Exploring the barriers to exclusive breastfeeding in black and minority ethnic groups and young mothers in the UK.
UK health policy for many years has been to increase rates of breastfeeding because of the health benefits conferred on mothers and babies. World Health Organization recommends that babies should be breastfed exclusively for 6 months (without water or other fluids) and the National Institute for Health and Clinical Excellence promotes the provision of peer supporters or breastfeeding support groups to increase breastfeeding rates. This study aimed to explore the barriers to exclusive breastfeeding to 6 months with black and minority ethnic groups and with young mothers, and the strategies for overcoming these barriers, including peer support. Twenty-two mothers from Somali, Afro-Caribbean and South Asian communities or young mothers groups attended five focus groups. Transcripts were analysed using thematic and framework methods. There was enthusiasm for breastfeeding support groups, but with a wider remit to discuss other baby-related issues and provide general social support as well as support for breastfeeding. The Somali and South Asian women preferred the groups to be for their ethnic group, Afro-Caribbean women were keen that they should be open to all cultures and young mothers would like groups for their peers only. Encouraging mothers to breastfeed exclusively to 6 months should be promoted more and emphasized by health professionals when supporting women post-natally, and good support with breastfeeding management should be given to enable mothers to achieve this goal. Breastfeeding support groups may play a part in increasing breastfeeding continuation of breastfeeding, but for the groups studied this was not the greatest influence, with families and older women in the community having more influence in changing practice.


Prevalence and predictors of bronchial hyperresponsiveness in children aged 7-16 years.
To study the prevalence and possible predictors of bronchial responsiveness we examined a cross-section of 527 children aged 7-16 years from Copenhagen. The method used included an interview with the child and the parents, skin prick test with common allergens and se-IgE. Bronchial responsiveness was measured by a histamine inhalation test. We found that 79 (16%) of the children had bronchial hyperresponsiveness (BH), defined as a 20% fall in FEV1 with a provoking concentration of histamine (PC20) at 8 mg/ml or less. Atopic symptoms defined as asthma, rhinitis or eczema were significantly (P less than 0.001) correlated to BH both in prevalence and degree of BH. None of the children with urticaria had BH. The degree of bronchial responsiveness was also significantly influenced (P less than 0.001) by family disposition to atopy, whereas we found no correlation between BH and "passive" smoking, specific skin test in unselected children, or elevation of IgE in children without atopic symptoms. We conclude that BH is severest in children with asthma, independent of elevated IgE or positive skin prick test. Children with rhinitis, dermatitis, or asymptomatic BH have the same degree of BH; this differed from that in children with asthma.


[What is important for the family of patients in the intensive care unit?].
The abundant bibliography shows us that the family plays a fundamental paper in the recovery of the hospitalized patients, and the patients in the intensive care units (ICU) are no exception. Several authors have demonstrated that a stress-free and calm setting helps in the care process. Thus, the family needs must be considered to improve their well-being. In this way, their attitude will help in the patient's recovery. Health care personnel must be aware of these needs and make up for their deficit as far as possible. The first study that evaluated this question used the CCFNI questionnaire (Critical Care Family Needs Inventory) that measures the degree of importance given by the relatives to the needs of safety, support, information, comfort and proximity. This study has aimed to detect the degree of importance given by the relatives of the patients in the ICU of the Hospital Dr. Josep Trueta of Girona, using the CCFNI questionnaire. All the relatives of the patients in said unit during the autumn of the year 2003 were interviewed and the needs considered to be most important were compared with the sociodemographic variables of the relatives. The total sample was made up of the 132 people interviewed. The need considered to be most important was safety with 50.3% followed by need for support with 47.2%. In the results, some differences were observed depending according to age and studies of those surveyed and according to the diagnosis and the origin of the hospitalization. The collected data did not differ with the reviewed bibliography. All the study was very valuable for the health care professionals of the unit and was taken into account to improve the deficiencies of the ICU of the hospital of Girona.


Cutaneous and pulmonary sarcoidosis in a Hong Kong Chinese woman with silicone breast prostheses.
Sarcoidosis is rarely reported in Hong Kong. We report cutaneous and pulmonary sarcoidosis in a 54-year-old Chinese woman, who presented with papular lesions over the face and neck. She had silicone breast augmentation surgery 4 years earlier. Skin biopsy revealed granulomatous inflammation and anti-tuberculosis treatment was started empirically but stopped 2 months later owing to a poor response. A right supraclavicular lymph node was aspirated and revealed granulomatous inflammation. The CXR was normal initially but subsequently showed diffuse reticulonodular opacities and a small right-sided pleural effusion. High-resolution CT of the thorax showed mediastinal lymphadenopathy and diffuse perilymphatic nodular opacities consistent with sarcoidosis. Sputum mycobacterial culture was negative. Fibreoptic bronchoscopy showed no endobronchial lesion but the transbronchial biopsy showed granulomatous inflammation with no evidence of infection, malignancy or foreign body. Pulmonary function tests were normal except for impairment of transfer factor. One year later, most of the cutaneous lesions had healed spontaneously. The CXR showed partial improvement of the right pleural opacification but little change in the lung field. The features of sarcoidosis and its association with silicone are reviewed.


The impact of diabetes mellitus on postoperative morbidity in laryngeal surgery.
The main aim of this study was to analyse risk factors of postoperative morbidity after extended laryngeal surgery comparing patients with diabetes mellitus and non-diabetic patients. In retrospective study 69 patients (63 male and 6 female), who underwent partial laryngo-pharyngectomy and total laryngectomy between 2003 and 2004, were evaluated. 13 % of the total group of examined patients had concurrent diabetes, while 87% were nondiabetic patients. We performed partial laryngopharyngectomy in 39 out of 69 patients (56.5%) and total laryngectomy in 30 patients (43.5%). Secondary wound infections (88.9%) and pharyngocutaneus fistula (44.5%) had a significantly higher rate in diabetic patients (p<0.001). Among diabetics the cases with intraoperative or postoperative blood transfusions were more frequent--44.4%(p<0.001). Diabetic patients with laryngectomy procedures had more frequently prolonged postoperative anemia (55.5%, p<0.001) and electrolitic disbalance (66.6%, p<0.001). Our results have confirmed that diabetes mellitus is an important independent general clinical factor, which increases postoperative morbidity and hospitalization time in laryngeal surgery. Our data indicate the need to make a very serious plan and clinical assesment for laryngeal surgical therapy in diabetic patients.


In vitro activity of DS-2969b and comparator antimicrobial agents against Clostridioides (Clostridium) difficile, methicillin-resistant Staphylococcus aureus, and other anaerobic bacteria.
The in vitro activity of DS-2969b, a novel GyrB inhibitor, and six comparator agents was studied against 101 recent North American Clostridioides difficile isolates, 46 other intestinal anaerobes and 51 strains of methicillin-resistant Staphylococcus aureus. The MIC ranges (MIC90s) of DS-2969b against C. difficile and S. aureus were 0.03-0.125 (0.125) μg/ml and 0.125-1 (0.5) μg/ml, respectively. DS-2969b showed the greatest activity of the agents tested. There was no difference in MICs of DS-2969b among different ribotypes.


Outcome after extended callosal section in patients with primary idiopathic generalized epilepsy.
We report the outcome of patients with refractory idiopathic generalized epilepsy (IGE) who were submitted to extended one-stage callosal section. Eleven patients with IGE who were submitted to extended one-stage callosal section were studied. Preoperative workup included history and neurologic examination, interictal, and ictal electroencephalography (EEG) recording, high resolution 1.5T magnetic resonance imaging (MRI) and intelligence quotient (IQ) testing. All patients were submitted to extended one-stage microsurgical callosal section, leaving only the splenium intact. Preoperative ictal patterns included repetitive spike and wave or polyspike and wave discharges or fast epileptic recruiting rhythm. MRI showed no focal lesions. Preoperatively, mean general IQ was 85. Postoperatively, at least a 75% reduction in the frequency of generalized tonic-clonic seizures was noted in all patients. In three patients absences disappeared completely, and the others had at least 90% reduction in seizure frequency. Only one patient had myoclonic seizures preoperatively, and these seizures disappeared after callosal section. After surgery, mean general IQ was 89. A very clear increase in attention level was noted in all patients. Postoperative interictal EEG recordings showed rupture of bilateral synchrony in all patients. This article reports on a large and homogeneous series of patients with refractory IGE submitted for callosal section. There was a marked decrease in generalized seizure frequency and increase in the attention level in this patient population. Our results suggest that corticocortical interaction might have a role in IGE pathogenesis. Callosotomy is a safe, effective, and underused palliative procedure in these well-selected patients with refractory IGE.


Heterologous expression and purification of the serotonin type 4 receptor from transgenic mouse retina.
Recent breakthroughs in the solution of X-ray structures for G protein-coupled receptors (GPCRs) with diffusible ligands have employed extensively mutated or recombined receptor fusion proteins heterologously expressed in conventional in vitro cell-based systems. While these advances now show that crystallization of non-rhodopsin members of this superfamily can be accomplished, the use of radically modified proteins may limit the relevance of the derived structures for precision-guided drug design. To better enable the study of native GPCR structures, we report here efforts to engineer an in vivo expression system that harnesses the photoreceptor system of the retina to express heterologous GPCRs with native human sequences in a biochemically homogeneous and pharmacologically functional conformation. As an example, we show that the human 5HT4 receptor, when placed under the influence of the mouse opsin promoter and an opsin rod outer segment (ROS) targeting sequence, localized to ROS of transgenic mouse retina. The resulting receptor protein was uniformly glycosylated and pharmacologically intact as demonstrated by immunoblotting and radioligand binding assays. Upon solubilization, the retinal 5HT4 receptor retained the binding properties of its initial state in retinal membranes. With the engineered T7 monoclonal epitope sequence, the solubilized receptor was easily purified by one-step immunoaffinity chromatography and the purified receptor in detergent solution preserved its ligand binding properties. This expression method may prove generally useful for generating functional, high-quality GPCR protein.


