The relationship between bifidobacteria and allergic asthma and/or allergic dermatitis: a prospective study of 0-3 years-old children in Turkey.
Bifidobacteria are beneficial bacteria for humans. These bacteria are particularly effective at protecting against infectious diseases and modulating the immune response. It was shown that in newborns, the fecal distribution of the colonizing Bifidobacterium species influences the prevalence of allergic diseases. This study aimed to compare the faecal Bifidobacterium species of allergic children to those of healthy children to detect species level differences in faecal distribution. Stool samples were obtained from 99 children between 0 and 3 years of age whose clinical symptoms and laboratory reports were compatible with atopic dermatitis and allergic asthma. Samples were also obtained from 102 healthy children who were similar to the case group with respect to age and sex. Bifidobacteria were isolated by culture and identified at the genus level by API 20 A. In addition, 7 unique species-specific primers were used for the molecular characterization of bifidobacteria. The McNemar test was used for statistical analyses, and p < 0.05 was accepted as significant. Bifidobacterium longum was detected in 11 (11.1%) of the allergic children and in 31 (30.3%) of the healthy children. Statistical analysis revealed a significant difference in the prevalence of B. longum between these two groups (X(2): 11.2, p < 0.001). However, no significant differences in the prevalence of other Bifidobacterium species were found between faecal samples from healthy and allergic children. (p > 0.05). The significant difference in the isolation of B. longum from our study groups suggests that this species favors the host by preventing the development of asthma and allergic dermatitis. Based on these results, we propose that the production of probiotics in accordance with country-specific Bifidobacterium species densities would improve public health. Thus, country-specific prospective case-control studies that collect broad data sets are needed.


Stress as a challenge in promoting mental health among dementia caregivers.
Caregiver stress is harmful to the health of both caregivers and people living with Alzheimer's disease or other dementias. The present study was conducted to assess stress and its predictors of people living with Alzheimer's disease or other dementias' caregivers. The present descriptive, analytical, cross-sectional study was conducted in December 2017-June 2018 in Isfahan, Iran. Data were collected by interviewing 99 caregivers had at least 6 months of experience caring for a patient diagnosed with Alzheimer's disease, through questionnaires developed by the researcher. A convenience sample (easy access) of caregivers was recruited from calling the home of formally diagnosed with Alzheimer's patient, that have registered in educational hospitals affiliated to Isfahan University of Medical Sciences and psychiatrists' office both paid caregivers (formal) and unpaid caregivers (family). All caregivers provided informed consent. The type and severity of the relationship between the dependent (stress) and independent variable were assessed using Pearson's and Spearman's correlation coefficients, the independent t-test, and the multivariate regression analysis. The caregivers' mean stress score was 25.4 ± 10.9 (range: 4-54). About 80% of the caregivers were female. Age and stress score was correlated (P = 0.004), the mean stress score was significantly higher in female caregivers (P = 0.04), informal caregivers (P < 0.001), and significantly lower in the caregivers with previous experience of caring for Alzheimer's patients (P = 0.02) or those introduced by service companies (P = 0.005). Variables including the family relationship with the patient (P = 0.01), kind of caregiving (P = 0.03), and previous experience of caring for Alzheimer's patients (P = 0.04) were stronger predictors of the stress score. Stress is a challenge in promoting mental health among dementia caregivers. Providing social support with an emphasis on physical, mental, and social health is mandatory, especially for female and family caregivers, to promote stress management, mental health in this group, and enable optimal and purposeful care.


Visualization of lymphotoxin-beta and lymphotoxin-beta receptor expression in mouse embryos.
The heteromeric lymphotoxin alphabeta ligand (LT) binds to the LTbeta receptor (LTbetaR) and provides an essential trigger for lymph node (LN) development. LTbetaR signaling is also critical for the emergence of pathological ectopic lymph node-like structures and the maintenance of an organized splenic white pulp. To better understand the role of LT in development, the expression patterns of LTbeta and LTbetaR mRNA were examined by in situ hybridization in the developing mouse embryo. Images of LTbeta ligand expression in developing peripheral LN in the E18.5 embryo revealed a relatively early phase structure and allowed for comparative staging with LN development in rat and humans. The LTbetaR is expressed from E16.5 onward in respiratory, salivary, bronchial, and gastric epithelium, which may be consistent with early communication events between lymphoid elements and epithelial specialization over emerging mucosal LN. Direct comparison of mouse fetal and adult tissues by FACS analysis confirmed the elevated expression of LTBR in some embryonic epithelial layers. Therefore, surface LTBR expression may be elevated during fetal development in some epithelial layers.


