Climate variability, socio-economic conditions and vulnerability to malaria infections in Mozambique 2016-2018: a spatial temporal analysis.
Temperature, precipitation, relative humidity (RH), and Normalized Different Vegetation Index (NDVI), influence malaria transmission dynamics. However, an understanding of interactions between socioeconomic indicators, environmental factors and malaria incidence can help design interventions to alleviate the high burden of malaria infections on vulnerable populations. Our study thus aimed to investigate the socioeconomic and climatological factors influencing spatial and temporal variability of malaria infections in Mozambique. We used monthly malaria cases from 2016 to 2018 at the district level. We developed an hierarchical spatial-temporal model in a Bayesian framework. Monthly malaria cases were assumed to follow a negative binomial distribution. We used integrated nested Laplace approximation (INLA) in R for Bayesian inference and distributed lag nonlinear modeling (DLNM) framework to explore exposure-response relationships between climate variables and risk of malaria infection in Mozambique, while adjusting for socioeconomic factors. A total of 19,948,295 malaria cases were reported between 2016 and 2018 in Mozambique. Malaria risk increased with higher monthly mean temperatures between 20 and 29°C, at mean temperature of 25°C, the risk of malaria was 3.45 times higher (RR 3.45 [95%CI: 2.37-5.03]). Malaria risk was greatest for NDVI above 0.22. The risk of malaria was 1.34 times higher (1.34 [1.01-1.79]) at monthly RH of 55%. Malaria risk reduced by 26.1%, for total monthly precipitation of 480 mm (0.739 [95%CI: 0.61-0.90]) at lag 2 months, while for lower total monthly precipitation of 10 mm, the risk of malaria was 1.87 times higher (1.87 [1.30-2.69]). After adjusting for climate variables, having lower level of education significantly increased malaria risk (1.034 [1.014-1.054]) and having electricity (0.979 [0.967-0.992]) and sharing toilet facilities (0.957 [0.924-0.991]) significantly reduced malaria risk. Our current study identified lag patterns and association between climate variables and malaria incidence in Mozambique. Extremes in climate variables were associated with an increased risk of malaria transmission, peaks in transmission were varied. Our findings provide insights for designing early warning, prevention, and control strategies to minimize seasonal malaria surges and associated infections in Mozambique a region where Malaria causes substantial burden from illness and deaths.


Influence of endometriosis on pain behaviors and muscle hyperalgesia induced by a ureteral calculosis in female rats.
Endometriosis and urinary calculosis can co-occur. Clinical studies have shown that both painful and non-painful endometriosis in women are associated with enhanced pain and referred muscle hyperalgesia from urinary calculosis, but the mechanisms underlying this phenomenon are still poorly understood. The aim of this study was to develop an animal model adequate to explore this viscero-visceral interaction in standardized conditions. Using a model of endometriosis previously developed to study reduced fertility and vaginal hyperalgesia, endometriosis (endo) or sham-endometriosis (sham-endo) was induced in rats by autotransplantation of small pieces of uterus (or, for sham-endo, fat) on cascade mesenteric arteries, ovary, and abdominal wall. After the endometrial, but not the fat autografts had produced fluid-filled cysts (3 weeks), urinary calculosis was induced by implanting an artificial stone into one ureter. Pain behaviors were monitored by continuous 24-h videotape recordings before and after stone implantation. Referred muscle hyperalgesia was assessed by measuring vocalization thresholds to electrical stimulation of the oblique musculature (L1 dermatome). The data were compared with previously reported data from rats that had received only the stone. Neither endo nor sham-endo alone induced pain behaviors. Following stone implantation, in endo rats compared to sham-endo and stone-only rats, pain behaviors specifically associated with urinary calculosis were significantly increased and new pain behaviors specifically associated with uterine pathology became evident. Muscle hyperalgesia was also significantly increased. To explore the relationship between the amount of endometriosis and that of ureteral pain behavior, two separate groups of endo rats were treated with either a standard non-steroidal anti-inflammatory drugs (ketoprofen) or placebo from the 12th to the 18th day after endometriosis induction. The stone was implanted on the 21st day. Ketoprofen treatment compared to placebo significantly reduced the size of the cysts and both ureteral and uterine pain behaviors post-stone implantation. The size of the cysts showed a significant linear correlation with the post-stone ureteral pain behaviors. In conclusion, endo increased pain crises and muscle hyperalgesia typically induced by a ureteral calculosis, and the ureteral calculosis revealed additional pain behaviors typically induced by uterine pathophysiology; and this enhancement was a function of the degree of endometriosis. This result closely reproduces the condition observed in humans and could be due to a phenomenon of 'viscero-visceral' hyperalgesia, in which increased input from the cyst implantation sites to common spinal cord segments (T10-L1) facilitates the central effect of input from the urinary tract.


Chromhidrosis--colored sweat in a toddler.
Chromhidrosis means production of coloured sweat. A toddler who presented with colored sweat was diagnosed to have chromhidrosis based on skin biopsy. No treatment was attempted considering the young age. Parents were counselled about the benign nature of this disorder. Identification of causes of colored sweat requires appropriate investigations.


Inhibition of prostaglandin synthesis: a possible mechanism for stress-induced hypertension.
Essential hypertension, while considered to be idiopathic, may be due to a variety of physiologic and/or psychologic factors, including stress. A possible mechanism for stress-induced hypertension is the inhibition of prostaglandin (PG) synthesis by the release of corticoids in the stereotypical stress response. PGI2 and PGE2, acting as vasodilators are important antagonists to the pressor effects of norepinephrine. However, a decreased synthesis of these PGs due to higher cortisol levels associated with stress, would negate their vasodilatory action, thus favoring vasoconstriction due to vascular suprasensitivity to norepinephrine. PGF2 alpha, a vasoconstrictor thought to be synthesized in the brain in response to a stressor, may also play a key role in the pathogenesis of hypertension.


Revisiting the hydroxylation phenomenon of SiO2: a study through "hard-hard" and "soft-soft" interactions.
Surface hydroxylation has been extensively studied over the years for a variety of applications, and studies involving hydroxylation of different silica surfaces are still carried out due to the interesting properties obtained from those modified surfaces. Although a number of theoretical studies have been employed to evaluate details on the hydroxylation phenomenon on silica (SiO2) surfaces, most of these studies are based on computationally expensive models commonly based on extended systems. In order to circumvent such an aspect, here we present a low-cost theoretical study on the SiO2 hydroxylation process aiming to evaluate aspects associated with water-SiO2 interaction. Details about local reactivity, chemical softness, and electrostatic potential were evaluated for SiO2 model substrates in the framework of the density functional theory (DFT) using a molecular approach. The obtained results from this new and promising approach were validated and complemented by fully atomistic reactive molecular dynamics (FARMD) simulations. Furthermore, the implemented approach proves to be a powerful tool that is not restricted to the study of hydroxylation, opening a promising route for low computational cost to analyze passivation and anchoring processes on a variety of oxide surfaces.


Blood pressure declines and less favorable outcomes in the NINDS tPA stroke study.
Hypertension is the most important modifiable risk factor for secondary stroke prevention but the immediate management of blood pressure after stroke is uncertain. We evaluated outcomes in the NINDS tPA stroke study in relation to blood pressure declines during the first 24 h after randomization. Declines in blood pressure compared to baseline and preceding time points were analyzed in relationship to favorable outcomes (by a global test), poor outcomes (Rankin scale >3) and death at 3 months. 551 patients did not receive immediate pre-randomization anti-hypertensive treatment and had available blood pressures. Multivariate analysis showed significantly and progressively reducing likelihoods of a favorable outcome with each 10 mmHg decline in systolic blood pressure (SBP) >50 mmHg compared to any preceding measurement. Poor outcomes were significantly more likely in patients with >50 mmHg SBP reduction (or >30 mmHg compared to any immediately preceding measurement). There was an increased risk of death with blood pressure declines >60 mmHg. tPA treatment still produced favorable outcomes compared with placebo even with blood pressure declines. The median largest SBP reduction from baseline in patients treated with tPA was 35 mmHg compared to 30 mmHg in placebo-treated patients (p<0.01). In this post hoc analysis, progressively reducing likelihoods of a favorable outcome were seen with increasing declines in SBP. Despite a greater likelihood of favorable outcomes, tPA treatment was associated with a greater reduction in blood pressure than placebo. Randomized trials of blood pressure management are needed.


Phyllodes tumor: an unexpected tumor of the breast. A report on six patients.
To evaluate the role of adjuvant radiotherapy for an unexpected malignancy of the breast, known as phyllodes tumor, a retrospective study was undertaken. Between 1994 and 2002, six female patients with a phyllodes tumor (borderline, n = 2; malignant, n = 4) were irradiated after modified radical mastectomy at our institution. No patient received adjuvant systemic therapy. Two patients experienced local failure, after 17 months (malignant) and 23 (borderline) months of observation. One of the patients with local relapse died intercurrently, the other because of multiple pulmonary metastases. Four patients are alive and show no evidence of disease. Median follow-up was 33.8 months (range 29-42 months). Based on the data from the literature and the authors' findings, it is concluded that surgery with wide negative margins is the preferred initial treatment option. There is no indication for axillary dissection, since these tumors rarely metastasize to regional lymph nodes. In patients with phyllodes tumors showing adverse prognostic factors, postoperative irradiation is recommended.


Flow cytometric analysis of CD133- and EpCAM-positive cells in the peripheral blood of patients with lung cancer.
Lung tumors are characterized by their high metastatic potential, which is the main cause of therapeutic failure. However, the exact cellular origin of metastasis remains unknown. Since the introduction of the cancer stem cell theory, lung cancer stem cells (LCSCs) have been thought to represent metastasis-founding cells. The current study aimed to evaluate whether LCSCs could be found in the circulation. Expression of the stem cell markers CD133 and EpCAM was confirmed in tumor and normal lung tissue by flow cytometry. Then, this technique was further used to investigate the expression of CD133 and EpCAM in the peripheral blood of 41 patients with primary lung cancer. Putative LCSCs (CD133?EpCAM?) were present in 6/7 tumor samples, and CD133?EpCAM? cells were identified in the blood samples of 15 patients at a median level of 40/ml of blood. EpCAM? cells were detected in 60 % of the patients, and the number of these cells was higher in patients with adenocarcinoma than patients with squamous cell carcinoma and was also higher in patients with less advanced disease. Moreover, the frequency of this subpopulation significantly correlated with the circulating level of SSEA-4? cells. Additionally, CD133?EpCAM- cells were found in 87 % of the patients, and the numbers of these cells were significantly higher in patients with distant metastases and correlated with disease stage. This study confirmed the presence of an LCSC subpopulation with a CD133?EpCAM? phenotype in the tumors and blood of patients with lung cancer, and these results suggest an important role for CD133 and EpCAM in lung cancer progression and their potential application as novel biomarkers of the disease.