Clinical Characteristics of Severe Erosive Esophagitis among Patients with Erosive Esophagitis: A Case-control Study.
Objective The risk factors associated with severe erosive esophagitis are not well defined in Japan. We aimed to evaluate the risk factors associated with the endoscopic severity of esophageal mucosal injury. Methods Eighty consecutive Japanese patients with severe erosive esophagitis [Los Angeles (LA) classification grade C or D] who had undergone upper endoscopies in the Gastroenterology Division of Omori Red Cross Hospital between June 2010 and March 2013 were retrospectively analyzed. For each case, a control with mild erosive esophagitis (LA classification grade A or B) who was matched by sex and age was randomly selected during the same period. Among the endoscopic findings, the condition of the gastroesophageal flap valve (GEFV) was graded according to Hill's classification. We identified the risk factors for severe erosive esophagitis using a multivariable logistic regression model. Results A poor performance status (PS) (odds ratio [OR]=17.1201, 95% confidence interval [CI]=3.0268-140.3121, p=0.0008) and an abnormal GEFV (OR=3.0176, 95% CI=1.0589-9.4939, p=0.0385) were risk factors for severe erosive esophagitis, while the presence of open-type gastric mucosal atrophy (GMA) was inversely associated with severe erosive esophagitis (OR=0.2772, 95% CI=0.1087-0.6675, p=0.0040). Conclusion Among patients with erosive esophagitis, a poor PS and an abnormal GEFV were associated while GMA was inversely associated with severe erosive esophagitis. Drug therapy alone or in combination with physical therapy may improve the therapeutic effect on severe erosive esophagitis in patients with a poor PS.


Assessment of meatal stenosis in neonates undergoing circumcision using Plastibell Device with two different techniques.
It was intended to compare meatal stenosis (MS) as a late complication of neonatal circumcision by using two different methods of Plastibell Device circumcision. A total of 2,307 healthy term newborns (6-36 hours) who were born between 2007 and 2009 in Niknafs Medical Center of Rafsanjan, Iran, were simply randomized into two groups in a controlled, nonblinded clinical trial. In group A (1,102 neonates), the frenulum was maintained intact without any manipulation, and in group B (1,205 neonates) frenular hemostasis was performed in all cases by thermal cautery. MS was assessed by follow-up visits that were made for all cases at the 24-72 hours, 60th day, 12th month, and 16th month after circumcision. At 2 months follow-up visit, the rate of MS in group A was 4.9% (54) and in group B was 5.9% (71), which was not statistically significant. After 12 months, MS in group A was 8.5% (94) and in group B was 13.7% (165), which was statistically significant (P<0.001). At 16 months after circumcision, in the frenulum intact group, MS was 13.8% (152) and in the cautery group, it was 18.9% (228), which was compatible with significant difference (P=0.001). Our experience with large group of cases revealed that neonatal circumcision by using Plastibell Device with intact frenulum technique decreases the rate of delayed MS.


Hair analysis of histamine and several metabolites in C3H/HeNCrj mice by ultra performance liquid chromatography with electrospray ionization time-of-flight mass spectrometry (UPLC-ESI-TOF-MS): influence of hair cycle and age.
According to a previous study, the concentration of HA in the hair of SD rats was similar in each rat and the variation in HA concentration was not so great. However, the concentration in human hair was fairly different in each person. As possible reasons for the higher variation in human hair, the differences in hair cycles and age in each person may be considerable. Based on this idea, the studies using C3H/HeNCrj mice who can synchronize their hair cycle were performed for resolution of the influence of hair cycle and age. The effects of hair cycle and age on the concentration of histamine (HA) and several metabolites, i.e., 1-methylhistamine (MHA), imidazole-4-acetic acid (IAA), and 1-methyl-4-imidazole-acetic acid (MIAA), in C3H/HeNCrj mice hair were investigated by ultra-performance liquid chromatography (UPLC) with electrospray ionization time-of-flight mass spectrometry (ESI-TOF-MS). HA and the metabolites were labeled with 4-(N,N-dimethylaminosulfonyl)-7-fluoro-2,1,3-benzoxadiazole (DBD-F) and 4-(N,N-dimethylaminosulfonyl)-7-piperazino-2,1,3-benzoxadiazole (DBD-PZ). The resulting derivatives were separated by UPLC and determined with ESI-TOF-MS. A good linearity was achieved from the calibration curves, obtained by plotting the peak area ratios of the analytes relative to the internal standard (IS), i.e., histamine-alpha,alpha,beta,beta-d4 (HA-d4) or 4-imidazolecarboxylic acid (ICA), against the injected amounts of each compound. The detection limits of HA, MHA, IAA, and MIAA on mass chromatograms were 0.21, 1.0, 0.17, and 0.11 pmol, respectively. The concentrations of HA and the metabolites in the hair shafts and hair root of C3H/HeNCrj mice were determined by this method. The concentration of HA in the hair shaft was relatively higher in the telogen phase. In contrast, the HA content in the anagen phase was increased only in the hair root of old mice. HA appears to possess some effect on hair growth, although the exact reason was not obvious. The HA metabolites, i.e., MHA, MIAA and IAA, were also determined the same as HA; however, the difference in the metabolite concentrations between the hair cycle and age was not clear in both hair shaft and hair root. Such studies of the effect of hair cycle and age on these concentrations are the first report. This analytical technique may be applicable to the determination of various biological compounds in hair.


Proton pump inhibitors as a risk factor for hepatic encephalopathy and spontaneous bacterial peritonitis in patients with cirrhosis with ascites.
Proton pump inhibitors (PPIs) may be a risk factor for hepatic encephalopathy (HE) in patients with cirrhosis, possibly through translocation of gut bacteria, which can also lead to spontaneous bacterial peritonitis (SBP). We examined the associations between PPIs and development of HE or SBP in patients with cirrhosis with ascites. We used data from three 1-year trials of satavaptan for ascites control. We used Cox regression to compare HE and SBP rates between users and nonusers of PPIs. At inclusion, 39% of the 865 patients with cirrhosis with ascites used PPIs, 52% used them at some point during the follow-up, and the proportion of current users was always in the 30%-39% range. There were 189 first-time HE episodes during the follow-up, and the cumulative 1-year risk was 31% for those who used PPIs at baseline versus 25% for those who did not. The confounder-adjusted hazard ratio (HR) of HE for current PPI use versus current nonuse was 1.36 (95% confidence interval [CI], 1.01-1.84). The HR for overt HE was higher (adjusted HR = 1.88; 95% CI, 1.21-1.91). During the follow-up, 86 patients developed SBP. The adjusted HR of SBP for current PPI users versus nonusers was 1.72 (95% CI, 1.10-2.69). PPIs were used by 52% of this international cirrhosis cohort during a 1-year period and was a risk factor for developing HE and SBP. These findings are consistent with the hypothesis that PPIs may increase translocation of gut bacteria. (Hepatology 2016;64:1265-1272).


The temporalis: blood supply and innervation.
Numerous reports have described the use of the temporalis muscle as a pedicled flap in reconstructive surgery. A detailed knowledge of the supplying vessels and nerves is necessary for functionally successful muscle transposition. However, controversial anatomic descriptions exist. In this study, 60 human cadavers were investigated to identify the arteries and nerves supplying the temporalis. Forty-three cadavers were dissected after embalming with 10% phenol/formaldehyde. An additional 10 cadavers were examined after injecting latex/barium sulfate (ratio, 1:1) to show the parts of the temporalis supplied by each artery using radiography. The innervating motor branches of the trigeminal nerve were identified by the Karnovsky technique in seven fresh cadavers. In all specimens, three arteries supplying the temporalis were identified: the anterior deep temporal artery (anterior part, 30 percent muscle mass), the posterior deep temporal artery (central part, 51 percent muscle mass), and the medial temporal artery (occipital and in 25 percent upper part, 19 percent muscle mass). Motor branches of the trigeminal nerve innervated the temporalis: the deep temporal nerves of the mandibular nerve (98 percent, central part), branches of the buccal nerve (95 percent, anterior part), and branches of the masseteric nerve (69 percent, posterior part). A remarkable variation of innervating nerve branches, and in 12 percent peripheral anastomoses between the motor nerve branches, were observed. The various numbers of innervating nerve branches demonstrate the difficulty of creating innervated or selectively denervated pedicled muscle flaps for reinnervation. Nevertheless, at least two different pedicled flaps using the anterior or central part of the temporalis can be selectively used for reconstructive surgery.


Clinical course of sepsis, severe sepsis, and septic shock in a cohort of infected patients from ten Colombian hospitals.
Sepsis has several clinical stages, and mortality rates are different for each stage. Our goal was to establish the evolution and the determinants of the progression of clinical stages, from infection to septic shock, over the first week, as well as their relationship to 7-day and 28-day mortality. This is a secondary analysis of a multicenter cohort of inpatients hospitalized in general wards or intensive care units (ICUs). The general estimating equations (GEE) model was used to estimate the risk of progression and the determinants of stages of infection over the first week. Cox regression with time-dependent covariates and fixed covariates was used to determine the factors related with 7-day and 28-day mortality, respectively. In 2681 patients we show that progression to severe sepsis and septic shock increases with intraabdominal and respiratory sources of infection [OR = 1,32; 95%IC = 1,20-1,46 and OR = 1.21, 95%CI = 1,11-1,33 respectively], as well as according to Acute Physiology and Chronic Health Evaluation II (APACHE II) [OR = 1,03; 95%CI = 1,02-1,03] and Sequential Organ Failure Assessment (SOFA) [OR = 1,16; 95%CI = 1,14-1,17] scores. The variables related with first-week mortality were progression to severe sepsis [HR = 2,13; 95%CI = 1,13-4,03] and septic shock [HR = 3,00; 95%CI = 1,50-5.98], respiratory source of infection [HR = 1,76; 95%IC = 1,12-2,77], APACHE II [HR = 1,07; 95% CI = 1,04-1,10] and SOFA [HR = 1,09; 95%IC = 1,04-1,15] scores. Intraabdominal and respiratory sources of infection, independently of SOFA and APACHE II scores, increase the risk of clinical progression to more severe stages of sepsis; and these factors, together with progression of the infection itself, are the main determinants of 7-day and 28-day mortality.


Bioactivity of Spongian Diterpenoid Scaffolds from the Antarctic Sponge Dendrilla antarctica.
The Antarctic sponge Dendrilla antarctica is rich in defensive terpenoids with promising antimicrobial potential. Investigation of this demosponge has resulted in the generation of a small chemical library containing diterpenoid secondary metabolites with bioactivity in an infectious disease screening campaign focused on Leishmania donovani, Plasmodium falciparum, and methicillin-resistant Staphylococcus aureus (MRSA) biofilm. In total, eleven natural products were isolated, including three new compounds designated dendrillins B-D (10-12). Chemical modification of abundant natural products led to three semisynthetic derivatives (13-15), which were also screened. Several compounds showed potency against the leishmaniasis parasite, with the natural products tetrahydroaplysulphurin-1 (4) and dendrillin B (10), as well as the semisynthetic triol 15, displaying single-digit micromolar activity and low mammalian cytotoxicity. Triol 15 displayed the best profile against the liver-stage malaria parasites, while membranolide (5) and dendrillin C (11) were strong hits against MRSA biofilm cultures.


