mutant replicated in roller cultures with equal efficiency as the original td PR-RSV-C. It was verified that td daPR-RSV-C does not transform chicken fibroblasts, is not oncogenic for 3-week-old chickens and has subgroup C host-range specificity. Both td mutants replicate in duck cells and reach the same titres.


Covariate adjusted inference of parent-of-origin effects using case-control mother-child paired multilocus genotype data.
It is of great interest to identify parent-of-origin effects (POEs) since POEs play an important role in many human heritable disorders and human early life growth and development. POE is sometimes referred to as imprinting effect in the literature. Compared with the standard logistic regression analyses, retrospective likelihood-based statistical methods are more powerful in identifying POEs when data are collected from related individuals retrospectively. However, none of existing retrospective-based methods can appropriately incorporate covariates that should be adjusted for if they are confounding factors. In this paper, a novel semiparametric statistical method, M-HAP, is developed to detect POEs by fully exploring available information from multilocus genotypes of case-control mother-child pairs and covariates. Some large sample properties are established for M-HAP. Finite sample properties of M-HAP are illustrated by extensive simulation studies and real data applications to the Jerusalem Perinatal Study and the Danish National Birth Cohort study, which confirm the desired superiority of M-HAP over some existing methods. M-HAP has been implemented in the updated R package CCMO.


Effects of GABA, THIP, and potassium on excitability of myelinated axons of isolated amphibian spinal roots.
The effects of direct applications of GABA (gamma-aminobutyric acid) and the GABAA agonist, THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) on the excitability of myelinated axons of individual dorsal and ventral spinal roots (lumbar VI and (or) VII) of the isolated bullfrog peripheral nerve are reported. Increases evoked by the GABA agonists (0.01-10 mM) in the amplitude of half-maximal A-fiber compound action potentials indicate the presence of depolarizing responses with apparently greater localization to the dorsal roots, and a sensitivity to GABA twofold greater than that for THIP. The changes evoked by GABA and THIP, as well as potassium have components that closely resemble those of sensory and motor fibers in the more distal, desheathed nerve bundle but are smaller and delayed, differences attributable to a closely attached root sheath that acts as a diffusion barrier. These results confirm the likely existence of GABAA receptors on both dorsal and ventral spinal roots.


Adenosine triphosphate stimulates inositol phospholipid metabolism and prostacyclin formation in adrenal medullary endothelial cells by means of P2-purinergic receptors.
In the adrenal medulla, chromaffin cells secrete high concentrations of catecholamines, ATP, peptides and other factors that must pass through an endothelial cell barrier to enter the bloodstream. We have measured the effect of several of these chromaffin cell secretory products on cultured bovine adrenal medullary endothelial cells and have found that only ATP stimulates prostacyclin formation. The stimulation of prostacyclin formation by ATP coincides with the metabolism of inositol phospholipids and the accumulation of the putative second messenger inositol trisphosphate. The time course, concentration dependence, and P2-purinergic receptor specificity were similar for ATP-stimulated prostacyclin formation and ATP-stimulated inositol phospholipid metabolism. Thus, the increase in prostacyclin formation may be secondary to mobilization of intracellular Ca2+ by inositol trisphosphate, leading to activation of phospholipase A2, liberation of arachidonic acid, and the conversion of arachidonic acid to prostacyclin. We propose that the function of ATP, which is often colocalized with cell-specific hormones in secretory cells, may be to regulate blood flow in the adrenal medulla and other endocrine tissues by interacting with adjacent endothelial cells.


Stage-specific antigenicity in Theileria annulata: a case report.
Blood from sick cattle in Bahrain transmitted piroplasms of Theileria annulata to a splenectomized calf. Larvae of Hyalomma anatolicum anatolicum were infected on the calf and, after moulting, induced clinical theileriosis, associated with numerous schizonts, in the same calf. The animal was cured by specific treatment. Antigenic differences thus shown between piroplasms on the one hand, and sporozoites and schizonts on the other hand, were confirmed in the indirect fluorescent antibody test, as a significant titre to T. annulata piroplasm antigen developed after the inoculation of blood, but to schizont antigen only after the infective ticks had induced the appearance of schizonts.