Biochemical and histological sequences of membranous ossification in ectopic site.
Porous hydroxyapatite ceramics alone (control) and ceramics combined with rat marrow cells were implanted subcutaneously in the back of syngeneic rats and harvested 1-8 weeks after implantation. The ceramics were examined biochemically and histologically. Alkaline phosphatase activity in the marrow cell/ceramic composites began to increase at 2 weeks and achieved a peak at 4 weeks, followed by a gradual decrease. Bone gla protein contents in the composites began to increase at 3 weeks and steadily increased as time passed. Histologically, osteoblastic cells were detected at 2 weeks and obvious de novo bone together with active osteoblasts began to appear at 3 weeks in the composites. The process was membranous ossification without cartilage formation and was observed in the pores of the composites. The pore areas occupied by bone increased as time passed. In contrast, ceramics alone did not show any bone formation and contained traces of these biochemical parameters. These results indicated that the biochemical sequences correlate with the histological sequences in the heterotopic membranous ossification.


Inhibition of cyclin D1 expression by cyclin D1 shRNAs in human oral squamous cell carcinoma cells is associated with increased cisplatin chemosensitivity.
Cyclin D1 is a well-known cell cycle regulator. Recently, its pro-survival function has been revealed in several tumors. Because increasing expression of cyclin D1 is a common event in oral squamous cell carcinoma (OSCC) and has been correlated with cisplatin resistance, we investigated if cyclin D1 inhibition could increase cisplatin chemosensitivity of OSCC. Five cyclin D1 shRNAs were prepared and 3 were selected for subsequent experiments. IC50 values for cisplatin were determined by an MTT assay. Cisplatin-induced apoptosis and cell cycle block were investigated. A tumor transplantation model was generated to examine the cisplatin sensitivity of Tca/cisplatin after in vivo cyclin D1 silencing. The role of nuclear factor-kappaB (NF-kappaB) and cyclin-dependent kinase 4 (CDK4) in cyclin D1-mediated cisplatin resistance was also examined. The most effective shRNA resulted in 84.51% knockdown of the cyclin D1 protein level. After the transfection with the 2 most effective shRNAs, the cisplatin IC50 decreased from 5.88 microg/ml to 1.36 microg/ml and 2.47 microg/ml, although overexpression of cyclin D1 rendered OSCC cells more resistant to cisplatin treatment (IC50 increased from 6.43 microg/ml to 12.24 microg/ml). This decreasing IC50 was correlated with the down-regulation of cisplatin-induced NF-kappaB activity in cyclin D1 knockdown cells, and was independent of CDK4 function. In vivo tumor transplantation models also confirmed a cisplatin-sensitizing effect of cyclin D1 shRNA in OSCC. A TUNEL assay validated the increase in apoptosis as induced by cisplatin in cyclin D1 knockdown cells. Cyclin D1 may be an important target for future therapy in patients with OSCC.


Growth rate of clinically diagnosed superficial basal cell carcinoma and changes in dermoscopic features over time.
Basal cell carcinoma (BCC) is the most commonly occurring skin cancer. BCCs have been found to generally grow slowly. Data are limited on how the dermoscopic characteristics of BCCs evolve. We set out to determine the growth rate of superficial BCCs (sBCC) and assess the change in dermoscopic features over time. A retrospective review was performed of clinically diagnosed sBCC. Images, demographic and dermoscopic data were collected by a melanographer. Mixed effects linear regression models were used to investigate sBCC growth and associations between size and dermoscopic/demographic variables. We tested differences in trends over time in dermoscopic features using non-parametric trend tests. 100 individual sBCC were evaluated in 70 patients (mean age 62; 59% male), 69% had Fitzpatrick skin phototype 1 or 2, and 81% had some degree of actinic damage. sBCC were present on the back in 58% and 22% of men and women, respectively. The median surface area was 41.9 mm2 with a growth rate of 0.81 mm2 /month. Males had larger sBCC than females. There was no association between sBCC size and Fitzpatrick skin phototype, history of skin cancer or family history of melanoma. There is some evidence larger sBCC gain shiny white structures (P = 0.053) over time. sBCC grow at a rate unlikely to adversely affect patient outcomes associated with long wait times. Our data suggest that dermoscopy can aid in appropriate treatment selection for sBCC.


Molecular characterizations of avian polyomavirus isolated from budgerigar in China.
Budgerigar fledgling disease is an acute viral infectious disease caused by avian polyomavirus (APV). In this study, 34 liver tissue samples of young, dead budgerigar with typical symptoms were collected in 2004. All the samples had positive polymerase chain reaction (PCR) test based on the VP1 specific primers. VP1 genes of these samples were sequenced and had high similarities to each other (99%-100%). A strain (HBYM02) was isolated and sequenced. As shown in the phylogenetic tree, there are two branches. One branch was composed by strains isolated from Passeriformes, and the other was composed only by one strain isolated from Falconiformes. The genome similarities between our isolate and other reported isolates were very high (> 99%), and the evolution distances in the phylogenetic tree were very short (< 0.005), which suggests that APV in China has the same genotype as those in other regions. The results will be useful for the diagnoses of, and vaccine development for, APV.


Metrics That Matter.
Increasingly, performance metrics are seen as key components for accurately measuring and improving health care value. Disappointment in the ability of chosen metrics to meet these goals is exemplified in a recent Institute of Medicine report that argues for a consensus-building process to determine a simplified set of reliable metrics. Overall health care goals should be defined and then metrics to measure these goals should be considered. If appropriate data for the identified goals are not available, they should be developed. We use examples from our work in the Veterans Health Administration (VHA) on validating waiting time and mental health metrics to highlight other key issues for metric selection and implementation. First, we focus on the need for specification and predictive validation of metrics. Second, we discuss strategies to maintain the fidelity of the data used in performance metrics over time. These strategies include using appropriate incentives and data sources, using composite metrics, and ongoing monitoring. Finally, we discuss the VA's leadership in developing performance metrics through a planned upgrade in its electronic medical record system to collect more comprehensive VHA and non-VHA data, increasing the ability to comprehensively measure outcomes.


Present Knowledge on Direct Oral Anticoagulant and Novel Oral Anti Coagulants and Their Specific Antidotes: A Comprehensive Review Article.
Thromboembolic diseases are one of the leading causes of morbidity and mortality worldwide. For a long time, heparin and Vitamin K antagonist (VKA) drugs were used for treatment and prophylaxis of the thromboembolic diseases. The development of newer direct and novel oral anticoagulant medications (DOACs/NOACs) has changed clinical practice significantly. Lesser monitoring, ease with dosing, less drug interactions have made these drugs useful to the providers and the patients. But these drugs have bleeding as a side effect. There is ongoing research on the specific antidotes of these anticoagulants in case of life-threatening bleeding. Though the use of the DOACs and NOACs have increased, there is still not enough clinical evidence about the specific antidotes of these medications. Unlike heparin or VKA, reversal of life-threatening bleeding in the setting of DOAC use is still a clinical challenge. We need more data on the dose, pharmacokinetics, and clinical efficacy of those antidotes. Authors have reviewed articles on DOACs and their antidotes in Pubmed and also in the clinical trial website. Specific antidotes including Idarucizumab for Dabigatran, Andexanet alfa for factor Xa inhibitors are being used to reverse the actions of the anticoagulants. Ciraparantag is a universal antidote for the DOACs, which is still under investigation. FXaI16L is currently being investigated as a potential universal antidote for multiple anticoagulants, including dabigatran and rivaroxaban. Though mostly safe, the use of DOACs can still carry a risk of severe bleeding in patients. More data on the use of the antidotes is required to reverse the side effect of DOACs if clinically indicated.


A validated mouse model capable of recapitulating the protective effects of female sex hormones on ascending aortic aneurysms and dissections (AADs).
Fewer females develop AADs (ascending aortic aneurysms and dissections) and the reasons for this protection remain poorly understood. The present study seeks to develop a mouse model that may be utilized to address this sexual dimorphism. Adult normolipidemic mice were challenged with BAPN (β-aminopropionitrile), AngII (angiotensin II), or BAPN + AngII. An initial protocol optimization found that 0.2% BAPN in drinking water plus AngII-infusion at 1,000 ng kg-1 min-1 produced favorable rates of AAD rupture (~50%) and dilation (~40%) in 28 days. Using these dosages, further experiments revealed that BAPN is toxic to naïve mature aortas and it acted synergistically with AngII to promote aortic tears and dissections. BAPN + AngII provoked early infiltration of myeloid cells and subsequent recruitment of lymphoid cells to the aortic wall. AADs established with BAPN + AngII, but not AngII alone, continued to expand after the cessation of AngII-infusion. This indefinite growth precipitated a 61% increase in the AAD diameter in 56 days. More importantly, with the optimized protocol, significant differences in AAD dilation (p = .012) and medial degeneration (p = .036) were detected between male and female mice. Treatment of ovariectomized mice with estradiol protected AAD formation (p = .014). In summary, this study developed a powerful mouse AAD model that can be used to study the sexual dimorphism in AAD formation.


Regulatory sequences driving expression of the sea urchin Otp homeobox gene in oral ectoderm cells.
PlOtp (Orthopedia), a homeodomain-containing transcription factor, has been recently characterized as a key regulator of the morphogenesis of the skeletal system in the embryo of the sea urchin Paracentrotus lividus. Otp acts as a positive regulator in a subset of oral ectodermal cells which transmit short-range signals to the underlying primary mesenchyme cells where skeletal synthesis is initiated. To shed some light on the molecular mechanisms involved in such a process, we begun a functional analysis of the cis-regulatory sequences of the Otp gene. Congruent with the spatial expression profile of the endogenous Otp gene, we found that while a DNA region from -494 to +358 is shown to drive in vivo GFP reporter expression in the oral ectoderm, but also in the foregut, a larger region spanning from -2044 to +358 is needed to give firmly established tissue specificity. Microinjection of PCR-amplified DNA constructs, truncated in the 5' regulatory region, and determination of GFP mRNA level in injected embryos allowed the identification of a 5'-flanking fragment of 184bp in length, essential for expression of the transgene in the oral ectoderm of pluteus stage embryos. Finally, we conducted DNAse I-footprinting assays in nuclear extracts for the 184bp region and detected two protected sequences. Data bank search indicates that these sites contain consensus binding sites for transcription factors.


Modified mini-abdominoplasty: navel transposition and horizontal residual scar.
The classic mini-abdominoplasty is a surgery generally indicated for cases in which cutaneous laxity of the abdomen's inferior region is associated with adiposity. However, in some cases, the characteristics of the abdomen are such that resort to a traditional mini-abdominoplasty would involve an unsatisfactory final result due to the unavoidable caudalization of the navel. In answer to this problem, Pontes developed the type 4 modified mini-abdominoplasty. This procedure adds to the classic technique a complete resection of the navel and its transposition so that it leaves a residual vertical scar. With our version of the technique, the scar is more aesthetic in shape and appearance, horizontal, and parallel to the suprapubic scar.