Presence of activated antigen-binding B cells during immunization enhances relative levels of IFN-gamma in T cell responses.
To examine the influence of Ag presentation by B cells on immune responses, we have used mice transgenic for an Ig heavy chain from a monoclonal anti-azobenzenearsonate (Ars) Ab to deliver Ag to B cells during immunization. A large proportion of transgene-expressing B cells in these mice binds Ars, while transgenic serum Ig shows poor Ars binding. Transgenic B cells present Ars proteins better than their nonhaptenated counterparts. This is associated with an increase in the proliferative responses of transgenic T cells to Ars protein immunization. Although B cell numbers in the transgenic mice are lower, many B cells in them show an activated phenotype, as identified by altered surface levels of peanut agglutinin reactivity, CD23, CD24, CD44, CD62L, and CD86. Even against nonhaptenated immunogens, transgenic responses show significant enhancement in the relative proportions of the Th1 cytokine IFN-gamma over the Th2 cytokines IL-4 and IL-10. Haptenated immunogens further enhance the predilection of transgenic mice to produce relatively more IFN-gamma. Consistent with this, there is an increase in IgG2a/IgG1 ratios in serum Abs in response to haptenated immunogens in transgenic mice. Adoptive transfer of primed hapten-specific secondary B cells into nontransgenic mice also induces an increase in relative levels of IFN-gamma in response to haptenated immunogens. Thus, presentation of immunogen in vivo by activated Ag-binding B cells contributes to enhanced immunogenicity and a Th1 cytokine bias.


[Experimental in vitro studies of the stability of tendon sutures].
In early mobilization tendon sutures must perform a sufficient stability. For the examination of a suture under tension tendons of cows with 4 to 6 mm diameter were taken as specimen. They were divided and then sutured with the techniques of Kirchmayr, of Lange and of Dychno-Bunnell. We used the resorbable Polydioxanon-Suture (PDS) and the non-resorbable Polypropylene-Suture (PPS) in 3-0, 4-0 and 5-0 of cross diameter (USP). Breaking-strength, elongation of the suture, the absorbed strength until a gap is developing and the extent of the gaps at their maximum were measured. The results recommend the suture techniques of Dychno-Bunnell and of Lange with 4-0 and 5-0 PDS as sufficient stable for early mobilization.


Organization, functions, and mechanisms of the BBSome in development, ciliopathies, and beyond.
The BBSome is an octameric protein complex that regulates ciliary transport and signaling. Mutations in BBSome subunits are closely associated with ciliary defects and lead to ciliopathies, notably Bardet-Biedl syndrome. Over the past few years, there has been significant progress in elucidating the molecular organization and functions of the BBSome complex. An improved understanding of BBSome-mediated biological events and molecular mechanisms is expected to help advance the development of diagnostic and therapeutic approaches for BBSome-related diseases. Here, we review the current literature on the structural assembly, transport regulation, and molecular functions of the BBSome, emphasizing its roles in cilium-related processes. We also provide perspectives on the pathological role of the BBSome in ciliopathies as well as how these can be exploited for therapeutic benefit.


Complete sequence and structure of the gene for human adenosine deaminase.
The nucleotide sequence of the human adenosine deaminase gene was determined. The gene was isolated in a series of overlapping lambda phage clones containing human germ line DNA. A total of 36,741 base pairs were sequenced, including 32,040 base pairs from the transcription initiation site to the polyadenylation site, 3935 base pairs of 5'-flanking DNA, and 766 base pairs of 3'-flanking DNA. The gene contains 12 exons separated by 11 introns. The exons range in size from 62 to 325 base pairs while the introns are 76-15 166 base pairs in size. The area sequenced contains 23 copies of Alu repetitive DNA and a single copy of an "O" family repeat. All but one of these repeat sequences are located in the first three introns or the 5'-flanking region. The apparent promoter region of the gene lacks the "TATA" and "CAAT" sequences often found in eucaryotic promoters and is extremely G/C rich. Contained within this region are areas homologous to other G/C-rich promoters, including six decanucleotide sequences that are highly homologous to sequences identified as functional binding sites for transcription factor Sp1.


Transcriptomic Changes Related to Cellular Processes with Particular Emphasis on Cell Activation in Lysosomal Storage Diseases from the Group of Mucopolysaccharidoses.
Although mucopolysaccharidoses (MPS), inherited metabolic diseases from the group of lysosomal storage diseases (LSD), are monogenic disorders, recent studies indicated that their molecular mechanisms are complicated. Storage of glycosaminoglycans (GAGs), arising from a deficiency in one of the enzymes involved in the degradation of these compounds, is the primary cause of each MPS type. However, dysfunctions of various cellular organelles and disturbance of cellular processes have been reported which contribute considerably to pathomechanisms of the disease. Here, we present a complex transcriptomic analysis in which all types and subtypes of MPS were investigated, with special emphasis on genes related to cell activation processes. Complex changes in expression of these genes were found in fibroblasts of all MPS types, with number of transcripts revealing higher or lower levels (relative to control fibroblasts) between 19 and over 50, depending on MPS type. Genes in which expression was significantly affected in most MPS types code for proteins involved in following processes, classified according to Gene Ontology knowledge database: cell activation, cell growth, cell recognition, and cell division. Levels of some transcripts (including CD9, CLU, MME and others) were especially significantly changed (over five times relative to controls). Our results are discussed in the light of molecular pathomechanisms of MPS, indicating that secondary and/or tertiary changes, relative to GAG storage, might significantly modulate cellular dysfunctions and contribute to molecular mechanisms of the disease. This may influence the efficacy of various therapies and suggests why various treatments are not fully effective in improving the complex symptoms of MPS.


[Laparoscopically assisted neovaginaplasty using peritoneum as vaginal mucous substitute].
To practice a more atraumatic, physiological and aesthetically valued approach of construction for neovagina. Laparoscopically using peritoneum as neovagina lining. From March 2005 to September 2006, this technique was adopted to treat 10 patients whose diagnosis was congenital absence of vagina. The ages of the patients were from 19 to 32. The operation lasted average 2.34 hours. And hospitalization was about 20.5 days. Follow-up ranged from 3 - 12 months. No complication occurred. All of the patients was satisfied with their sexual life. Laparoscopically assisted neovaginaplasty, in which peritoneum was substituted for vaginal mucous membrane, was a kind of ideal approach of vaginal creation.


A fragile secondary constriction on chromosome 2 in a severely mentally retarded patient.
A case is presented of an eighteen-year-old girl suffering from severe mental retardation associated with a fragile secondary constriction on the long arm of chromosome 2. The question of the relationship between the phenotypic and chromosomal abnormalities is discussed. We acknowledge the co-operation of Dr M. E. Elsarag and Dr K. M. Laurence in allowing this investigation to be made.


Nanofluidic device for continuous multiparameter quality assurance of biologics.
Process analytical technology (PAT) is critical for the manufacture of high-quality biologics as it enables continuous, real-time and on-line/at-line monitoring during biomanufacturing processes. The conventional analytical tools currently used have many restrictions to realizing the PAT of current and future biomanufacturing. Here we describe a nanofluidic device for the continuous monitoring of biologics' purity and bioactivity with high sensitivity, resolution and speed. Periodic and angled nanofilter arrays served as the molecular sieve structures to conduct a continuous size-based analysis of biologics. A multiparameter quality monitoring of three separate commercial biologic samples within 50 minutes has been demonstrated, with 20 µl of sample consumption, inclusive of dead volume in the reservoirs. Additionally, a proof-of-concept prototype system, which integrates an on-line sample-preparation system and the nanofluidic device, was demonstrated for at-line monitoring. Thus, the system is ideal for on-site monitoring, and the real-time quality assurance of biologics throughout the biomanufacturing processes.


Structure and variability of the a sequence in the genome of human cytomegalovirus (Towne strain).
We have defined the boundaries of the a sequence from human cytomegalovirus (CMV) strain Towne, characterized internal variability and determined the position of the cleavage site used to generate genomic termini. The cleavage site is positioned a fixed distance from two stretches of sequence homology that have been observed near the ends of many herpesvirus genomes. Unlike a comparable region in CMV (AD169), the CMV (Towne) a sequence has a relatively low level of variability within the a sequence and its structure is stable through repeated virus passage.


Coordinate expression of coproporphyrinogen oxidase and cytochrome c6 in the green alga Chlamydomonas reinhardtii in response to changes in copper availability.
To maintain photosynthetic competence under copper-deficient conditions, the green alga Chlamydomonas reinhardtii substitutes a heme protein (cytochrome c6) for an otherwise essential copper protein, viz. plastocyanin. Here, we report that the gene encoding coproporphyrinogen oxidase, an enzyme in the heme biosynthetic pathway, is coordinately expressed with cytochrome c6 in response to changes in copper availability. We have purified coproporphyrinogen oxidase from copper-deficient C.reinhardtii cells, and have cloned a cDNA fragment which encodes it. Northern hybridization analysis confirmed that the protein is nuclear-encoded and that, like cytochrome c6, its expression is regulated by copper at the level of mRNA accumulation. The copper-responsive expression of coproporphyrinogen oxidase parallels cytochrome c6 expression exactly. Specifically, the copper-sensing range and metal selectivity of the regulatory components, as well as the time course of the responses, are identical. Hence, we propose that the expression of these two proteins is controlled by the same metalloregulatory mechanism. Our findings represent a novel metalloregulatory response in which the synthesis of one redox cofactor (heme) is controlled by the availability of another (Cu).


Adherence to risk-factor instructions one year following coronary artery bypass surgery.
A convenience sample (n = 60) of two comparable groups of cardiac bypass patients was studied to assess the effectiveness of a structured teaching guide used by nurses in educating patients and families about normal postoperative recovery and risk-factor modification. One group was educated by an unstructured method, and the other group received structured teaching with the use of a written guide developed by nurses experienced in open-heart recovery. Both groups had higher total knowledge scores postoperatively than preoperatively. To assess whether the type of teaching had affected changes in behavior, a six-week postoperative health interview was conducted, and a follow-up questionnaire was mailed at one year.