Intracellular mechanism of action of vasodilators.
Vasodilators that act directly at the level of the vasculature may be classified as either endothelium-dependent or endothelium-independent agents. Endothelium-dependent agents stimulate the endothelium to produce endothelium-derived relaxing factor (recently identified as NO) which relaxes vascular smooth muscle and increases cGMP. Endothelium-independent vasodilators may be divided into calcium antagonists, alpha 1-adrenergic antagonists, cAMP-elevating agents and cGMP-elevating agents. It is generally accepted that calcium-dependent phosphorylation of myosin light chains initiates smooth muscle contraction. A variety of evidence suggests that certain vasodilators inhibit calcium-dependent phosphorylation of myosin light chains and smooth muscle contraction via activation of cAMP- and cGMP-dependent protein phosphorylation. Since vascular smooth muscle cells and platelets have many properties in common, and since cAMP- and cGMP-elevating vasodilators inhibit both smooth muscle contraction and platelet aggregation, human platelets were used to study the effects of vasodilators on protein phosphorylation. It could be demonstrated that cAMP- and cGMP-regulated protein kinases are the intracellular mediators for prostaglandin-E1- and nitroprusside-induced protein phosphorylation, respectively. Furthermore, prostaglandin-E1- and nitroprusside-stimulated protein phosphorylation was found to be associated with an inhibition of the phosphatidylinositol cycle. Cyclic nucleotide-elevating vasodilators may inhibit smooth muscle contraction and platelet aggregation by regulating the flux through the phosphatidylinositol cycle, and the activity of myosin light-chain kinase and of calcium ATPases.


Safety and efficacy of lorcaserin: a combined analysis of the BLOOM and BLOSSOM trials.
Lorcaserin, a novel selective 5-HT2C receptor agonist, is approved by the US Food and Drug Administration (FDA) for weight management in combination with lifestyle modification for adults with obesity and adults with overweight and ≥ 1 weight-related comorbid condition. The safety and effectiveness of lorcaserin in adult patients without type 2 diabetes mellitus was established based on 2 phase III clinical trials of similar design: Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) and Behavioral Modification and Lorcaserin Second Study for Obesity Management (BLOSSOM). This report presents a prespecified analysis of pooled data from these trials. Co-primary end points in this analysis include the proportion of patients with a reduction in baseline body weight of ≥ 5% and ≥ 10%, and a change in weight from baseline. Key secondary end points include changes from baseline values in lipid parameters, quality-of-life measures, glycemic indicators, and vital signs. At week 52, more than twice as many lorcaserin-treated patients achieved a weight loss of ≥ 5% compared with placebo (lorcaserin, 47.1%; placebo, 22.6%), and lorcaserin-treated patients lost significantly more body weight (lorcaserin, -5.8%; placebo, -2.5%). A significantly greater proportion of lorcaserin-treated patients achieved a weight loss of ≥ 10% (lorcaserin, 22.4%; placebo, 8.7%). There were statistically significant improvements in lipid parameters, glycemic indicators, quality-of-life measures, and vital signs in the lorcaserin group compared with placebo. The most common adverse events associated with lorcaserin treatment were headache, upper respiratory tract infection, and nasopharyngitis. Lorcaserin-treated patients had a rate of FDA-defined valvulopathy similar to placebo. This pooled analysis of the phase III BLOOM and BLOSSOM trials shows that lorcaserin 10 mg twice daily, in combination with diet and exercise, is safe and tolerable, and is associated with statistically significant weight loss and clinically relevant improvements in cardiometabolic parameters.


Commissioning and clinical implementation of a mega-voltage cone beam CT system for treatment localization.
The improvement in conformal radiotherapy techniques with steep dose gradients has allowed for the delivery of higher doses to a tumor volume while maintaining the sparing of surrounding normal tissue. In this situation, verification of patient setup and evaluation of internal organ motion just prior to radiation delivery is a crucial step. To this end, several volumetric image-guided techniques have been developed for patient localization, such as the Siemens MVision mega-voltage cone beam CT (MV-CBCT) system. In this work, the commissioning and clinical implementation of the MVision system is presented. The geometry and gain calibration procedures for the system are described, and guidelines for quality assurance procedures are provided. Different MV-CBCT clinical protocols, ranging from daily to weekly image-guidance, which includes image acquisition, reconstruction, registration with planning CT, and treatment couch offsets corrections, were commissioned. The image quality characteristics of the MVision system were measured and assessed qualitatively and quantitatively, including the image noise and uniformity, low-contrast resolution, and spatial resolution. Furthermore, the image reconstruction and registration software was evaluated. Data show that a 2 cm large object with 1% electron density contrast can be detected with the MVision system with 10 cGy at isocenter and that the registration software is accurate within 2 mm in the anterior-posterior, left-right, and superior-inferior directions.