Cardioprotective and antioxidant activities of a polysaccharide from the root bark of Aralia elata (Miq.) Seem.
A water-soluble polysaccharide (AEP-w1) was isolated from the root bark of Aralia elata and its molecular weight was about 4.5×10(4)Da. Monosaccharide component analysis indicated that AEP-w1 appeared to be arabinogalactan, consisting of arabinose, galactose and trace glucose with molar ratios of 6.3:3.5:0.2. The antioxidant and cardioprotective potential of AEP-w1 were evaluated in vitro for the first time. AEP-w1 showed potent superoxide and hydroxyl radical scavenging activities and reducing power in vitro. Treatment with H2O2 resulted in the death of H9c2 cells, whereas pretreatment with 50-400μg/ml AEP-w1 for 24h prior to H2O2 exposure significantly increased cell viability. Furthermore, AEP-w1 evidently suppressed cardiomyocyte apoptosis, the mitochondrial membrane potential change and cytochrome c release in H2O2-treated H9c2 cells. In addition, intracellular reduced glutathione (GSH) reduction caused by H2O2 in H9c2 cells was also restored by AEP-w1 pretreatment. Taken together, these date provided the first evidence that the cardioprotective effects of AEP-w1 in H9c2 cells were at least in part associated with its antioxidant activity and inhibition effect on mitochondrial dysfunction.


Use of a partially covered self-expandable metallic stent to treat a biliary stricture secondary to chronic pancreatitis complicated by recurrent cholangitis: a case report.
The patient was a 69 year old man who had been diagnosed with alcoholic chronic pancreatitis and lower common bile duct (CBD) stricture. He subsequently developed cholangitis 2-3 times a year, and we replaced the endoscopic biliary stent (EBS) each time. In April 2010, he was admitted because of complication by a liver abscess and acute cholangitis. We performed percutaneous transhepatic liver abscess drainage. The inflammatory findings then rapidly improved, but the patient developed acute cholangitis due to the sludge and the stones. Then, we placed a partially covered self-expandable metallic stent (C-SEMS) in the lower CBD and performed endoscopic lithotripsy through the C-SEMS, and the cholangitis subsequently improved. Two weeks after, we removed the C-SEMS endoscopically and replaced it with a 10 Fr plastic stent; since then there have been no recurrences of cholangitis. Our experience in this case suggested that when a plastic stent is placed long-term to treat a biliary stricture associated with chronic pancreatitis, it might be useful to also control biliary sludge and stones using a C-SEMS.


Erectile dysfunction drugs and oxidative stress in the liver of male rats.
Erectile dysfunction (ED) affected the lives of more than 300 million men worldwide. Erectile dysfunction drugs (EDD), known as phosphodiesterase inhibitors (PDEIs), have been used for treatment of ED. It has been shown that oxidative stress plays an important role in the progression of erectile dysfunction. Oxidative stress can be alleviated or decreased by antioxidant enzymes. Therefore, the present study aims at investigating the changes in the activity of antioxidant enzymes such as superoxide dismutase, catalase, and glutathione reductase as well as protein expression of glutathione peroxidase and glutathione S-transferase after treatment of male rats with a daily dose of sildenafil (1.48 mg/kg), tadalafil (0.285 mg/kg) and vardenafil (0.285 mg/kg) for three weeks. In addition, levels of reduced glutathione and malondialdyhyde (MDA) were assayed. The present study showed that sildenafil, vardenafil, and tadalafil treatments significantly decreased the levels of glutathione, MDA and the activity of glutathione reductase. In addition, vardenafil and sildenafil increased the activity of superoxide dismutase and catalase. Interestingly, western immunoblotting data showed that vardenafil induced the activity of glutathione peroxidase (GPX) and its protein expression, whereas tadalafil and sildenafil inhibited such enzyme activity and its protein expression. In addition, the protein expression of GST π isozyme was markedly reduced after treatment of rats with sildenafil. It is concluded that ED drugs induced the activities of both SOD and catalase which consequently decreased MDA level. Therefore, decrement in MDA levels could increase nitric oxide-cGMP level which in turn promotes the erection mechanism.


Role of zinc deficiency in carcinogenesis.
Zinc is a trace element required for the growth of normal and neoplastic tissues in a variety of species. Zinc deficiency is associated with alterations in the activity of zinc-dependent enzymes essential for cell replication. Dietary zinc deficiency also increases the incidence of certain tumors while decreasing the incidence of others. The mechanism by which zinc deficiency alters carcinogenesis is not fully understood. Among those tumors whose incidence is increased by dietary zinc deficiency are carcinomas induced by dialkylnitrosamines. This class of carcinogens requires microsomal cytochrome P-450 activation to be mutagenic. Zinc deficiency is known to increase the cytochrome P-450-dependent metabolism of methylbenzylnitrosamine (MBN), an esophageal carcinogen of this class. Examination of the kinetics of this reaction reveals zinc to be a direct noncompetitive inhibitor of the microsomal metabolism of MBN. Thus the lower rate of MBN metabolism by zinc-adequate versus zinc-deficient microsomes may be due to normal tissue zinc acting as a noncompetitive inhibitor of cytochrome P-450 activity in vivo. This effect of zinc on carcinogen metabolism may explain the increased incidence of nitrosamine-induced carcinomas observed with dietary zinc deficiency.


Changes in in vivo [(3)H]-Ro15-4513 binding induced by forced swimming in mice.
Mice were forced to swim for 5 min in water at a temperature of 12 degrees C (cold water swim stress) or 32 degrees C (warm water swim stress), and stress-induced analgesia (SIA) was measured using the tail-flick test. The cold water swim stress induced non-opioid SIA as well as hypothermia, whereas the warm water swim stress caused opioid SIA. The in vivo binding of [(3)H]-Ro15-4513 was measured in the stressed mice and compared with that in control mice. The specific binding of [(3)H]-Ro15-4513 in the cerebral cortex, hippocampus, and cerebellum was significantly altered by forced swimming in cold water. Apparent association and dissociation rate of [(3)H]-Ro15-4513 binding were decreased, and the change in the dissociation rate was most pronounced in the hippocampus. In contrast, no significant alterations were observed in in vitro binding. The hypothermia induced by the cold water swim stress seems to be the main reason for alterations in the specific binding of [(3)H]-Ro15-4513. The kinetics of a saturable amount of [(3)H]-Ro15-4513 in the blood and brain were also measured. The relative ratio of the radioactivity concentration in the brain to that in the blood was significantly decreased by forced swimming in cold water, indicating that the cold water swim stress induced changes in the nonspecific binding of [(3)H]-Ro15-4513 in the brain. These results together with previous reports suggested that non-opioid SIA induced by the cold water swim stress might be related to alterations in the rates of general ligand-receptor interactions including GABA(A)/benzodiazepine system. Changes in the nonspecific binding might be also involved in non-opioid SIA.


Neuroendoscopic management of suprasellar arachnoid cysts.
The first case of an intracranial arachnoid cyst was described by Bright in 1831. In 1935, Barlow published the first case of a suprasellar arachnoid cyst. Fewer than 200 cases of suprasellar-prepontine arachnoid cysts have been reported in the literature as of January 2011. Between 1994 and 2010, the senior author operated on 34 cases of suprasellar-prepontine arachnoid cysts. Eighteen female and 16 male patients ranged in age from 6 days to 16 years (mean 5.2 years). Follow-up of the patients ranged from 1 year to 16 years. Outcome may be evaluated according to radiological and clinical follow-up data. Postoperative radiological examinations must reveal: 1) the adequacy of fenestrations and flow through fenestration sites, 2) reduction of the cyst and ventricle size, and 3) reorientation of the chiasma and mammillary bodies to an acceptable anatomical position. In our series, no mortality occurred. Postoperative complication occurred in 3 cases. Suprasellar arachnoid cysts can be treated with favorable clinical and radiological results with endoscopic interventions when feasible. Results with ventriculocystocisternostomy are believed superior to those of ventriculocystostomy.


Induction of leukemia-specific antibodies by immunotherapy with leukemia-cell-derived heat shock protein 70.
Cancer immunotherapy using heat shock protein (HSP) derived from autologous tumor requires cluster of differentiation (CD)4(+) as well as CD8(+) T-cells for the prolongation of patient survival, suggesting that a humoral immune response through CD4(+) T-cells is important in addition to cellular immunity. However, the role of humoral responses in HSP-based autologous tumor immunotherapy remains unclear. In the present study, we investigated whether leukemia-specific antibodies and antibody-mediated cytotoxicity against autologous leukemia cells have a crucial role in a mouse A20 leukemia model by immunizing A20-derived HSP70. Immunization with A20-derived HSP70 induced the production of anti-A20-antibodies and the antibodies recognized HSP70-binding peptides derived from A20. One of those was a major histocompatibility complex (MHC) class-I binding peptide, which has been clarified as the target peptide of CD8+ cytotoxic T-cells (CTL) against A20. The anti-A20-antibodies produced by immunization with A20-derived HSP70 induced complement-dependent cytotoxicity (CDC) against A20 in vitro. In addition, immunization with A20-derived HSP70 increased intracellular interleukin-4 (IL4)-production of CD4(+) T-cells, confirming the activation of type-2 helper T-cells. Taken together, immunization with leukemia-cell-derived HSP70 induces antibodies against leukemia-cell-specific peptides and might play a crucial role in the eradication of leukemia cells by CDC in mice. These findings will enable future establishment of a novel therapeutic strategy using antileukemia antibodies in HSP-based autologous tumor immunotherapy.


Successful experience of tofacitinib treatment in patients with Fibrodysplasia Ossificans Progressiva.
Fibrodysplasia ossificans progressive (FOP) is an ultra-rare genetic disorder that is caused by a mutation in the ACVR1 gene and provokes severe heterotopic ossification. Since flares of the disease are associated with inflammation, it is assumed that JAK inhibitors can control active FOP due to blocking multiple signaling pathways.


A statistical assessment of QT data following placebo and moxifloxacin dosing in thorough QT studies.
The ICH guidelines indicate that a single "thorough QT study" should be conducted to evaluate the effects of new drugs on cardiac repolarization. A positive control, such as moxifloxacin, is required to be assessed as part of the thorough QT study to validate the assay sensitivity of each study. In order to better understand the effect of moxifloxacin, a meta-analysis of nine thorough QT studies has been undertaken to assess the overall moxifloxacin effect. The data was analyzed using a repeated measures mixed model to test various covariance structures to identify the most suitable model for this and future meta-analyses of thorough QT studies.