Detrusor activity and outflow resistance in stress incontinence.
The successful treatment of urinary stress incontinence in females dependends on a careful study of urodynamics. Pre-operative measurements of urine flow rate and residual urine can be useful only in differentiating compensated from deconpensated micturition. However, some selected problems require a more detailed investigation. Therefore synchronous cine/pressure/flow/cystourethrographic studies were performed in 20 stress-incontinent women. In some of them, an increased outflow resistance was thus demonstrated. Any type of operation for stress incontinence which raises outflow resistance must be avoided in these cases. Long-distanced urethrocystopexy which permits to avoid an unwanted increase of outflow resistance with following retention of urine should be preferred.


TOXsIgN: a cross-species repository for toxicogenomic signatures.
At the same time that toxicologists express increasing concern about reproducibility in this field, the development of dedicated databases has already smoothed the path toward improving the storage and exchange of raw toxicogenomic data. Nevertheless, none provides access to analyzed and interpreted data as originally reported in scientific publications. Given the increasing demand for access to this information, we developed TOXsIgN, a repository for TOXicogenomic sIgNatures. The TOXsIgN repository provides a flexible environment that facilitates online submission, storage and retrieval of toxicogenomic signatures by the scientific community. It currently hosts 754 projects that describe more than 450 distinct chemicals and their 8491 associated signatures. It also provides users with a working environment containing a powerful search engine as well as bioinformatics/biostatistics modules that enable signature comparisons or enrichment analyses. The TOXsIgN repository is freely accessible at http://toxsign.genouest.org. Website implemented in Python, JavaScript and MongoDB, with all major browsers supported. Supplementary data are available at Bioinformatics online.


Quantitative trait loci controlling leaf venation in Arabidopsis.
Leaf veins provide the mechanical support and are responsible for the transport of nutrients and water to the plant. High vein density is a prerequisite for plants to have C4 photosynthesis. We investigated the genetic variation and genetic architecture of leaf venation traits within the species Arabidopsis thaliana using natural variation. Leaf venation traits, including leaf vein density (LVD) were analysed in 66 worldwide accessions and 399 lines of the multi-parent advanced generation intercross population. It was shown that there is no correlation between LVD and photosynthesis parameters within A. thaliana. Association mapping was performed for LVD and identified 16 and 17 putative quantitative trait loci (QTLs) in the multi-parent advanced generation intercross and worldwide sets, respectively. There was no overlap between the identified QTLs suggesting that many genes can affect the traits. In addition, linkage mapping was performed using two biparental recombinant inbred line populations. Combining linkage and association mapping revealed seven candidate genes. For one of the candidate genes, RCI2c, we demonstrated its function in leaf venation patterning.


Imaging docking and fusion of insulin granules induced by antidiabetes agents: sulfonylurea and glinide drugs preferentially mediate the fusion of newcomer, but not previously docked, insulin granules.
Sulfonylurea and glinide drugs, commonly used for antidiabetes therapies, are known to stimulate insulin release from pancreatic beta-cells by closing ATP-sensitive K+ channels. However, the specific actions of these drugs on insulin granule motion are largely unknown. Here, we used total internal reflection fluorescence (TIRF) microscopy to analyze the docking and fusion of single insulin granules in live beta-cells exposed to either the sulfonylurea drug glibenclamide or the glinide drug mitiglinide. TIRF images showed that both agents caused rapid fusion of newcomer insulin granules with the cell membrane in both control and diabetic Goto-Kakizaki (GK) rat pancreatic beta-cells. However, in the context of beta-cells from sulfonylurea receptor 1 (SUR1) knockout mice, TIRF images showed that only mitiglinide, but not glibenclamide, caused fusion of newcomer insulin granules. Compositely, our data indicate that 1) the mechanism by which both sulfonylurea and glinide drugs promote insulin release entails the preferential fusion of newcomer, rather than previously docked, insulin granules, and that 2) mitiglinide can induce insulin release by a mechanism independent of mitiglinide binding to SUR1.


[Helmet delivered CPAP for in-patients].
The scanty availability of intensive care beds in our hospital, compared with the needings of the area, led us to employ surgical department beds as post-intensive beds. The possibility of delivering non invasive ventilation by head helmet allowed, also in such settings, the ventilation of patients. This paper analyses the main capacities and problems that are faced by the nurse in the management of head helmet delivered CPAP. Main systems for gas delivery that can be used in the departments, PEEP application modalities and psychologic management of the patient are detailed.


Impaired ability of voluntary quadriceps activation bilaterally interferes with function testing after knee injuries. A twitch interpolation study.
Central activation deficits have been recognised to be partially responsible for quadriceps muscle weakness after knee injuries effecting the injured as well as the uninjured leg. The purpose of this study was to assess the extent of bilateral activation deficits and its effect on functional muscle tests using the uninjured leg as reference. The study included 30 patients with isolated rupture of the anterior cruciate ligament (group 1), 42 patients with rupture of the anterior cruciate ligament and accompanying joint damage (group 2) and 34 healthy volunteers as reference. The maximum isometric knee extension torque and the maximal voluntary muscle activation (VA) were measured bilaterally using a sensitive twitch-interpolation method. The measured and the true functional deficit, adjusted to a physiological VA of the uninjured side, was calculated. Isolated rupture of the anterior cruciate ligament caused a minor VA-deficit and severe knee injuries more severe VA-deficits of the quadriceps muscles of the injured (VA group 1: 83.8 +/- 1.9 %; group 2: 76.9 +/- 1.8 %) and on the uninjured side (VA group 1: 85.9 +/- 1.8 %; group 2: 77.9 +/- 1.8 %) compared to the control group (VA 91 +/- 0.64 %). Due to contralateral VA-deficits the mean underestimation of the isometric muscle-force deficit was 22 % in group 1 and 48% in group 2. Unilateral knee injuries lead to significant VA-deficits of the quadriceps muscles on both the injured and uninjured legs related to the severity of injury. The validity of tests for the assessment of muscle function is questionable when using the uninjured side as reference.


Nuclear effects of the cAMP pathway activation in somatotrophs.
Activation of the cAMP pathway from the cell surface to the nucleus plays a major role in somatotroph differentiation and growth. This pathway is regulated mainly by the antagonistic hypothalamic hormones GHRH and somatostatin. Several pituitary-specific, as well as ubiquitous, expressed genes are regulated by cAMP in GH-secreting cells. Among them are the GH, GHF-1/Pit-1, c-fos and GHRH-receptor genes. Protein kinase A phosphorylation of Ser 133 of the transcription factor cAMP-responsive element binding protein (CREB), seems to play a pivotal role in the activation of the cAMP pathway in normal and tumoral somatotrophs. The oncogenic activating mutations of the G-protein as subunit stimulate transcription and CREB phosphorylation in somatotroph cells. The implications of the nuclear targets of cAMP in the differentiation and growth of somatotrophs are discussed in this review.


Genetic risk, incident colorectal cancer, and the benefits of adhering to a healthy lifestyle: A prospective study using data from UK Biobank and FinnGen.
Genetic factors increase the individual risk of colorectal cancer (CRC); however, the extent to which a healthy lifestyle can offset increased genetic risk is unknown. This study investigated whether a healthy lifestyle is associated with lower CRC risk, regardless of genetic risk. We recruited 390,365 participants without cancer at baseline (2006-2010) from the UK Biobank. The primary outcome was CRC incidence. A healthy lifestyle score constructed using 16 factors of six dimensions (smoking, drinking, body mass index, diet, exercise, and sleep) was categorized into three risk categories: favorable, intermediate, and unfavorable. To calculate the polygenic risk scores (PRSs) of UK Biobank participants, we extracted 454,678 single nucleotide polymorphisms (SNPs) from the UK Biobank and FinnGen Biobank after quality control. Cox proportional hazards regression was performed to evaluate the associations and was expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). During a median follow-up of 10.90 years, 4,090 new CRC cases were reported in the UK Biobank. The "best-fit" PRSs were constructed using 59 SNPs based on the UK Biobank cohort and FinnGen genome-wide association study summary data (R2 = 0.23%) and were divided into low (lowest quintile), intermediate (including second-fourth quintile), and high (highest quintile) genetic risk categories. The multivariate-adjusted Cox model revealed that participants with favorable lifestyles had HRs of 0.66 (95% CI = 0.60-0.72) for developing CRC vs. those with unfavorable lifestyles; low genetic risk was associated with a decreased risk of CRC (HR = 0.67, 95% CI =0.61-0.74) compared with those with high genetic risk. The HRs for low genetic risk participants with favorable lifestyles were 0.44 (95% CI =0.36-0.55) vs. participants with high genetic risk and unfavorable lifestyles. Among the participants with low, intermediate, or high genetic risk, the HRs of favorable vs. unfavorable lifestyles were 0.74, 0.64, and 0.72 (all p< 0.05). Low genetic risk and a favorable lifestyle were significantly associated with a decreased risk of CRC. A favorable lifestyle was associated with a lower CRC risk, regardless of genetic risk.


Pre- and postnatal findings in Pena Shokeir I syndrome: case report and a review of the literature.
The Pena Shokeir type I syndrome is considered to be a lethal disorder in most cases. Infrequently, some of the affected children may reach the age of 1 year and beyond. When there is a history of another affected sib, the entity can be suspected prenatally. It is an uncommon autosomal recessive disorder. Out of 33 reported infants reviewed by us, six survived the neonatal period; among a further 27 cases, reported more recently, none survived the neonatal period. The clinical findings at birth are multiple and involve mainly the musculoskeletal and respiratory systems, accompanied by characteristic facial changes. The possibility of a primary hereditary malformation affecting the motor neuron cells of the spinal cord is postulated with the subsequent changes representing a fetal akinesia deformation sequence.


Self-Amputation in Patient with Body Integrity Dysphoria in Comorbidity with Gender Dysphoria: A Case Report.
We present a rare, atypical case of a 24-year-old transgender male (assigned as a female at birth) admitted to the hospital after the planned self-amputation of his left hand. The patient described his motivation for this self-amputation as coming from deep-rooted and persistent feelings that this hand was not a part of his body. He identified himself as having, according to internet peer group definition, body integrity identity disorder. This condition is now referred to as body integrity dysphoria (BID). This patient was later diagnosed as having gender dysphoria and other conditions, including bipolar disorder and gaming disorder. The follow-up 2 years after self-amputation is presented, during which, despite antipsychotic and antidepressant treatment, the symptoms of BID remained unchanged and the high variability of other psychopathology was observed. This is an unusual case of BID simply because several other comorbidities are presented. Like many other rare clinical situations, this case also presents a particular challenge to our understanding of the dynamics and interrelationships between comorbidities, raising concerns and questions.