Subjects with osteoporosis to remain at high risk for fracture despite benefit of prior bisphosphonate treatment-a Danish case-control study.
The benefits of pharmaceutical treatment for osteoporosis may be limited for a number of patients, as they continue to experience fractures. Alternative treatments may be considered for subjects whom remain at high risk for future fractures. Previous studies have investigated the effects of good adherence to anti-osteoporosis medication. However, very few studies have described why some patients experience fractures and loss of BMD despite adherence to treatment. The aim of this study was to estimate the proportion of patients at high risk for fracture despite being compliant to bisphosphonate treatment and examine which factors influence why some osteoporotic patients remain at a high risk for fracture despite being compliant to bisphosphonate treatment. This case-control study is based on Danish national health registry data. The subjects had to have either one BMD test or a fracture prior to inclusion. "High-risk" subjects (cases) were defined as BMD t-score < =-2.5 SD, any drop in BMD from baseline or a fracture 24-36 months following inclusion. A total of 2406 subjects (66.3 % women; 33.7 % men) fulfilled the inclusion criteria, and of these, 352 (14.6 %) were identified as high risk subjects. A multiple logistical regression analysis showed that high risk subjects were more likely to have lower plasma calcium and/or vitamin D levels (OR: 2.9) and were more frequently diagnosed with hyperparathyroidism (OR: 2.6). Based on Danish national health registry data, 14.6 % patients were identified as patients remaining at high risk for fracture despite being compliant to bisphosphonate treatment. Lower plasma calcium and/or vitamin D level is the greatest predictor of high risk for fracture despite persistent bisphosphonate treatment. Secondary causes of osteoporosis should be considered and alternative treatments may be advised for subjects whom remain at high risk.


Discovery of Potent, Dual-Inhibitors of Diacylglycerol Kinases Alpha and Zeta Guided by Phenotypic Optimization.
We describe a phenotypic screening and optimization strategy to discover compounds that block intracellular checkpoint signaling in T-cells. We identified dual DGKα and ζ inhibitors notwithstanding the modest similarity between α and ζ relative to other DGK isoforms. Optimized compounds produced cytokine release and T-cell proliferation consistent with DGK inhibition and potentiated an immune response in human and mouse T-cells. Additionally, lead inhibitor BMS-502 demonstrated dose-dependent immune stimulation in the mouse OT-1 model, setting the stage for a drug discovery program.


Balanced Eyes See Stereopsis More Quickly, but Not More Finely.
To quantify ocular sensory dominance and investigate its relationship to stereopsis. A total of 69 subjects participated in the study. Ocular dominance was measured by a continuous flashing technique, with the tested eye viewing a Gabor patch increasing in contrast, and the fellow eye viewing a Mondrian noise decreasing in contrast. In each trial, the log ratio of Mondrian to Gabor's contrasts was recorded as a subject first detected the Gabor. We collected 50 trials for each eye and an interocular difference was analyzed with a rank-sum test. The z-value was used as the ocular dominance index (ODI) to quantify the degree of ocular dominance. A subject with ODI ≥ 2 was categorized as having a clear ocular dominance, and a subject with ODI < 2 was considered as having balanced eyes (unclear dominance). The stereoacuity was measured with random dot patterns with durations varying from 50 to 1000 ms. The best achievable stereoacuity (Dmin) and the integration time needed to acquire that (Tmin) were calculated. A total of 30 subjects had balanced eyes and 39 had clear ocular dominance. Tmin was significantly longer in subjects with clear ocular dominance than in subjects with balanced eyes (180.18 vs. 121.17 ms, P < 0.01). Tmin was positively correlated with ODI (P < 0.01). However, Dmin in subjects with clear dominance was not different from that in subjects with balanced eyes (40.60 vs. 35.73 arcsec, P = 0.18). Ocular dominance is not associated with how fine the stereoacuity is, but rather how quickly the best stereoacuity is acquired.