In vivo and in vitro properties of an intravenous lipid emulsion containing only medium chain and fish oil triglycerides.
The triglyceride (TG) fatty acyl composition in lipid emulsions influences their metabolism. Little is known about the effects of long chain omega-3 polyunsaturated fatty acids (PUFA) on lipid emulsion metabolism. We investigated possible differences between omega-3 containing emulsions in their metabolism and tissue-targeting in vivo in a mouse model, and in vitro using lipolysis and cell culture experiments. Soy oil (LCT), MCT/LCT/omega-3 (5:4:1, wt/wt/wt), and MCT/omega-3 (8:2, wt/wt) emulsions were radiolabeled with nondegradable 1alpha,2alpha (n)-[3H] cholesteryl oleoyl ether to trace core particle metabolism in C57BL/6J mice following a bolus injection. Blood samples obtained over 25 min and extracted organs were used to measure the tissue distribution of lipid emulsion particles. Lipoprotein lipase (LpL)-mediated hydrolysis experiments and cell uptake studies in cultured J774 murine macrophages were also performed. Blood clearance of 8:2 was 13.4% and 29.8% faster compared to 5:4:1 and LCT, respectively. LCT had greatest liver uptake. LpL-mediated hydrolysis was greatest in 8:2 and lowest in LCT. Overall, cell TG accumulation in the presence of apolipoprotein E was least with 8:2. Our data shows that 8:2 had the most efficient blood clearance but less hepatic uptake in vivo. In vitro, 8:2 had both highest hydrolysis by LpL and intracellular TG utilization in the presence of apoE. Thus, an 8:2 lipid emulsion undergoes efficient blood clearance and may direct omega-3 PUFA more towards extrahepatic tissues.


Synthesis and antituberculosis activity of novel unfolded and macrocyclic derivatives of ent-kaurane steviol.
New derivatives of steviol 1, the aglycone of the glycosides of Stevia rebaudiana, including a novel class of semisynthetic diterpenoids, namely macrocyclic ent-kauranes were synthesized. These compounds possess antituberculosis activity inhibiting the in vitro growth of Mycobacterium Tuberculosis (H37R(V) strain) with MIC 5-20 μg/ml that is close to MIC 1 μg/ml demonstrated by antituberculosis drug isoniazid in control experiment. For the first time it was found that the change of ent-kaurane geometry (as in steviol 1) of tetracyclic diterpenoid skeleton to ent-beyerane one (as in isosteviol 2) influences on antituberculosis activity.


Fast, microbore, and fast microbore high-performance liquid chromatography of nucleic acid constituents.
Fast high-performance liquid chromatography (HPLC) (5-10 cm X 4.6 mm I.D. columns), microbore HPLC (25 cm X 2.1 mm and 1 mm I.D. columns), and fast microbore HPLC (5-10 cm X 2.1 mm and 1 mm I.D. columns) were successfully applied to the separation of nucleic acid constituents in standard mixtures and physiological fluids. Separations were obtained in isocratic and gradient elution modes. The separations obtained were compared with those achieved on a conventional 25 cm X 4.6 mm I.D. column. Factors evaluated included separation time, retention time reproducibility, peak height reproducibility, resolution, efficiency, sensitivity and linear response range. Practical factors, such as the amount of sample required and cost per analysis, were also examined.


Abortion decision making by focusing: a preliminary study.
In 2005, 28,738 Dutch women underwent an abortion. Of this group, 10% were in doubt whether or not to have their pregnancy terminated. The author wished to show that focusing facilitates the decision-making process in such cases. The article starts by describing the psychological consequences and accompanying problems of unplanned pregnancy. Thereafter the method of decision making by focusing is described. Two cases with verbatim transcription are given to illustrate the focusing process. The article ends with the presentation of the results of a small pilot survey concerning the method. The two case examples with verbatim transcriptions clarify the psychological process of decision making by using the method of focusing. The pilot survey shows that 16 of the 22 women (73%) were happy with the focusing method which suited them to various degrees (from 'somewhat' to 'very much'), and which helped them making the final decision (from 'somewhat' to 'totally'). For 18 of the women (82%) the approach differed from the discussions they had had previously with other people. Decision making by focusing is promising, and further research is recommended.


Immunoreactive calmodulin in supernatant fraction of platelet homogenates from humans, guinea pigs, rats, and rabbits.
Immunoreactive Calmodulin (CM) was measured in the supernatant fraction of homogenates of platelets obtained from humans, rats, guinea pigs and rabbits, using a commercial RIA kit. The levels (microgram/g wet weight of platelets) of immunoreactive CM were 6.8 +/- 0.5, 6.9 +/- 0.4, 8.6 +/- 1.8 and 9.7 +/- 3.1 (mean +/- SEM) for rat, human, rabbit and guinea pig, respectively. There was no statistically significant difference in values between these four species. The refractoriness of rat platelets to aggregate to certain agonists such as platelet activating factor (PAF) cannot be explained on differences in amount of immunoreactive CM.


Heterogeneous receptor expression underlies non-uniform peptidergic modulation of olfaction in Drosophila.
Sensory systems are dynamically adjusted according to the animal's ongoing needs by neuromodulators, such as neuropeptides. Neuropeptides are often widely-distributed throughout sensory networks, but it is unclear whether such neuropeptides uniformly modulate network activity. Here, we leverage the Drosophila antennal lobe (AL) to resolve whether myoinhibitory peptide (MIP) uniformly modulates AL processing. Despite being uniformly distributed across the AL, MIP decreases olfactory input to some glomeruli, while increasing olfactory input to other glomeruli. We reveal that a heterogeneous ensemble of local interneurons (LNs) are the sole source of AL MIP, and show that differential expression of the inhibitory MIP receptor across glomeruli allows MIP to act on distinct intraglomerular substrates. Our findings demonstrate how even a seemingly simple case of modulation can have complex consequences on network processing by acting non-uniformly within different components of the overall network.


Algae on the brain in bioengineering.
Özugur et al. recently pushed the boundaries of augmented physiology through artificial symbioses. They microinjected algal cultures into tadpole (Xenopus laevis) hearts. The resulting capillary-bound algae produced physiologically relevant levels of oxygen, which could rescue neuronal hypoxia. This work contributes to the growing field of artificial photosymbioses.


Cigarette smoking blocks the benefit from reduced weight gain for insulin action by shifting lipids deposition to muscle.
Cigarette smoking (CS) is known to reduce body weight and this often masks its real effect on insulin action. The present study tested the hypothesis that CS can divert lipid deposition to muscles to offset the supposed benefit of reduced body weight gain on insulin signalling in this major site for glucose tolerance (or insulin action). The study was conducted in mice exposed to chronic CS followed by either a chow (CH) diet or a high-fat (HF) diet. CS increased triglyceride (TG) levels in both plasma and muscle despite a reduced body weight gain and adiposity. CS led to glucose intolerance in CH-fed mice and they retained the glucose intolerance that was induced by the HF diet. In adipose tissue, CS increased macrophage infiltration and the mRNA expression of TNFα but suppressed the protein expression of adipose triglyceride lipase and PPARγ. While CS increased hormone-sensitive lipase and suppressed the mRNA expression of leptin, these effects were blunted in HF-fed mice. These results imply that CS impairs insulin signalling in skeletal muscle via accumulated intramuscular lipids from lipolysis and lipodystrophy of adipose tissues. This may explain why smokers may not benefit from insulin sensitising effects of reduced body weight gain.


Chronic treatment with a superoxide dismutase mimetic prevents vascular remodeling and progression of hypertension in salt-loaded stroke-prone spontaneously hypertensive rats.
Oxidative stress has been implicated in the pathogenesis of hypertension. The aim of the present study was to determine whether increased generation of vascular superoxide anion (*O2-) contributes to blood pressure elevation by influencing vascular function and structure in severely hypertensive rats. Sixteen-week-old stroke-prone spontaneously hypertensive rats (SHRSP) (n = 12) were randomly divided into two groups to receive the superoxide dismutase mimetic, tempol (4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl) (1 mmol/L in drinking water) or tap water. Both groups were fed a high-salt diet (4% NaCl). Systolic blood pressure (SBP) was measured weekly for 6 weeks by the tail-cuff method. Rats were killed, and vascular structure (media:lumen ratio) and endothelial function (acetylcholine [Ach]-induced vasodilation) were assessed in small mesenteric arteries mounted as pressurized preparations. Vascular *O2- concentration was measured by lucigenin (5 micromol/L) chemiluminescence. Plasma total antioxidant status was assessed spectrophotometrically. The SBP increased significantly (P < .01) in the control group, whereas progression of hypertension was prevented in the tempol-treated group. Tempol reduced (P < .01) the media:lumen ratio (7.2%+/-0.01%) compared with that in controls (12.0%+/-0.01%). Maximal Ach-induced dilation was altered in control rats (40%+/-9%) but was not influenced by tempol (57%+/-17%). Vascular *O2- concentration was lower (P < .01) and plasma total antioxidant concentration was higher (P < .05) in the treated group compared with the control. In conclusion, tempol prevents progression of hypertension. These processes are associated with attenuated vascular remodeling, decreased vascular *O2- concentration, and increased antioxidant status. Our data suggest that oxidative stress plays an important role in vascular damage associated with severe hypertension in salt-loaded SHRSP.


Acinic cell carcinoma of the glottis: case report.
Acinic cell carcinoma is a rare tumor of the head and neck that mainly affects the parotid gland but occasionally involves the minor salivary glands of the upper aerodigestive tract. The authors present a case report of an occurrence of a low-grade acinic cell carcinoma of the true vocal fold, which they believe to be the first reported case of this type of carcinoma in this location. Laryngoscopy and laser excision was completed for what was initially thought to be a granuloma, and pathology confirmed low-grade acinic cell carcinoma of the right true vocal fold. The mass was well circumscribed and did not invade adjacent structures. After complete excision, postoperative radiation therapy was used to reduce local recurrence.