[Fats and oils (including omega3, omega6)].
Saturated fatty acids contribute essentially to atherogenesis, especially to coronary artery disease. In contrast, the protective effect of monounsaturated fatty acids such as oleic acid, contained in olive oil and as a constituent of a Mediterranean diet is very well shown epidemiologically. There is a modest beneficial effect on the clinical manifestation of coronary heart disease when saturated fatty acids of animal provenience are partially replaced by omega 6 fatty acids (linoleic acid). However, studies with the addition of omega-3-fatty acids in the diet (fish oil rich in eicosapentaenoic and docosaexaenoic acid and rape seed oil rich in alpha linolenic acid) demonstrate a significant decrease of sudden cardiac death and non fatal myocardial infarction. Long-chain omega-3-fatty acids have a direct antiarrhythmic effect on myocytes. The reduction of non-fatal myocardial infarctions during consumption of diets rich in long chain omega-3-fatty acids could at least in part be attributed to inhibitory effects on platelet aggregation and thus on thrombus formation and to a stabilization of atherosclerotic plaques.


Investigation of the efficacy of synbiotics in the treatment of functional constipation in children: a randomized double-blind placebo-controlled study.
The aim of this study was to demonstrate the efficacy of synbiotic (Lactobacillus casei, L. rhamnosus, L. plantarum, and Bifidobacterium lactis and prebiotics [fiber, polydextrose, fructo-oligosaccharides, and galacto-oligosaccharides]) treatment in children with functional constipation. This study was performed in patients aged 4-18 years, and the patients were diagnosed to have functional constipation according to the Roma III diagnostic criteria. In this prospective study, the first group received synbiotic and the second group received a placebo. At the end of 4 weeks, patients were questioned about the initial symptoms. Patients who showed improvement in the initial symptoms at the end of the 4-week treatment period were considered to completely benefit from the treatment and those with some improvement in initial symptom were considered to partially benefit from the treatment. The synbiotic and placebo groups comprised 72 and 74 patients, respectively. The mean age in the whole study group was 9.18±3.48 years with a male:female ratio of 1:21. After 4 weeks of treatment, significant improvement was not observed in any of the findings in the placebo group. Conversely, a significant improvement was observed in the weekly number of defecations, abdominal pain, painful defecation, and pediatric Bristol scale (p≤0.001) in the synbiotic group. Complete benefit from the treatment was achieved in 48 (66.7%) and 21 (28.3%) patients in the synbiotic and placebo groups, respectively, and a significant difference was observed between the groups (p≤0.001). Our studies have shown that the use of synbiotics in the treatment of functional constipation in children is beneficial.


Immunocytochemical evidence for the maintenance of cytochrome P-450 isozymes, NADPH cytochrome C reductase, and epoxide hydrolase in pure and mixed primary cultures of adult human hepatocytes.
Specific polyclonal antibodies were used to investigate the distribution of two cytochrome P-450 isozymes (5 and 8), NADPH cytochrome c reductase, and epoxide hydrolase in adult human hepatocytes cultured alone or co-cultured with rat liver epithelial cells. The enzymes were localized by the indirect immunoperoxidase technique following fixation with a paraformaldehyde-glutaraldehyde mixture and membrane permeabilization with saponin. The pattern of distribution of the four enzymes after 24 hr in culture was similar to that found in vivo. Virtually all the hepatocytes exhibited nearly homogeneous positive staining for cytochrome P-450-8, whereas only 60-80% were positive for cytochrome P-450-5. Nearly homogeneous staining was also observed in all hepatocytes for NADPH cytochrome c reductase and epoxide hydrolase. During the first 12 days in pure culture, the intensity of staining, as well as the number of positively stained cells, decreased slightly except for epoxide hydrolase, which did not show any obvious change. In contrast, even after 15 days in co-culture the extent of staining for all the enzymes decreased less than in pure culture. These results indicate that adult human hepatocytes continue to express specific drug-metabolizing enzymes for several days in culture and provide further evidence that those cells are more stable than rodent hepatocytes in primary culture.


Endolymphatic deafness: a particular variety of cochlear disorder.
Experimental and clinical data made us consider some types of perceptive hearing loss secondary to an alteration of the secretory structures of the cochlea including stria vascularis, spiral ligament and supporting cells. These structures are responsible for the secretion of endolymph, a fluid characterized by a high potassium concentration (150-180 mM), a low sodium concentration (<1 mM) and a positive potential (80-100 mV). This intracellular-like fluid fills the endolymphatic compartment and is essential in the transduction process which takes place in the organ of Corti. Experimental studies have shown that drugs such as loop diuretics induced marked histological lesions in the stria vascularis and profound alterations in the electrochemical features of endolymph. Histopathological data have demonstrated that several entities such as prebyacusis, sudden deafness, and congenital or acquired progressive hearing loss could be related to strial abnormalities. Recent genetic studies have shown that a mutation of genes encoding connexins, a gap junction protein present in the secretory structures, was involved in some dominant or recessive forms of congenital deafness. Finally, the evaluation of labyrinthine fluids in humans has evidenced a decreased endocochlear potential in two cases of progressive flat hearing loss. All these arguments suggest that among the various types of so-called 'sensorineural' deafness, several entities including strial presbyacusis, diuretic-induced ototoxic deafness, some forms of congenital hearing loss and sudden deafness should be classified as endolymphatic deafness. Such an identification seems necessary since these entities result from different pathogenetic mechanisms, do not have the same evolution nor will they probably benefit from the same therapeutic management.


Cooking and eating facilities in migrant farmworker housing in North Carolina.
We sought to (1) describe observed cooking and eating facilities in migrant farmworker camps, (2) compare observed conditions with existing farmworker housing regulations, and (3) examine associations of violations with camp characteristics. We collected data in 182 farmworker camps in eastern North Carolina during the 2010 agricultural season. We compared our observations with 15 kitchen-related housing regulations specified by federal and state housing standards. We observed violations of 8 regulations in at least 10% of camps: improper refrigerator temperature (65.5%), cockroach infestation (45.9%), contaminated water (34.4%), rodent infestation (28.9%), improper flooring (25.8%), unsanitary conditions (21.2%), improper fire extinguisher (19.9%), and holes or leaks in walls (12.1%). Logistic regression showed that violations were related to the time of the agricultural season, housing type, number of dwellings and residents, and presence of workers with H-2A visas. Cooking and eating facilities for migrant farmworkers fail to comply with regulations in a substantial number of camps. Greater enforcement of regulations, particularly during occupancy during the agricultural season, is needed to protect farmworkers.


Invasive fungal infection in the immunosuppressed host.
Immunosuppression, whether arising as a consequence of disease (haematopoietic and lymphoreticular malignancies) or therapy (against hemograft rejection or malignancy results in a higher than normal incidence of invasive fungal infections such as candidiasis, aspergillosis, mucormycosis and cryptococcosis. Normal host defense mechanisms, both immunologic and non-immunologic, are not fully functional and may contribute to the pathogenesis of these diseases.Candida, normally a superficial colonizer, may invade the gastrointestinal, respiratory or urinary tracts. Aspergillus and mucor species may cause hemorrhagic or necrotising pneumonias and secondarily spread to the brain. Cryptococcus may infect the meninges in the appropriate host. Therapeutics for these diseases is limited. Amphotericin B may alter the course of any of the four diseases. Fluorocystosine has found some use in the treatment of candidiasis and cryptococcosis.


Sharing Pathological Mechanisms of Insomnia and Osteoporosis, and a New Perspective on Safe Drug Choice.
Lack of adequate sleep has become increasingly common in our 24/7 modern society. Reduced sleep has significant health consequences including metabolic and cardiovascular disorders, and mental problems including depression. In addition, although the increase in life expectancy has provided a dream of longevity to humans, the occurrence of osteoporosis is a big obstacle to this dream for both male and female. It is known that insomnia and bone health problems, which are very critical conditions in human life, interestingly, share a lot of pathogenesis in recent decades. Nevertheless, due to another side effects of the synthetic drugs being taken for the treatment of insomnia and osteoporosis, patients have substantial anxiety for the safety of drugs with therapeutic expectation. This review examines the pathogenesis shared by sleep and osteoporosis together and herbal medicine, which has recently been shown to be safe and efficacious in the treatment of both diseases other than synthetic drugs. We suggestions for how to treat osteoporosis. These efforts will be the first step toward enabling patients to have comfortable and safe prescriptions through a wide selection of therapeutic agents in the future.


Polar domain fluctuations in doped liquid nitrobenzene.
Improved spectral measurements of the narrow spike in the high resolution hyper-Rayleigh light scattering spectrum for deuterated liquid nitrobenzene (C(6)D(5)NO(2)) doped with triflic acid (CF(3)SO(3)H) determined that the reorientation time for the dopant-induced polar domains is 2.9 micros in the dilute limit. Two models based on ions dissolved in nitrobenzene fit the measured spectral broadening function.


Pneumonia mortality trends in all Brazilian geographical regions between 1996 and 2012.
To analyze the temporal trends in pneumonia mortality rates (standardized by age, using the 2010 population of Brazil as the standard) in all Brazilian geographical regions between 1996 and 2012. This was an ecological time-series study examining secondary data from the Mortality Database maintained by the Information Technology Department of the Brazilian Unified Health Care System. Polynomial and joinpoint regression models, and corresponding 95% CIs, were used for trend analysis. The pneumonia mortality rates in the South, Southeast, and Central-West showed a decreasing behavior until 2000, followed by increases, whereas, in the North and Northeast, they showed increasing trends virtually throughout the period studied. There was variation in annual percent change in pneumonia mortality rates in all regions except the North. The Central-West had the greatest decrease in annual percent change between 1996 and 2000, followed by an increase of the same magnitude until 2005. The 80 years and over age group was the one most influencing the trend behavior of pneumonia mortality rates in all regions. In general, pneumonia mortality trends reversed, with an important increase occurring in the years after 2000.


Leukoaraiosis is a chronic atherosclerotic disease.
White matter changes (WMCs), or leukoaraiosis (LA), are associated with increased age, hypertension, diabetes mellitus, and history of stroke. Although several lines of evidence suggest a role of atherosclerosis in atherothrombotic vascular events, their involvement in LA remains to be determined. Our study examines this association in ischemic stroke patients. One hundred and seventy consecutive ischemic stroke or transient ischemic attack (TIA) patients were included. All patients underwent brain computed tomography (CT) with assessment of the extension and severity of WMCs, carotid arteries duplex scan with measurements of intima-media thickness (IMT) and plaques. Seventy-two patients (42.4%) were found to have white matter lesions, of whom 28.8% had advanced LA. Mean IMT was significantly higher in patients with LA and with advanced LA (P = 0.002, P = 0.003, resp.). In addition, LA and LA severity were associated with existence of carotid plaque (P = 0.007, P = 0.004, resp.). In multivariate logistic regression analysis, including all vascular risk factors, LA was found to be associated with age and IMT. This study reinforces the tight association between LA and carotid atherosclerosis in ischemic stroke patients. We conclude that a chronic atherosclerotic disease underlies the pathophysiology of leukoaraiosis and its progression.


Deferoxamine lowers tissue damage after 80% exchange transfusion with polymerized hemoglobin.
Hemoglobin (Hb) solutions have been proposed as potential substitutes for erythrocytes to maintain oxygen-carrying capacity in situations in which blood is not available. This study investigated systemic and microvascular hemodynamics as well as tissue oxygenation and viability after an 80% exchange transfusion with an oxygen-carrying blood substitute based on polymerized bovine hemoglobin (PBH). Studies were carried in unanesthetized hamsters prepared with a window-chamber model for microcirculation evaluation. Heme iron-mediated injury to the tissue was analyzed by using deferoxamine (an iron chelator), which reduces free iron toxicity. Exchange transfusion led to a significant decrease in hematocrit (Hct) and an increase in plasma Hb, in addition to a significant decrease of arteriolar and venular diameters, flow velocity, and, therefore, microvascular blood flow. Capillary perfusion was severely compromised after exchange, but tissue pO2 increased above baseline, and oxygen extraction was reduced. Apoptotic and necrotic cells increased significantly after the exchange; however, this effect was only partially due to the toxicity of free iron. Iron therapy decreased the microvascular and oxygenation changes but did not fully reverse the adverse effects. Assessment of tissue viability after exchange suggests that chelation treatment in cases of large exchange transfusions with acellular Hb could be potentially beneficial.


The macrophage in HIV-1 infection: from activation to deactivation?
Macrophages play a crucial role in innate and adaptative immunity in response to microorganisms and are an important cellular target during HIV-1 infection. Recently, the heterogeneity of the macrophage population has been highlighted. Classically activated or type 1 macrophages (M1) induced in particular by IFN-gamma display a pro-inflammatory profile. The alternatively activated or type 2 macrophages (M2) induced by Th-2 cytokines, such as IL-4 and IL-13 express anti-inflammatory and tissue repair properties. Finally IL-10 has been described as the prototypic cytokine involved in the deactivation of macrophages (dM). Since the capacity of macrophages to support productive HIV-1 infection is known to be modulated by cytokines, this review shows how modulation of macrophage activation by cytokines impacts the capacity to support productive HIV-1 infection. Based on the activation status of macrophages we propose a model starting with M1 classically activated macrophages with accelerated formation of viral reservoirs in a context of Th1 and proinflammatory cytokines. Then IL-4/IL-13 alternatively activated M2 macrophages will enter into the game that will stop the expansion of the HIV-1 reservoir. Finally IL-10 deactivation of macrophages will lead to immune failure observed at the very late stages of the HIV-1 disease.


Capitation and control of risk in managed care.
In the environment of capitation for health care, physicians assume risks for the condition of their patients and, in essence, act as a type of insurance company. For example, in patients with diabetes, risks include retinopathy and cataracts, peripheral vascular disease and amputations, cardiovascular disease, hyperlipidemia, hypertension, high-risk pregnancies, and renal failure as well as its long-term consequences. Transplantation and million-dollar births are uncommon but extremely expensive events that may be best managed by a partnering arrangement that distributes the risk (and also shares in the potential profit). Health maintenance organizations manage risks by eliminating high-cost patients, decreasing length of stay, and reducing payments to physicians. In formulation of a proposal to assume care for a specific population, the characteristics of the patients and their history of utilization of health-care services should be well understood. With background information, projection of risks becomes more accurate. For management of a contract under capitation, the ability to track long-term outcomes will help to optimize the health care provided.


Establishment of a radial glia-like mouse fetal hypothalamic neural stem cell line (AC1) able to differentiate into neuroendocrine cells.
The present study describes the generation and the characterization of a stable cell line of neural stem cells derived from embryonic mouse hypothalamus. These cells (AC1) grow as an adherent culture in defined serum-free medium and express typical markers of neurogenic radial glia and of hypothalamic precursors. After prolonged expansion, AC1 cells may be efficiently induced to differentiate into neurons and astroglial cells in vitro and start to express some hormonal neuropeptides, like TRH, CRH, and POMC. Based on the capabilities of AC1 cells to be stably expanded and to develop neuroendocrine lineages in vitro, these cells might represent a novel tool to elucidate the mechanisms involved in the development of the hypothalamus and in the specific differentiation of neuroendocrine neurons.


[Effects of temperature on combined process of ABR and MBR for domestic sewage treatment and analysis of microbial community].
Effects of temperature on the combined process of ABR and MBR ( CAMBR) for domestic sewage treatment were investigated and the changes in the bacterial community structure were analyzed by PCR-DGGE technique. The HRT, recycle ratio 1, recycle ratio 2, pH and DO were 7.5 h, 200% , 50%, 6.5~8.5 and 3 mg.L-1, respectively. The temperature were controlled at three gradients: middle (25°C ±5°C ), low (10°C±5°C) and high (35°C±5°C ). The results showed that the change of temperature had little influence on COD removal, and the CAMBR in stable state showed good performance in COD removal. In addition, the CAMBR achieved good effluent quality in middle or high temperature environment, and the average TN removal efficiency was 70% with an effluent TN of 9 mg L-1, and the average TP removal efficiency was 73% with the effluent TP below 0. 8 mg L-1. For the process operated in low temperature environment, the average TN removal efficiency was only 57% with an effluent TN of 15 mg L-1, and the average TP removal efficiency was decreased to 67% with an effluent TP of 1 mg.L-1. DGGE analysis indicated that throughout the process, the microbial population within the system maintained its diversity in distribution, while the dominant flora was prominent. During the same period, microbial populations in each compartment were similar. However, the structure of microbial community had significant differences between the ABR and the MBR due to the change of microenvironment in each compartment. Thus, the contributions of the ABR and the MBR were intensified, guaranteeing the efficiency of nitrogen and phosphorus removal in the system.


High voltage endurance and switchable resistance effect observed in nanoscale copper groove structure.
A switchable lateral resistance effect with high reverse voltage has been observed in nanoscale copper groove structure. With the stimulation of electric pulse and local illumination of laser, the lateral resistance of the structure can be modulated in a non-volatile manner. We attribute this phenomenon to the different width of depletion region and the Schottky barrier change caused by the nanoscale charge trapping effect. This work may inspire a new approach of resistance modulation and help the development of laser-assisted electric pulse merged devices.


Expression analysis of Cell wall invertase under abiotic stress conditions influencing specialized metabolism in Catharanthus roseus.
Catharanthus roseus is a commercial source for anti-cancer terpenoid indole alkaloids (TIAs: vincristine and vinblastine). Inherent levels of these TIAs are very low, hence research studies need to focus on enhancing their levels in planta. Since primary metabolism provides precursors for specialized-metabolism, elevating the former can achieve higher amounts of the latter. Cell Wall Invertase (CWIN), a key enzyme in sucrose-metabolism catalyses the breakdown of sucrose into glucose and fructose, which serve as carbon-skeleton for specialized-metabolites. Understanding CWIN regulation could unravel metabolic-engineering approaches towards enhancing the levels of TIAs in planta. Our study is the first to characterize CWIN at gene-expression level in the medicinal plant, C. roseus. The CWINs and their inter-relationship with sucrose and TIA metabolism was studied at gene and metabolite levels. It was found that sucrose-supplementation to C. roseus leaves significantly elevated the monomeric TIAs (vindoline, catharanthine) and their corresponding genes. This was further confirmed in cross-species, wherein Nicotiana benthamiana leaves transiently-overexpressing CrCWIN2 showed significant upregulation of specialized-metabolism genes: NbPAL2, Nb4CL, NbCHS, NbF3H, NbANS, NbHCT and NbG10H. The specialized metabolites- cinnamic acid, coumarin, and fisetin were significantly upregulated. Thus, the present study provides a valuable insight into metabolic-engineering approaches towards augmenting the levels of therapeutic TIAs.


[Glycosuria with SGLT-2 inhibitors--a new treatment approach for type 2 diabetes mellitus].
A new mechanism of action in the form of sodium-glucose co-transporter-(SGLT-)2 inhibitors will be available shortly for the treatment of type 2 diabetic patients. Overview. Fasting and postprandial blood glucose and HbA(1c) concentrations are indirectly reduced by the inhibition of glucose reabsorption and increased glycosuria. SGLT-2 inhibitors also have a positive impact on body weight and blood pressure of type 2 diabetics. In the available registration trials conducted to date, the SGLT-2 inhibitors appeared overall as a safe class of drugs. The clinical importance of an increased incidence of genital infections--in particular in special patientpopulations--requires further clarification. Long-term trials are currently underway to verify safety and in particular cardiovascular effects of this drug class.


Ubiquitination of G protein-coupled receptors: functional implications and drug discovery.
G protein-coupled receptors (GPCRs) comprise the largest and most diverse family of signaling receptors and control a vast array of physiological responses. Modulating the signaling responses of GPCRs therapeutically is important for the treatment of various diseases, and discovering new aspects of GPCR signal regulation is critical for future drug development. Post-translational modifications are integral to the regulation of GPCR function. In addition to phosphorylation, many GPCRs are reversibly modified with ubiquitin. Ubiquitin is covalently attached to lysine residues within the cytoplasmic domains of GPCRs by ubiquitin ligases and removed by ubiquitin-specific proteases. In many cases, ubiquitin functions as a sorting signal that facilitates trafficking of mammalian GPCRs from endosomes to lysosomes for degradation, but not all GPCRs use this pathway. Moreover, there are distinct types of ubiquitin conjugations that are known to serve diverse functions in controlling a wide range of cellular processes, suggesting broad roles for GPCR ubiquitination. In this review, we highlight recent studies that illustrate various roles for ubiquitin in regulation of GPCR function. Ubiquitination is known to target many GPCRs for lysosomal degradation, and current studies now indicate that basal ubiquitination, deubiquitination, and transubiquitination of certain GPCRs are important for controlling cell surface expression and cellular responsiveness. In addition, novel functions for ubiquitin in regulation of GPCR dimers and in mediating differential GPCR regulation induced by biased agonists have been reported. We will discuss the implications of these new discoveries for ubiquitin regulation of GPCR function in the context of drug development.