Prognosis and Outcomes of Clinically Diagnosed Cardiac Sarcoidosis Without Positive Endomyocardial Biopsy Findings.
Diagnosis of cardiac sarcoidosis (CS) is sometimes difficult due to a low positive rate of epithelioid granulomas by endomyocardial biopsy (EMB). Accordingly, Japanese guidelines can allow the CS diagnosis using clinical data alone without EMB results (clinical CS) since 2006. However, little is known about prognosis and outcome of clinical CS. Purpose of this study was to analyze the prognosis, outcomes, and response to corticosteroid of clinical CS using large-scale cohort survey. Overall, 422 CS patients (mean age 60 ± 13 years, 68% female, median follow-up period of 5 years), including 345 clinical CS and 77 EMB-positive patients, histologically diagnosed CS (histological CS) by Japanese guidelines, were enrolled and examined. Clinical profile (age, sex, initial cardiac arrhythmias, and abnormal uptake of gallium-67 scintigraphy or 18F-fluorodeoxyglucose positron emission tomography in heart) was similar in both groups. Although clinical CS had better prognosis (P = 0.018) and outcome (all-cause death, appropriate defibrillator therapy, and heart transplantation; P = 0.008), multivariate Cox hazard analysis revealed that left ventricular ejection fraction (LVEF) and sustained ventricular tachycardia history were independently associated with outcome (P < 0.001 and P = 0.002, respectively), but not with the diagnosed CS category. Moreover, similar LVEF recovery after corticosteroid was observed in both groups with low LVEF (≤35%) at the 1-year follow-up period (P < 0.001). In clinical CS according to the Japanese guideline, prophylactic implantable-cardioverter-defibrillator and immunosuppressive therapy are important in patients with low LVEF or ventricular tachycardia history, similar to histological CS.


Perillaldehyde improves diabetic cardiomyopathy by upregulating miR-133a-3p to regulate GSK-3β.
Diabetic cardiomyopathy (DCM) is part of the most important causes of death from cardiovascular disease. Perillaldehyde (PAE), a major component of the herb perilla, has been shown to ameliorate doxorubicin-induced cardiotoxicity, but it is unclear whether PAE exerts beneficial effects on DCM. Exploring the potential molecular mechanisms of PAE for the treatment of DCM through network pharmacology and molecular docking. The SD rat type 1 diabetes model was established by a single intraperitoneal injection of streptozotocin (60 mg/kg), the cardiac function indexes of each group were detected by echocardiography; the morphological changes, apoptosis, protein expression of P-GSK-3β (S9), collagen I (Col-Ⅰ), collagen III (Col-Ⅲ) and alpha-smooth muscle actin (α-SMA), and miR-133a-3p expression levels were detected. An DCM model of H9c2 cells was established in vitro and transfected with Mimic and Inhibitor of miR-133a-3p. The results showed that PAE ameliorated cardiac dysfunction, reduced fasting glucose and cardiac weight index, and improved myocardial injury and apoptosis in DCM rats. It reduced high glucose-induced apoptosis, promoted migration and improved mitochondrial division injury in H9c2 cells. PAE decreased P-GSK-3β (S9), Col-Ⅰ, Col-Ⅲ and α-SMA protein expression and upregulated miR-133a-3p expression levels. After miR-133a-3p Inhibitor treatment, the expression of P-GSK-3β (S9) and α-SMA expression were significantly increased; after miR-133a-3p Mimic treatment, the expression of P-GSK-3β (S9) and α-SMA decreased significantly in H9c2 cells. It suggests that the mechanism of action of PAE to improve DCM may be related to the upregulation of miR-133a-3p and inhibition of P-GSK-3β expression.


Al5+αSi5+δN12, a new Nitride compound.
The family of III-Nitride semiconductors has been under intensive research for almost 30 years and has revolutionized lighting applications at the dawn of the 21st century. However, besides the developments and applications achieved, nitride alloys continue to fuel the quest for novel materials and applications. We report on the synthesis of a new nitride-based compound by using annealing of AlN heteroepitaxial layers under a Si-atmosphere at temperatures between 1350 °C and 1550 °C. The structure and stoichiometry of this compound are investigated by high resolution transmission electron microscopy (TEM) techniques and energy dispersive X-Ray (EDX) spectroscopy. Results are supported by density functional theory (DFT) calculations. The identified structure is a derivative of the parent wurtzite AlN crystal where the anion sublattice is fully occupied by N atoms and the cation sublattice is the stacking of 2 different planes along <0001>: The first one exhibits a ×3 periodicity along <11-20> with 1/3 of the sites being vacant. The rest of the sites in the cation sublattice are occupied by an equal number of Si and Al atoms. Assuming a semiconducting alloy, a range of stoichiometries is proposed, Al5+αSi5+δN12 with α being between -2/3 and 1/4 and δ between 0 and 3/4.


Modification of spectral sensitivities by screening pigments in the compound eyes of twilight-active fireflies (Coleoptera: Lampyridae).
1. ERG S(lambda) were determined in dark-adapted intact preparations of 6 North American firefly species (Photinus collustrans, marginellus, pyralis, macdermotti, scintillans and Bicellonycha wickershamorum) which restrict their flashing activity to twilight hours. The curves possess narrow (1/2 bandwidth = 50-60 nm) peaks in the yellow (560-580 nm) and a shoulder in the violet (370-420 nm), with a marked attenuation (1.4-2.2 log units) of sensitivity in the green (480-530 nm) region of the spectrum (Fig. 1). Two additional species (Photuris potomaca and frontalis) which initiate flashing at twilight and continue on late into the night (twi-night) possess broad sensitivity maxima around 560 nm (Fig. 3). 2. Selective adaptation experiments isolated near-UV and yellow in P. scintillans (Fig. 2). In the dorsal frontal region of the compound eyes in P. frontalis, high sensitivity existed only in the short wavelength region (near-UV and blue) with a maximum in the blue (lambda max 435 nm) (Fig. 4). 3. The in situ MSP absorption spectrum of the screening pigments was determined in preparations of firefly retina. a) Two kinds of dark brown granules were found in the clear zone region. These granules absorb all across the spectrum with a gradual increase in optical density in the shorter wavelength region in P. pyralis (Fig. 5). b) Besides dark granules, pink-to-red colored screening pigments were present in the vicinity of the rhabdoms. The absorption spectra of these pigments determined in five species were narrow (1/2 bandwidth = 50-80 nm) with species-specific differences in their peak absorption in the green at 525 nm, 510 nm, 512 nm and 517 nm in P. scintillans, macdermotti, collustrans and pyralis, respectively (Fig. 6). A similar pigment was found in P. marginellus with a lambda max at 512 nm (Fig. 7). In all cases, transmission increased both at long and short wavelengths, but more sharply in the long wavelength region (Figs. 6 and 7). Hence each twilight-restricted species has its own unique colored screening pigment. A yellow pigment whose absorption spectrum differed from those found in genus Photinus was found in twi-night active Photuris potomaca (lambda max 461 nm) and night-active P. versicolor (lambda max 456 nm). The transmission of the Photuris pigment increased sharply only in the long wave-length region (Fig. 8).(ABSTRACT TRUNCATED AT 400 WORDS)


Elements That Regulate the DNA Damage Response of Proteins Defective in Cockayne Syndrome.
Cockayne syndrome (CS) is a premature aging disorder characterized by developmental defects, multisystem progressive degeneration and sensitivity to ultraviolet light. CS is divided into two primary complementation groups, A and B, with the CSA and CSB proteins presumably functioning in DNA repair and transcription. Using laser microirradiation and confocal microscopy, we characterized the nature and regulation of the CS protein response to oxidative DNA damage, double-strand breaks (DSBs), angelicin monoadducts and trioxsalen interstrand crosslinks (ICLs). Our data indicate that CSB recruitment is influenced by the type of DNA damage and is most rapid and robust as follows: ICLs>DSBs>monoadducts>oxidative lesions. Transcription inhibition reduced accumulation of CSB at sites of monoadducts and ICLs, but it did not affect recruitment to (although slightly affected retention at) oxidative damage. Inhibition of histone deacetylation altered the dynamics of CSB assembly, suggesting a role for chromatin status in the response to DNA damage, whereas the proteasome inhibitor MG132 had no effect. The C-terminus of CSB and, in particular, its ubiquitin-binding domain were critical to recruitment, while the N-terminus and a functional ATPase domain played a minor role at best in facilitating protein accumulation. Although the absence of CSA had no effect on CSB recruitment, CSA itself localized at sites of ICLs, DSBs and monoadducts but not at oxidative lesions. Our results reveal molecular components of the CS protein response and point to a major involvement of complex lesions in the pathology of CS.


[Animal experiments on the modification of fracture healing by growth hormone (STH)].
Human growth hormone seems to improve fracture healing. Using rat experiments, the clinical experiences of other authors were reviewed critically. Examination of metabolic parameters showed no useful results. Measurement of bone length and circumference and comparison of radiographs, scintigraphs, and histologic examinations indicated positive results with regard to the improvemnt of osseous consolidation when influenced by growth hormone.


Role of obesity on all-cause mortality in whites with type 2 diabetes from Italy.
Mortality rate of diabetic patients is twice as much that of non-diabetic individuals. The role of obesity on mortality risk in patients with type 2 diabetes is controversial. Aim of our study was to address the relationship between obesity and all-cause mortality in a real-life set of white patients with type 2 diabetes from central-southern Italy from the Gargano Mortality Study (GMS). In addition, we used genetic data from genome-wide association studies (GWAs)-derived single nucleotide polymorphisms (SNPs) firmly associated with body mass index (BMI), in order to investigate the intrinsic nature of reduced mortality rate we, in fact, observed in obese patients. Study subjects with type 2 diabetes (n = 764) are part of the GMS, which is aimed at unraveling predictors of incident all-cause mortality. Time-to-death analyses were performed by Cox regression. Association between genotype risk score and obesity was tested by logistic regression. Of the 32 SNPs firmly associated with BMI, we investigated those with BMI β value ≥0.10 kg/m(2) and allele frequency ≥10 %. Genotyping was performed by KBioscience (http://www.lgcgenomics.com/). In GMS, obesity predicted a 45 % reduction in all-cause mortality. Individuals with high "obesity genetic load" (i.e., those carrying >9 risk alleles) were 60 % more likely to be obese as compared to individuals with low "obesity genetic load." Most importantly, mortality rate was not different in individuals with high and low "obesity genetic load," thus indicating no role of obesity genes on all-cause mortality and speaking against a cause-effect relationship underlying the association between obesity and reduced mortality rate.


The reciprocal association between mammographic breast density, hyaluronan synthesis and patient outcome.
Low mammographic breast density (MBD) and increased hyaluronan (HA) synthesis have been shown to have adverse effects on breast cancer prognosis. We aimed at elucidating the background of risk associated with mammographic characteristics, MBD and HA and its synthesizing isoforms in an attempt to uncover potential underlying biological mechanisms. MBD and mammographic characteristics of 270 patients were classified according to percentile density (very low density VLD, ≤25 %; mixed density MID, >25 %) and the BI-RADS 5th edition lexicon. Breast density and mammographic features were correlated with the localization and expression of HA, CD44, and HAS1-3 isoforms, and their combined effect on patients' survivals was explored. VLD showed an increased level of HA-positive carcinoma cells and stromal HA, HAS2, and HAS3. Tumors presenting as masses had more HA-positive carcinoma cells and more stromal HAS2 and HAS3. Indistinct margin tumors showed more stromal HA and HAS3. Patients who combined both VLD breasts with either high HA in carcinoma cells or stroma showed a worse prognosis compared to low levels (carcinoma cells 58.0 vs. 80.5 %, p = 0.001; stroma 64.2 vs. 79.6 %, p = 0.017), while no similar HA-related effect was observed in MID breasts. Our findings suggest a strong reciprocal relationship between low MBD and HA expression and synthesis. The expression of both factors simultaneously leads to an especially adverse prognostic effect which might have an impact on treatment decision in the future. Moreover, HA around cancer cells may inhibit chemotherapy agents and antibody treatments from reaching cancer cells.


Drivers of Individual and Regional Variation in CMS Hierarchical Condition Categories Among Florida Beneficiaries.
To explore hierarchical condition categories (HCC) risk score variation among Florida Fee for Service (FFS) Medicare beneficiaries between 2016 and 2018. This study analyzed HCC risk score variation using Medicare claims data for Florida beneficiaries enrolled in Parts A & B between 2016 and 2018. The CMS methodology analyzed HCC risk score variation using annual mean county- and beneficiary-level risk score changes. The association between variation and beneficiary characteristics, diagnoses, and geographic location was characterized using mixed-effects negative binomial regression models. Not applicable. Counties in the Northeast [marginal effect (ME)=-0.003], Central (ME=-0.021), and Southwest (ME=-0.009) Florida have relatively lower mean risk scores. A higher number of lifetime (ME=0.246) and treatable (ME=0.288) conditions were associated with higher county-level risk scores, while more preventable conditions (ME=-0.249) were associated with lower risk scores. Counties with older beneficiaries (ME=0.015) and more Blacks (ME=0.070) have higher risk scores, while having female beneficiaries reduced risk scores (ME=-0.005). Individual risk scores did not vary by age (ME=0.000), but Blacks (ME=0.001) had higher rates of variation relative to Whites, while other races had comparatively lower variation (ME=-0.003). In addition, individuals diagnosed with more lifetime (ME=0.129), treatable (ME=0.235), and preventable (ME=0.001) conditions had higher risk score variation. Most condition-specific indicators showed small associations with risk score changes; however, metastatic cancer/acute leukemia, respirator dependence/tracheostomy, and pressure ulcers of the skin were significantly associated with both types of HCC risk score variation. Results showed demographics, HCC condition classifications (ie, lifetime, preventable, and treatable), and some specific conditions were associated with higher variation in mean county-level and individual risk scores. Results suggest consistent coding and reductions in the prevalence of certain treatable or preventable conditions could reduce the county and individual HCC risk score year-to-year change.


Synergistic effects of testosterone and growth hormone on protein metabolism and body composition in prepubertal boys.
During human puberty there is a substantial increase in growth hormone (GH) and sex steroidal hormone concentrations, as well as in GH production rates and insulin-like growth factor-I (IGF-I) These studies were designed to investigate some of the interactions of testosterone (T) and GH in the metabolic changes of puberty. Ten boys with severe GH deficiency (GHD) were studied (mean age, 12.5 +/- 0.5 years) using stable isotope infusions, indirect calorimetry, and body composition analysis. After the baseline study, they received 2 doses of T enanthate (50 to 75 mg, intramuscular [IM]), and they were studied again 4 weeks later. The boys were then begun on daily subcutaneous (SC) GH (0.3 mg/kg/wk), while T therapy was continued for another 4 weeks and the studies repeated a third time. The treatment order was randomized. Protein oxidation rates decreased after T alone (-28%, P <.01), decreasing further after combined T/GH treatment (-36% v baseline, P <.01). The nonoxidative leucine disposal (NOLD), a measure of whole body protein synthesis, increased significantly after combined T/GH regardless of treatment order. The combination of T/GH also resulted in greater changes in body composition than T alone, with comparable decreases in %FM and corresponding increases in fat free mass (FFM). Measures of carbohydrate (CHO) metabolism, including glucose production and oxidation rates, were unaffected by either T or T/GH combination. Plasma IGF-I concentrations increased after T treatment and even more after T/GH combination, regardless of the treatment order. In conclusion GH and T are synergistic on whole body protein anabolism and body composition in males, even at a young age, but the positive effects of T on protein anabolism and body composition appear to need a basal amount of GH for those effects to be observed. GH and T both potentiate the development of the full body composition and metabolic changes of puberty.


Group B streptococcal epidemiology and vaccine needs in developed countries.
Development of a group B streptococcal vaccine (GBS) vaccine is the most promising approach for the prevention of GBS infections in babies, given the potential adverse effects of intrapartum antibiotic prophylaxis as well as the need for effective prevention of both adult and late perinatal disease. There are numerous prevention strategies at this time but none are 100% effective in the eradication of neonatal early onset GBS disease and there are no preventative strategies for late onset disease. The need for a GBS vaccine is therefore, of utmost importance. Efforts applying genomics to GBS vaccine development have led to the identification of novel vaccine candidates. The publication of GBS whole genomes coupled with new technologies including multigenome screening and bioinformatics has also allowed researchers to overcome the serotype limitation of earlier vaccine preparations in the search of a universal effective vaccine against GBS. This review brings together the key arguments concerning the potential need of a GBS vaccine in developed countries and describes the current status with GBS epidemiology and microbiology in these countries.


Sub-Saharan red cell antigen phenotypes and glucose-6-phosphate dehydrogenase deficiency variants in French Guiana.
The treatment of Plasmodium vivax infections requires the use of primaquine, which can lead to severe haemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. However, most of the Latin American countries, which are still endemic for vivax malaria, lack information on the distribution of G6PD deficiency (G6PDd). No survey has been performed so far in French Guiana. Herein, 80 individuals of the French Guianan Noir Marron population were scrutinized for red cell surface antigens of six blood group systems (ABO, Rh, Kell, Kidd, Duffy and MNS) and G6PD genetic polymorphisms. First, the sub-Saharan origin of the red cell phenotypes was assessed in relation with the literature. Then, given that the main sub-Saharan G6PDd variants are expected to be encountered, only the G6PD sequences of exons 4, 5, 6 and 9 were screened. This work aims at appraising the G6PD gene variation in this population, and thus, contributing to the G6PD piecemeal information in Latin America. Ninety-seven percent (97 %) of the red cells are Fy(a- b-), either D+ C- E- c+ e+ or D+ C+ E- c+ e+ and 44 % exhibited the Fya-/Jkb-/S- combined phenotype. Noteworthy is the detection of the G6PD(Val68Met) variant characterized by c.202G > A transition, G6PD(Asn126Asp) variant characterized by c.376A>G transition and G6PD(Asp181Val) variant characterized by c.542A>T transversion of the G6PD gene in 22.5 % of the sample, characteristic of the A(-(202)), A and Santamaria G6PDd variants, respectively. French Guianan Noir Marron population represents a pool of Rh-D antigen positive, Duffy-negative and G6PD-deficient erythrocytes, the latter accounting for one in every eight persons. The present study provides the first community-based estimation of the frequency of G6PDd polymorphisms in French Guiana. These results contribute to the G6PD genetic background information puzzle in Latin America.


Metabolic Phenotyping of Diet and Dietary Intake.
Nutrition provides the building blocks for growth, repair, and maintenance of the body and is key to maintaining health. Exposure to fast foods, mass production of dietary components, and wider importation of goods have challenged the balance between diet and health in recent decades, and both scientists and clinicians struggle to characterize the relationship between this changing dietary landscape and human metabolism with its consequent impact on health. Metabolic phenotyping of foods, using high-density data-generating technologies to profile the biochemical composition of foods, meals, and human samples (pre- and postfood intake), can be used to map the complex interaction between the diet and human metabolism and also to assess food quality and safety. Here, we outline some of the techniques currently used for metabolic phenotyping and describe key applications in the food sciences, ending with a broad outlook at some of the newer technologies in the field with a view to exploring their potential to address some of the critical challenges in nutritional science.


Discovery of novel 4-anilinoquinazoline derivatives as potent inhibitors of epidermal growth factor receptor with antitumor activity.
Two new series of new compounds containing a 6-amino-substituted group or 6-acrylamide-substituted group linked to a 4-anilinoquinazoline nucleus have been discovered as potential EGFR inhibitors. These compounds proved efficient effects on antiproliferative activity and EGFR-TK inhibitory activity. Especially, N(6)-((5-bromothiophen-2-yl)methyl)-N(4)-(3-chlorophenyl)quinazoline-4,6-diamine (5e), showed the most potent inhibitory activity (IC50=3.11μM for Hep G2, IC50=0.82μM for A549). The EGFR molecular docking model suggested that the new compound is nicely bound to the region of EGFR, and cell morphology by Hoechst stain experiment suggested that these compounds efficiently induced apoptosis of A549 cells.


Comparative assessment of button cells using a normalized index for potential pollution by heavy metals.
Many household batteries worldwide still end up in landfills or are incinerated due to inefficient collection and recycling schemes. Toxic heavy metals from improperly discarded button cells pose a serious risk to human health and the environment, as they can pollute air, soil and water. This paper analyses a series of button cells selected from batteries available on the retail market, and compares their polluting potential. A total of 64 batteries were subjected to chemical analyses of 19 elements - including metals and metalloids - , and energy density measurements. The samples were from four different brands of each of the four most common button cell technologies (alkaline, zinc-air, silver oxide and lithium). An energy-normalized index - the Weighted Potential Pollution Index (WPPI) - was proposed to compare the polluting potential of the different batteries. The higher the battery WPPI score, the greater the content in toxic elements and the lower the energy output. The results of the chemical composition and energy density varied depending on the construction technology of the button cells. However, significant differences in both variables were also found when comparing different brands within the same technology. The differences in WPPI values confirmed the existence of a significant margin to reduce the environmental impact of discarded button cells simply by avoiding the most polluting options. The choice of the battery with the most favourable WPPI produced a reduction in potential pollution of 3-53% for silver oxide batteries, 4-39% for alkaline, 20-28% for zinc-air and 12-26% for lithium. Comparative potential pollution could be assessed when selecting batteries using an energy-normalized index such as WPPI to reduce the environmental impact of improperly disposed button cells.