Traumatic Axonal Injury: A Case Report.
A 17-year-old prisoner was found unconscious during a morning check. The previous night, he had been struck on the chin multiple times by one of the other inmates. The patient remained unconscious and eventually died after nearly 1.5 months of care. The primary task of the forensic pathological examination was to investigate the events leading to his death; therefore, it was necessary to examine whether there was a connection between the abuse and eventual death. In our case, the key element was the repetitive, mild-to-moderate force in abuse, resulting in grade I traumatic diffuse axonal damage. Due to progressive brain edema, aspiration subsequently developed, which eventually resulted in irreversible hypoxic damage of the brain.


miRNA-183 suppresses apoptosis and promotes proliferation in esophageal cancer by targeting PDCD4.
In our previous study, miRNA-183, a miRNA in the miR-96-182-183 cluster, was significantly over-expressed in esophageal squamous cell carcinoma (ESCC). In the present study, we explored the oncogenic roles of miR-183 in ESCC by gain and loss of function analysis in an esophageal cancer cell line (EC9706). Genome-wide mRNA microarray was applied to determine the genes that were regulated directly or indirectly by miR-183. 3'UTR luciferase reporter assay, RT-PCR, and Western blot were conducted to verify the target gene of miR-183. Cell culture results showed that miR-183 inhibited apoptosis (p < 0.05), enhanced cell proliferation (p < 0.05), and accelerated G1/S transition (p < 0.05). Moreover, the inhibitory effect of miR-183 on apoptosis was rescued when miR-183 was suppressed via miR-183 inhibitor (p < 0.05). Western blot analysis showed that the expression of programmed cell death 4 (PDCD4), which was predicted as the target gene of miR-183 by microarray profiling and bioinformatics predictions, decreased when miR-183 was over-expressed. The 3'UTR luciferase reporter assay confirmed that miR-183 directly regulated PDCD4 by binding to sequences in the 3'UTR of PDCD4. Pearson correlation analysis further confirmed the significant negative correlation between miR-183 and PDCD4 in both cell lines and in ESCC patients. Our data suggest that miR-183 might play an oncogenic role in ESCC by regulating PDCD4 expression.


Adipose-Derived Mesenchymal Stem Cells for Treatment of Airway Injuries in A Patient after Long-Term Exposure to Sulfur Mustard.
Sulfur mustard (SM) is a potent mutagenic agent that targets several organs, particularly lung tissue. Changes in morphological structure of the airway system are associated with chronic obstructive pulmonary deficiency following exposure to SM. Although numerous studies have demonstrated pathological effects of SM on respiratory organs, unfortunately there is no effective treatment to inhibit further respiratory injuries or induce repair in these patients. Due to the extensive progress and achievements in stem cell therapy, we have aimed to evaluate safety and potential efficacy of systemic mesenchymal stem cell (MSC) administration on a SM-exposed patient with chronic lung injuries. In this clinical trial study, our patient received 100×106cells every 20 days for 4 injections over a 2-month period. After each injection we evaluated the safety, pulmonary function tests (PFT), chronic obstructive pulmonary disease (COPD) Assessment Test (CAT), St. George's Respiratory Questionnaire (SGRQ), Borg Scale Dyspnea Assessment (BSDA), and 6 Minute Walk Test (6MWT). One-way ANOVA test was used in this study which was not significant (P>0.05). There were no infusion toxicities or serious adverse events caused by MSC administration. Although there was no significant difference in PFTs, we found a significant improvement for 6MWT, as well as BSDA, SGRQ, and CAT scores after each injection. Systemic MSC administration appears to be safe in SM-exposed patients with moderate to severe injuries and provides a basis for subsequent cell therapy investigations in other patients with this disorder (Registration Number: IRCT2015110524890N1).


Profile of mood states changes during and after 5 weeks of nightly triazolam administration.
This double-blind, placebo-controlled study investigated rebound anxiety during and after 5 weeks of nightly use of triazolam 0.5 mg, a short half-life, rapidly absorbed benzodiazepine hypnotic. The study subjects were chronic insomniacs with moderate levels of psychopathology and prior use of hypnotics. Anxiety was assessed with the Profile of Mood States (POMS), instead of the anxiety scales more typically used in psychopharmacology: the Hamilton Rating Scale for Anxiety and a visual analogue scale. The POMS test was administered twice a day during the study. The results indicated that triazolam was not associated with increased anxiety the morning or the evening after previous-night drug administration. The results are discussed in view of the methodological issues in assessing anxiety in prior studies.


Rotenone Attenuates Renal Injury in Aldosterone-Infused Rats by Inhibiting Oxidative Stress, Mitochondrial Dysfunction, and Inflammasome Activation.
Reactive oxygen species (ROS) and inflammation both contribute to the progression of aldosterone-induced renal injury. To better understand the underlying mechanisms, we examined mitochondrial dysfunction and NLRP3 inflammasome activation in aldosterone-infused rats, and explored the role of rotenone in attenuating these injuries. Sprague-Dawley rats were divided into 3 groups: vehicle-treated, aldosterone-infused, and aldosterone plus rotenone. Renal damage was evaluated using PAS staining and electron microscopy. Levels of ROS were measured from renal tissue and serum; immunohistochemistry analysis examined the inflammation pathway; Western blot and real-time PCR assessed NLRP3 inflammasome activity. Glomerular segmental sclerosis, foot process effacement, and proteinuria were demonstrated in the aldosterone-infused rats. Specifically, the thiobarbituric acid-reactive substances (TBARS) oxidative stress marker, MDA, was significantly increased; ATP content and mtDNA copy number were markedly decreased; inflammatory mediators NF-κB p65 and CTGF were upregulated; and NLRP3 inflammasome and its related target proteins, IL-1β and IL-18, were also increased. Treatment with rotenone, an inhibitor of mitochondrial complex I, significantly attenuated oxidative stress, mitochondrial dysfunction, and inflammasome response in aldosterone-infused rats. Rotenone ameliorated aldosterone-infused renal injury, possibly by inhibiting oxidative stress, mitochondrial dysfunction, and NLRP3 inflammasome activity. These results provide novel evidence for the role of rotenone in aldosterone-induced renal injury or other chronic kidney disease.


A case of mosaic deletion of paternally-inherited PLAGL1 and two cases of upd(6)mat add to evidence for PLAGL1 under-expression as a cause of growth restriction.
PLAGL1 is one of a group of imprinted genes, whose altered expression causes imprinting disorders impacting growth, development, metabolism, and behavior. PLAGL1 over-expression causes transient neonatal diabetes mellitus (TNDM type 1) and, based on murine models, under-expression would be expected to cause growth restriction. However, only some reported individuals with upd(6)mat have growth restriction, giving rise to uncertainty about the role of PLAGL1 in human growth. Here we report three individuals investigated for growth restriction, two with upd(6)mat and one with a mosaic deletion of the paternally-inherited allele of PLAGL1. These cases add to evidence of its involvement in pre- and early post-natal human growth.


Silver-catalyzed C(sp2)-H functionalization/C-O cyclization reaction at room temperature.
Silver-catalyzed C(sp(2))-H functionalization/C-O cyclization has been developed. The scalable reaction proceeds at room temperature in an open flask. The present method exhibits good functional-group compatibility because of the mild reaction conditions. Using a AgNO3 catalyst and a (NH4)2S2O8 oxidant in CH2Cl2/H2O solvent, various lactones are obtained in good to excellent yields. A kinetic isotope effect (KIE) study indicates that the reaction may occur via a radical process.


Inhibitors of immune checkpoints-PD-1, PD-L1, CTLA-4-new opportunities for cancer patients and a new challenge for internists and general practitioners.
The treatment of cancer patients with immune checkpoint inhibitors (ICI) (anti-CTLA-4, anti-PD-1, anti-PD-L1, combined therapy anti-PD-1/PD-L1 with anti-CTLA-4) has without doubt been a significant breakthrough in the field of oncology in recent years and constitutes a major step forward as a novel type of immunotherapy in the treatment of cancer. ICIs have contributed to a significant improvement in the outcome of treatment and prognosis of patients with different types of malignancy. With the expansion of the use of ICIs, it is expected that caregivers will face new challenges, namely, they will have to manage the adverse side effects associated with the use of these drugs. New treatment options pose new challenges not only for oncologists but also for specialists in other clinical fields, including general practitioners (GPs). They also endorse the need for taking a holistic approach to the patient, which is a principle widely recognized in oncology and especially relevant in the case of the expanding use of ICIs, which may give rise to a wide variety of organ complications resulting from treatment. Knowledge and awareness of the spectrum of immune-related adverse events (irAEs) will allow doctors to qualify patients for treatment more appropriately, prevent complications, correctly recognize, and ultimately treat them. Additionally, patients with more non-specific symptoms would be expected, in the first instance, to consult their general practitioners, as complications may appear even after the termination of treatment and do not always proceed in line with disease progression. Dealing with any iatrogenic complications, will not only be the remit of oncologists but because of the likelihood that specific organs may be affected, is likely to extend also to specialists in various fields of internal medicine. These specialists, e.g., endocrinologists, dermatologists, pulmonologists, and gastroenterologists, are likely to receive referrals for patients suffering from specific types of adverse events or will be asked to provide care in cases requiring hospitalization of patients with complications in their field of expertise. In view of these considerations, we believe that there is an urgent need for multidisciplinary teamwork in the treatment of cancer patients undergoing immunotherapy and suffering the consequent adverse reactions to treatment.