Brainstem auditory evoked potentials with the use of acoustic clicks and complex verbal sounds in young adults with learning disabilities.
Acoustic signals are transmitted through the external and middle ear mechanically to the cochlea where they are transduced into electrical impulse for further transmission via the auditory nerve. The auditory nerve encodes the acoustic sounds that are conveyed to the auditory brainstem. Multiple brainstem nuclei, the cochlea, the midbrain, the thalamus, and the cortex constitute the central auditory system. In clinical practice, auditory brainstem responses (ABRs) to simple stimuli such as click or tones are widely used. Recently, complex stimuli or complex auditory brain responses (cABRs), such as monosyllabic speech stimuli and music, are being used as a tool to study the brainstem processing of speech sounds. We have used the classic 'click' as well as, for the first time, the artificial successive complex stimuli 'ba', which constitutes the Greek word 'baba' corresponding to the English 'daddy'. Twenty young adults institutionally diagnosed as dyslexic (10 subjects) or light dyslexic (10 subjects) comprised the diseased group. Twenty sex-, age-, education-, hearing sensitivity-, and IQ-matched normal subjects comprised the control group. Measurements included the absolute latencies of waves I through V, the interpeak latencies elicited by the classical acoustic click, the negative peak latencies of A and C waves, as well as the interpeak latencies of A-C elicited by the verbal stimulus 'baba' created on a digital speech synthesizer. The absolute peak latencies of waves I, III, and V in response to monoaural rarefaction clicks as well as the interpeak latencies I-III, III-V, and I-V in the dyslexic subjects, although increased in comparison with normal subjects, did not reach the level of a significant difference (p<0.05). However, the absolute peak latencies of the negative wave C and the interpeak latencies of A-C elicited by verbal stimuli were found to be increased in the dyslexic group in comparison with the control group (p=0.0004 and p=0.045, respectively). In the subgroup consisting of 10 patients suffering from 'other learning disabilities' and who were characterized as with 'light' dyslexia according to dyslexia tests, no significant delays were found in peak latencies A and C and interpeak latencies A-C in comparison with the control group. Acoustic representation of a speech sound and, in particular, the disyllabic word 'baba' was found to be abnormal, as low as the auditory brainstem. Because ABRs mature in early life, this can help to identify subjects with acoustically based learning problems and apply early intervention, rehabilitation, and treatment. Further studies and more experience with more patients and pathological conditions such as plasticity of the auditory system, cochlear implants, hearing aids, presbycusis, or acoustic neuropathy are necessary until this type of testing is ready for clinical application.


Role of Gonadotropin-releasing Hormone Stimulation Test in Diagnosing Gonadotropin Deficiency in Both Males and Females with Delayed Puberty.
Delayed puberty can result either from constitutional delay of growth and puberty (CDP) or idiopathic hypogonadotropic hypogonadism (IHH). Gonadotropin-releasing hormone (GnRH) stimulation test has been generally accepted as a current method for diagnosing delayed puberty. The objective of this research was to assess the cut-off values and the efficacy of GnRH stimulation test in the diagnosis of delayed puberty in both males and females. A study of 91 IHH, 27 CDP patients, 6 prepubertal children, and 20 pubertal adults was undertaken. Blood samples were obtained at 0, 30, 60, and 120 min after GnRH administration and the levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured. For each parameter, the sensitivities and specificities were estimated, and the receiver operating characteristic (ROC) curves were constructed. The ROC curves indicated that a serum basal LH <0.6 IU/L or peak LH <9.74 IU/L resulted in moderate sensitivity (73.8% or 80.0%) and specificity (90.9% or 86.4%) in the diagnosis of HH in males. Serum basal LH <0.85 IU/L or basal FSH <2.43 IU/L resulted in moderate sensitivity (80.0% or 100.0%) and specificity (75.0% or 50.0%) in the diagnosis of HH in females. Our data suggest that isolated use of the gonadorelin stimulation test is almost sufficient to discriminate between HH and CDP in males, but unnecessary in females. The most useful predictor is serum basal or peak LH to differentiate these two disorders in males, but serum basal LH or FSH in females.


Cavernosal nerve preservation during robot-assisted radical prostatectomy is a graded rather than an all-or-none phenomenon: objective demonstration by assessment of residual nerve tissue on surgical specimens.
To demonstrate the existence of different degrees of nerve sparing (NS) (graded NS) by comparing the surgeon's intent of NS with the residual nerve tissue on prostatectomy specimens. We performed a prospective study of 133 consecutive patients who underwent robot-assisted radical prostatectomy in January and February of 2011. The surgeon graded the amount of NS intraoperatively independently for either side as follows: 1, no NS; 2, <50% NS; 3, 50% NS; 4, 75% NS; and 5, ≥ 95% NS. A pathologist who was unaware of the surgeon's score measured the area of residual nerve tissue on the posterolateral surface of the prostate. A greater NS score correlated significantly with a decreasing area of residual nerve tissue on the prostatectomy specimens (P < .001). Overall, the area of residual nerve tissue on the prostatectomy specimens was significantly different among the NS groups (P < .001). On specific intergroup analysis, significant differences were found in the area of residual nerve tissue on the prostatectomy specimens between the greater NS groups: NS score 3 versus 4, median 13 mm(2) (interquartile range [IQR] 7-23) versus 3 mm(2) (IQR 0-8; P = .01); NS score 4 versus 5, median 3 mm(2) (IQR 0-8) versus 0.5 mm(2) (IQR 0-2; P = .001). Subjective NS classification using the surgeon's intraoperative perception correlated significantly with the area of residual nerve tissue on the prostatectomy specimens determined by the pathologist. It is possible to intentionally tailor the amount of NS performed at surgery. This finding demonstrates that NS is a graded rather than an all-or-none phenomenon that can even go beyond the traditional concept of complete, partial, or no NS.


Risk factors and outcomes of Escherichia coli bacteremia caused by strains that produce CTX-M or non-CTX-M extended-spectrum-beta-lactamases.
To determine whether there are differences in risk factors and outcomes among patients with E. coli bacteremia caused by strains that produce CTX-M or non-CTX-M extended-spectrum beta-lactamases. From 1 July 2005 to 30 June 2007, patients with positive blood culture of extended-spectrum β-lactamases (ESBL)-producing E. coli were reviewed. Sixty patients with ESBL-producing E. coli bacteremia were identified. These included 41 (68.3%) isolates with CTX-M β-lactamases. CTX-M-14 accounted for 31 (75.6%) and CTX-M-3 for 9 (22.0%) of the 41 CTX-M isolates. Patients with CTX-M strains were less likely, by univariate analysis, to have significant risk factors for infection including age ≥ 65 years, chronic renal insufficiency, ICU stay at bacteremia onset, central venous catheter use and mechanical ventilation. Multivariate analysis revealed that chronic renal failure and ICU stay were independent predictors. Antibiograms were similar for CTX-M and non-CTX-M producers except that CTX-M strains were significantly more susceptible to cefmetazole (92.7 vs 36.8%, p < 0.0001). The overall mortality and length of hospitalization were not significantly different between the two groups. E. coli with CTX-M β-lactamases was more likely than non-CTX-M strains to invade non-compromised patients. There were no differences in clinical outcomes between the two groups.


Factors affecting postoperative pregnancy rate after endoscopic management of large endometriomata.
To identify factors influencing postoperative pregnancy rate in women with extensive endometriosis and large endometriomata as the only identified cause of infertility that were treated by laparoscopy. Sixty-four infertile patients with endometriomata (> or = 3 cm) and no other apparent cause of infertility. The latter were removed by operative laparoscopy. Life table calculations, the Student's t-test and the chi2 test were used where appropriate. Thirty-four patients (53%) became pregnant during the 2-year follow-up period. A significantly increased pregnancy rate was found for the first year compared to the second (76 vs. 24%). The existence of adhesions affected adversely the outcome of the operation only as far as early achievement of pregnancy is considered. The number and size of endometriomata and the existence of peritoneal implants have not been found to affect pregnancy rates. The severity of the disease did not affect pregnancy rate, but in the cases with moderate disease most of the pregnancies were achieved during the first postoperative year. The duration of infertility was significantly associated only at the 10% level with decreased pregnancy rates. Extensive endometriosis with large endometriomata can be safely and effectively treated with laparoscopy using the traditional laparoscopic tools providing the infertile patient with a high chance to conceive in a relatively short period of time postoperatively.


Novel autoantibodies to a voltage-gated potassium channel Kv1.4 in a severe form of myasthenia gravis.
Sera from patients with myasthenia gravis (MG) were screened for autoantibodies to skeletal muscle-specific antigens by immunoprecipitation assay, using rhabdomyosarcoma and leukemia cell lines. Eleven of 61 MG sera immunoprecipitated a rhabdomyosarcoma-specific 70-kDa protein, which was identified as the voltage-gated K+ channel 1.4 (Kv1.4). This antibody specificity was not detected in 30 patients with polymyositis/dermatomyositis, 9 with thymoma alone, or 30 healthy controls. Clinical features associated with anti-Kv1.4 antibody included bulbar involvement, myasthenic crisis, thymoma, myocarditis, and QT prolongation on electrocardiogram. These findings suggest that anti-Kv1.4 antibody is a novel autoantibody associated with a severe MG subset and thymoma.


Induced transient hyperammonemia in Rana hexadactyla with reference to the ammonia and urea excretion.
Different ammonia toxicity induced by ammonium acetate administration in frogs lead to variable excretion of ammonia and urea into the medium. When 11.45 mM/kg body weight of ammonium acetate was administered, ammonia excretion increased while urea excretion decreased. When 4.17 mM/kg body weight of ammonium acetate is administered, the urea excretion increased while ammonia excretion decreased. The possible metabolic conversion of ammonia and urea by the animal at high and low ammonium acetate administration has been discussed.


Routine pelvic X-rays in asymptomatic hemodynamically stable blunt trauma patients: A meta-analysis.
There is no consensus on how pelvic X-rays should be ordered selectively in blunt trauma patients which may save time, reduce radiation exposure and costs. The aim of this systematic review and meta-analysis was to assess the need for routine pelvic X-rays in awake, respiratory and hemodynamically (HD) stable blunt trauma patients without signs of pelvic fracture. Criteria to identify patients who could safely forgo pelvic X-ray were evaluated. A literature search was performed for prospective comparative cohort studies. Inclusion criteria were: blunt force trauma, hemodynamically and respiratory stable and awake patients, physical examination (PE) for pelvic fractures was adequately described, and the reliability of negative PE findings could be evaluated. Primary outcome was the negative predictive value (NPV) of PE for all and for clinically relevant pelvic fractures. Additionally sensitivity, specificity and positive predictive value (PPV) were calculated. Ten studies were included; yielding a total of 11,423 patients. The NPV of PE for all pelvic fractures ranged from 0.96 to 1.00 with a median of 0.996. Combining studies, total NPV was 0.991. For clinically relevant fractures, the NPV of PE ranged from 0.996 to 1.00 with a median of 1.00. In patients with negative findings during PE, 0.9% had fractures, and 0.1% had clinically relevant fractures, none requiring surgical management. In awake, hemodynamically and respiratory stable blunt trauma patients, PE could identify those patients who could safely forgo pelvic X-ray. Selective ordering of pelvic X-ray may lead to a decrease in patient work-up time, lower radiation exposure, and reduce costs. A decision making flow chart is proposed..


A meta-analysis of association between C677T polymorphism in the methylenetetrahydrofolate reductase gene and hypertension.
The C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene was implicated to be associated with hypertension due to its role in catalyzing the formation of 5-methylenetetrahydrofolate, a co-substrate for the conversion of homocysteine to methionine. Association studies were reported in different populations; however, a great number of subsequent studies have produced contrary results, possibly reflecting inadequate statistical power. With the cumulative data in recent years in both Caucasian and Asian populations, it was necessary to carry out a comprehensive analysis of previous findings. In this meta-analysis, we combined 26 English and Chinese studies in Caucasian and Asian populations published up to November 2006 to give a new picture of the role of the C677T polymorphism in the MTHFR gene. Evidence of significant association was detected between C677T polymorphism and hypertension in both populations. Additionally, the significant association between C677T polymorphism and hypertension/hypertension-in-pregnancy suggested that this polymorphism was one independent risk factor of hypertension.


Lithium treatment and human hippocampal neurogenesis.
Lithium is a first-line treatment for bipolar disorder, where it acts as a mood-stabilizing agent. Although its precise mechanism remains unclear, neuroimaging studies have shown that lithium accumulates in the hippocampus and that chronic use amongst bipolar disorder patients is associated with larger hippocampal volumes. Here, we tested the chronic effects of low (0.75 mM) and high (2.25 mM) doses of lithium on human hippocampal progenitor cells and used immunocytochemistry to investigate the effects of lithium on cell parameters implicated in neurogenesis. Corresponding RNA-sequencing and gene-set enrichment analyses were used to evaluate whether genes affected by lithium in our model overlap with those regulating the volume of specific layers of the dentate gyrus. We observed that high-dose lithium treatment in human hippocampal progenitors increased the generation of neuroblasts (P ≤ 0.01), neurons (P ≤ 0.01), and glia (P ≤ 0.001), alongside the expression of genes, which regulate the volume of the molecular layer of the dentate gyrus. This study provides empirical support that adult hippocampal neurogenesis and gliogenesis are mechanisms that could contribute to the effects of lithium on human hippocampal volume.


Three-year efficacy of argon laser trabeculoplasty.
The authors report on the effect of argon laser trabeculoplasty on intraocular pressure (IOP) over a 3-year period with a mean follow-up period of 1.8 years in patients with uncontrolled primary open-angle glaucoma who had not undergone prior surgery. An analysis of the effect of laser trabeculoplasty using the criteria for success of an IOP of 22 mmHg or less with no further laser trabeculoplasty or glaucoma surgery, showed a cumulative success of 79% (112 eyes) at 1 year, 69% (85 eyes) at 2 years, and 59% (58 eyes) at 3 years. Similar results are presented for 22 eyes from patients with pseudoexfoliation glaucoma. The authors conclude that although the initial success rate of laser trabeculoplasty is high, it diminishes progressively over time.


A novel egg-shell membrane based hybrid nanofibrous scaffold for cutaneous tissue engineering.
The main issue in cutaneous regeneration is to develop engineered scaffolds based on natural extracellular matrix to promote dynamics of skin progenitor cells and accelerate differentiation into mature keratinocytes. In this study, nanofibrous scaffolds composed of a blend poly (ɛ-caprolactone) (PCL), silk fibroin (SF), soluble eggshell membrane (SESM), and Aloe vera (AV) gel were developed by electrospinning method and human basal cells were used to examine differentiation capacity toward keratinocyte-like cells. For this propose, cells were allocated to four distinct groups; control, PCL/SF, PCL/SF/SESM, and PCL/SF/SESM/AV. In all groups, cells were incubated with differentiation medium. Morphology, composition, hydrophilicity and mechanical features of PCL/SF, PCL/SF/SESM and PCL/SF/SESM/AV nanofibers were studied by scanning electron microscopy (SEM), Fourier transforms infrared spectroscopy (FT-IR), water contact angle and tensile tests. To examine the orientation of basal cells to mature keratinocytes, we performed immunofluorescence analysis by monitoring cytokeratin-19. The expression of genes such as involucrin, keratin-14 and -5 was monitored by real-time PCR assay. PCL/SF, PCL/SF/SESM, and PCL/SF/SESM/AV had suitable physic chemical indices and biological activities to be applied as biomimetic scaffolds for the restoration cutaneous tissue. Compared to control, we found an increased basal cell proliferation at 7 and 14 days after plating on scaffolds and reach maximum levels in group PCL/SF/SESM/AV on day 14 (p < 0.05). Electron microscopy showed cell flattening, morphological adaptation. An integrated cell-to-cell connection was generated after cell seeding on scaffolds in all groups. Immunofluorescence imaging showed the ability of basal cells to synthesize cytokeratin-19 in PCL/SF, PCL/SF/SESM, and positive control cells after exposure to differentiation medium. However, these values were less in PCL/SF/SESM/AV compared to other groups. Real-time PCR analysis showed the potency of all scaffolds to induce the transcription of involucrin, keratin-14 and -5, especially involucrin in PCL/SF/SESM/AV group compared to the negative control. Modulation of scaffolds with natural biopolymers could enable us to synthesize structures appropriate for cutaneous regeneration.


Frequency of adoption of children and adolescents with learning disabilities.
Students from three different facilities who were diagnosed as learning disabled were studied to determine the frequency of adoption with this population as compared to the national norm. The frequency of adoption was found to be 4.5 times higher than the norm, that is, 17.3% versus 3.9%. The possible reasons for this high incidence are discussed.


Left transperitoneal laparoendoscopic single-site radical nephrectomy in the presence of a duplicated inferior vena cava with associated complex renal vascular anomalies.
Laparo-endoscopic single-site (LESS) renal surgery is steadily gaining momentum. LESS by itself is technically challenging, with a potentially increased procedural risk, and the presence of major vascular anomaly may increase the risk of intraoperative mishap. Here we present a case of left transperitoneal LESS radical nephrectomy that was successfully performed in the presence of double inferior vena cava with associated complex renal vascular anomalies. What is more important is to bring such an aberrant vascular anatomy to the attention of laparoscopic, especially LESS, surgeons.


Utilization of cardiac graft with single coronary artery for orthotopic heart transplantation.
Anomalous coronary arteries arise in a small subset of the population, with each configuration conveying a varying degree of long-term risk. The utilization of cardiac grafts with these anomalies have not been well described. An anomalous single coronary artery with the left main coronary artery arising from the right coronary ostium was discovered in a 40-year old male evaluated for cardiac donation. After evaluation, this heart was successfully procured and utilized for orthotopic heart transplantation. In this report, we demonstrate that in select cases, a cardiac graft with single coronary artery anatomy can be successfully procured and transplanted with excellent outcomes.


Long jumps in the surface diffusion of large molecules.
We have studied the diffusion of the two organic molecules DC and HtBDC on the Cu(110) surface by scanning tunneling microscopy. Surprisingly, we find that long jumps, spanning multiple lattice spacings, play a dominating role in the diffusion of these molecules--the root-mean-square jump lengths are as large as 3.9 and 6.8 lattice spacings, respectively. The presence of long jumps is revealed by a new and simple method of analysis, which is tested by kinetic Monte Carlo simulations.


A combined approach for quantitation of each specific HLA-A or -B antigen expressed on cells.
In order to measure the amount of each individual HLA-A or -B antigen expressed in or on a cell without relying on monoclonal antibodies to different specific HLA antigens, we have developed a combined approach that consists of two separate measurements. The first measurement is to determine the relative quantities of different HLA-A and -B antigens in lysates of whole cells using IEF gel electrophoresis, immunoblotting with 171.4 anti-HLA heavy chain monoclonal antibody, and scanning densitometry. The second measurement is to determine the concentration of total HLA antigens expressed in or on a cell using an enzyme-linked immunoassay or a surface binding assay based on W6/32 anti-HLA monoclonal antibody. The quantity of each specific HLA antigen in or on a cell then is calculated from the results of these two measurements. To validate this combined approach, we conducted studies to show that the amounts of different specific HLA antigens measured by this approach were linearly correlated with those measured by FITC-labeled monoclonal antibodies and immunofluorescence flow cytometry in platelets and lymphoblastoid cell lines. We also demonstrated that the relative quantities of different HLA-A and -B antigens determined from the lysates of whole cells were the same as those expressed on the cell surface. These findings indicated that the newly developed combined approach can be applied to quantify each specific HLA-A or -B antigen expressed in or on a cell.


A Human IgSF Cell-Surface Interactome Reveals a Complex Network of Protein-Protein Interactions.
Cell-surface protein-protein interactions (PPIs) mediate cell-cell communication, recognition, and responses. We executed an interactome screen of 564 human cell-surface and secreted proteins, most of which are immunoglobulin superfamily (IgSF) proteins, using a high-throughput, automated ELISA-based screening platform employing a pooled-protein strategy to test all 318,096 PPI combinations. Screen results, augmented by phylogenetic homology analysis, revealed ∼380 previously unreported PPIs. We validated a subset using surface plasmon resonance and cell binding assays. Observed PPIs reveal a large and complex network of interactions both within and across biological systems. We identified new PPIs for receptors with well-characterized ligands and binding partners for "orphan" receptors. New PPIs include proteins expressed on multiple cell types and involved in diverse processes including immune and nervous system development and function, differentiation/proliferation, metabolism, vascularization, and reproduction. These PPIs provide a resource for further biological investigation into their functional relevance and may offer new therapeutic drug targets.


Gold-based nanospheres and nanorods particles used as theranostic agents: An in vitro and in vivo toxicology studies.
The adverse effect of gold-based nanoparticles is still an open question since it depends on several factors as shape, surface charge or route of administration. In this study, we investigated the influence of shape and human serum albumin (HSA) coating on the adverse effects of spherical (AuNP) and nanorods (AuNR) gold-based particles. F C3H (fibroblast) and HTC (hepatocellular carcinoma) cell lines both from liver were exposed to 25, 75 and 125 μg mL-1, which correspond to 109 NP mL-1. For in vivo studies, Wistar rats received these materials by oral administration in doses of 10 μg kg-1 or 40 μg kg-1. Systemic toxicity was verified after 24 h and 48 h by morphological analysis, blood parameters and myeloperoxidase enzyme activity. Our results revealed that HSA corona does not influence totally the pathway of interactions between AuNP and AuNR. In vitro results evidenced that AuNP can decrease in at least 50% viability of F C3H and cell adhesion of HTC, but corona significantly overcomes these effects. No differences between shape or corona were observed in function of cell lines. In vivo studies showed that 40 μg kg-1 of AuNP-HSA caused an enhancement of the myeloperoxidase response indicating inflammatory processes. An increase from 40% to 80% on alkaline phosphatase levels were found for all groups. Our findings suggested that gold-based particles coated or not with HSA do not cause expressive adverse effects on in vitro or in vivo systems, and their oral administration cannot cause a systemic effect in the experimental conditions used here.