Plasmid pLXSN-Mediated Adrenomedullin Gene Therapy for Cerebral Vasospasm Following Subarachnoid Hemorrhage in Rats.
BACKGROUND The aim of this study was to investigate the protective effect of ADM gene mediated by plasmid pVAX1 on cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH). MATERIAL AND METHODS The recombinant plasmid pVAX-ADM was successfully established, and 40 SD rats were randomly divided into normal saline, pVAX1, pVAX1-ADM low-dose, pVAX1-ADM mid-dose, and pVAX1-ADM high-dose groups. The circumference and diameter of basilar artery, diameter of middle cerebral artery and internal carotid artery, and thickness of basilar artery wall were observed. The levels of circulating endothelial cells (CEC) and levels of regional cerebral blood flow (rCBF) of the parietal cortex were detected at different time-points. The expression levels of serum ADM, ET-1, and NOS of each group and the neurological functions were compared. RESULTS The circumference and diameter of basilar artery and the diameter of the middle cerebral artery and internal carotid artery in pVAX1-ADM groups were significantly longer than those in the saline group and pVAX1 group (P<0.05), but the thickness of the basilar artery wall in pVAX1-ADM groups was significantly lower (P<0.05), and the levels of growth or decrease were both dose-dependent (P<0.05). Compared with the saline group and pVAX1 group, the expression levels of serum ADM, NOS, and rCBF in pVAX1-ADM groups were significantly higher (P<0.05), but the levels of serum ET-1 and CEC were significantly lower (P<0.05). The scores of neurobehavioral functions of pVAX1-ADM groups were significantly lower (P<0.05), and the scores were also dose-dependent (P<0.05). CONCLUSIONS The recombinant eukaryotic expression plasmid pVAX1-ADM can significantly relieve cerebral vasospasm, increase the expression of serum ADM and NOS, and decrease the expression of serum ET-1 in a rat model of CVS; it is dose-dependent and can also improve nervous system function.


Important molecular genetic markers of colorectal cancer.
Colorectal cancer (CRC) ranks third in the incidences of cancer morbidity and mortality worldwide. CRC is rather heterogeneous with regard to molecular genetic characteristics and pathogenic pathways. A wide spectrum of biomarkers is used for molecular subtype determination, prognosis, and estimation of sensitivity to different drugs in practice. These biomarkers can include germline and somatic mutations, chromosomal aberrations, genomic abnormalities, gene expression alterations at mRNA or protein level and changes in DNA methylation status. In the present review we discuss the most important and well-studied CRC biomarkers, and their potential clinical significance and current approaches to molecular classification of colorectal tumors.


Rhox13 is required for a quantitatively normal first wave of spermatogenesis in mice.
We previously described a novel germ cell-specific X-linked reproductive homeobox gene (Rhox13) that is upregulated at the level of translation in response to retinoic acid (RA) in differentiating spermatogonia and preleptotene spermatocytes. We hypothesize that RHOX13 plays an essential role in male germ cell differentiation, and have tested this by creating a Rhox13 gene knockout (KO) mouse. Rhox13 KO mice are born in expected Mendelian ratios, and adults have slightly reduced testis weights, yet a full complement of spermatogenic cell types. Young KO mice (at ~7-8 weeks of age) have a ≈50% reduction in epididymal sperm counts, but numbers increased to WT levels as the mice reach ~17 weeks of age. Histological analysis of testes from juvenile KO mice reveals a number of defects during the first wave of spermatogenesis. These include increased apoptosis, delayed appearance of round spermatids and disruption of the precise stage-specific association of germ cells within the seminiferous tubules. Breeding studies reveal that both young and aged KO males produce normal-sized litters. Taken together, our results indicate that RHOX13 is not essential for mouse fertility in a controlled laboratory setting, but that it is required for optimal development of differentiating germ cells and progression of the first wave of spermatogenesis.


Transmission of herpes simplex virus type 1 infection in rugby players.
Skin infections, both bacterial and viral, are endemic in contact sports such as wrestling and rugby football. In this report, we describe four cases of extensive cutaneous herpes simplex virus in players on a rugby team. All players had a prodrome of fever, malaise, and anorexia with a weight loss of 3.6 to 9.0 kg. Two players experienced ocular lesions associated with cutaneous vesicular lesions of the face. A third player, who had herpetic lesions on his lower extremity, experienced paresthesias, weakness, and intermittent urinary retention and constipation. All infected players on the team were forwards or members of the "scrum," which suggests a field-acquired infection analogous to the herpetic infections seen in wrestlers (herpes gladiatorum). Considering the serious sequelae of recurrent herpes simplex keratitis, the traumatic skin lesions in rugby football players should be cultured for herpes virus, and infected individuals should be restricted from playing until crusted lesions have disappeared.


A new series of antiallergic agents. I. Synthesis and activity of 11-(2-aminoethyl)thio-6,11-dihydrodibenz[b,e]oxepin derivatives.
A new series of 11-substituted 6,11-dihydrodibenz[b,e]oxepin derivatives was synthesized and evaluated for antiallergic activity. Convenient methods for the preparation of sulfides from alcohols were developed. Structure-activity relationships are described. Compound 7, 11-[2-(dimethylamin)ethyl]thio-6,11-dihydrodibenz[b,e] oxepin-2-carboxylic acid hydrochloride, was the most potent in the rat passive cutaneous anaphylaxis test (ED50 = 0.92 mg/kg p.o.). It had a potent inhibitory effect on anaphylactic bronchoconstriction in guinea pigs (ED50 = 0.029 mg/kg p.o.) and H1 receptor antagonistic effect (Ki = 14 nM) with few central nervous system side effects. Additionally, an antagonistic effect against prostaglandin D2-induced contraction of isolated guinea pig trachea (pA2 = 5.73) was an attractive mechanism of action of the new antiallergic agent. Compound 7 was selected for further evaluation as KW-4994.


The molecular mechanism for nuclear transport and its application.
Transportation between the cytoplasm and the nucleoplasm is critical for many physiological and pathophysiological processes including gene expression, signal transduction, and oncogenesis. So, the molecular mechanism for the transportation needs to be studied not only to understand cell physiological processes but also to develop new diagnostic and therapeutic targets. Recent progress in the research of the nuclear transportation (import and export) via nuclear pore complex and four important factors affecting nuclear transport (nucleoporins, Ran, karyopherins, and nuclear localization signals/nuclear export signals) will be discussed. Moreover, the clinical significance of nuclear transport and its application will be reviewed. This review will provide some critical insight for the molecular design of therapeutics which need to be targeted inside the nucleus.


Gastric cancer with brain metastasis and the role of human epidermal growth factor 2 status.
Central nervous system (CNS) metastases from cancers of the gastrointestinal tract (GIT) are rare, and occur in 0.16-0.69% of patients with gastric or gastro-esophageal (GE) junction cancer. Overexpression of the human epidermal growth factor 2 (HER-2) is associated with poor prognosis in the absence of HER-2-targeted therapy, and with an increased incidence of CNS metastases in patients with breast cancer. The role of HER-2 overexpression in CNS metastases is not well known in gastric adenocarcinoma. The purpose of the present retrospective study was to assess the incidence of CNS metastases and to evaluate the associations between the CNS and HER-2 status in a series of consecutive patients with gastric or GE junction cancer. Between 2007 and 2013, 300 patients with gastric cancer (GC) or gastroesophageal junction, were admitted to Piacenza General Hospital, Italy. These cases were retrospectively analyzed to evaluate CNS metastases. The metastases were diagnosed with imaging techniques performed on symptomatic patients. Gastric histological samples of patients with CNS metastases were reviewed and tested for HER-2. A total of 7 of the 300 patients (2.33%) with GC were observed to have CNS metastases and 6 (85.71%) had HER-2 positive disease. These patients exhibited a poor prognosis with a median overall survival rate of 4.1 months (range, 2.1-6.6 months). These results suggested there may be CNS recurrence susceptibility in patients with HER-2 positive GC. To the best of our knowledge, this is the first report that associates CNS metastases and HER-2 status in gastric or GE junction cancer.


Examination of increased annual range of a Tana mangabey (Cercocebus galeritus) group.
A group of Tana mangabeys (Cercocebus galeritus) has greatly expanded its annual range over three decades: from 17.25 hectares (ha) in 1974 (Homewood [1976] Ph.D. dissertation, University College London) and 18.75 ha in 1988-1989 (Kinnaird [1990a] Ph.D. dissertation, University of Florida) to 46.75 ha in 2000-2001. Utilizing 5-min mapping samples, phenological samples, vegetation data, and statistical and descriptive comparisons with previous data, three hypotheses concerning this range increase were postulated. The hypothesis with the strongest support is an increase in intragroup feeding competition, which was measured by a decrease in fruit availability per hectare and an increase in group size. Fruit biomass estimates of four species individually and of eight species combined showed significant decreases between earlier findings (Kinnaird [1990] Ph.D. dissertation, University of Florida) and this study. Group size decreased from 36 in 1974 to 17 in 1988-1989, and is now 50 individuals. There is no support for the hypotheses that the group is no longer constrained in home range size by neighboring groups or by the extent of forest cover. The changes in group and home range size are also discussed in the context of historical forest loss in the lower Tana River. The ability of the Tana mangabey to increase its home range, especially by traveling through nonforest habitat, is an important aspect of its ecological flexibility in a fragmented and threatened habitat.


Increased plasma olfactomedin 2 after interventional therapy is a predictor for restenosis in lower extremity arteriosclerosis obliterans patients.
Animal studies have indicated that olfactomedin 2 (OLFM2) is involved in the process of vascular remolding. The aim of the present study was to investigate circulating OLFM2 levels in lower extremity arteriosclerosis obliterans (LEASO) patients and the association of OLFM2 with postoperative restenosis in patients. A total of 203 LEASO patients were enrolled in the present study. Plasma OLFM2 was measured before and 6 h after interventional therapy. After 6 months, patients were divided into a restenosis group and a non-restenosis group. Inter-group and intra-group differences in plasma OLFM2 were compared. The correlation between plasma OLFM2 and the severity of restenosis was analyzed by Spearman's correlation analysis. An receiver operating characteristic (ROC) curve was used to evaluate the predictive efficacy of plasma OLFM2 on restenosis. Logistic regression was used to determine the risk factors for restenosis. Postoperative OLFM2 in the restenosis group was significantly higher compared with the non-restenosis group (34.07 ± 5.76 ng/mL vs. 19.53 ± 2.99 ng/mL). No significant difference in preoperative plasma OLFM2 levels was identified between the two groups (10.92 ± 2.49 ng/mL vs. 11.54 ± 3.18 ng/mL). Postoperative OLFM2 levels were positively correlated with the severity of restenosis (r = 0.728, p < .001). The area under the ROC curve was 0.902 (95% confidence interval (CI): 0.874-0.965), with a cutoff value of 26.91 ng/mL (95% CI: 26.16-28.32). Plasma OLFM2 was an independent risk factor for restenosis. Our results suggest that plasma OLFM2 is a potential biomarker for restenosis and may be a novel target for the treatment of restenosis.