Index Finger Flexor Digitorum Profundus Function Deficit after Shoulder Arthroscopy Treated by Neurolysis: A Case Report.
A 60-year-old woman presented functional deficit of the index finger flexor digitorum profundus (FDP) tendon after shoulder arthroscopic rotator cuff repair. As no recovery was observed for 10 months, we conducted an operative exploration of the median nerve and the anterior interosseous nerve, followed by an external neurolysis. The patient recovered FDP function 4.5 months after the second operation. In a patient with persistent isolated FDP dysfunction after shoulder arthroscopy, operative exploration and external neurolysis could facilitate functional recovery. Level of Evidence: Level V (Therapeutic).


Sensorial suppression of self-generated sounds and its dependence on attention.
The auditory processing of self-generated sounds is characterized by an attenuated vertex N1-component of the event-related potential (ERP) compared to the responses elicited by externally generated sounds. Typically, a motor condition where sounds are actively produced by button presses is compared with a passive listening condition. While this effect is usually interpreted as reflection of an internal forward model system, the impact of attention and arousal on the so called self-generation effect has not been systematically controlled in these studies: Is the auditory stimulation more attended during the active task compared to passive listening, e.g., caused by a higher arousal level? Or is it rather attended less and attention is drawn away from the task-irrelevant stimulation to the motor task? Accordingly, the self-generation effects reported in the literature can easily be over- or underestimated. In the present study we disentangled attention from the self-generation effect by introducing an active listening condition, in which attention is focused to the same feature as in the self-generation condition - the stimulus onset-to-onset interval. We observed a classical 'self-generation effect', i.e. attenuated amplitudes for self-generated compared to passive listened sounds at frontocentral electrodes. As expected this effect was overlapped by attention effects in space and time. However, topographical and tomographical analyses allowed us to clearly disentangle both effects. Our results argue for the existence of a genuine self-generation effect, but emphasize the problem of possible over- or underestimation caused by attentional confounds.


Inhibition of neovascularization but not fibrosis with the fluocinolone acetonide implant in autosomal dominant neovascular inflammatory vitreoretinopathy.
OBJECTIVE To review the effect of the fluocinolone acetonide implant in subjects with autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV), an inherited autoimmune uveitis. METHODS A retrospective case series was assembled from patients with ADNIV who received fluocinolone acetonide implants. Visual acuity and features of ADNIV, including inflammatory cells, neovascularization, fibrosis, and cystoid macular edema, were reviewed. RESULTS Nine eyes of 5 related patients with ADNIV with uncontrolled inflammation were reviewed. Follow-up ranged from 21.7 to 56.7 months. Visual acuity at implantation ranged from 20/40 to hand motion. Preoperatively, 8 eyes had vitreous cells (a ninth had diffuse vitreous hemorrhage). Eight eyes had cystoid macular edema, 7 had an epiretinal membrane, and 3 had retinal neovascularization. Following implantation, vitreous cells resolved in all eyes and neovascularization regressed or failed to develop. Central macular thickness improved in 4 eyes. During the postoperative course, however, visual acuity continued to deteriorate, with visual acuity at the most recent examination ranging from 20/60 to no light perception. There was also progressive intraocular fibrosis and phthisis in 1 case. Four eyes underwent cataract surgery. Six of the 7 eyes without previous glaucoma surgery had elevated intraocular pressure at some point, and 3 of these required glaucoma surgery. CONCLUSIONS The fluocinolone acetonide implant may inhibit specific features of ADNIV such as inflammatory cells and neovascularization but does not stabilize long-term vision, retinal thickening, or fibrosis. All eyes in this series required cataract extraction, and more than half required surgical intervention for glaucoma. Further studies may identify additional therapies and any benefit of earlier implantation.


Sequence dependency of canonical base pair opening in the DNA double helix.
The flipping-out of a DNA base from the double helical structure is a key step of many cellular processes, such as DNA replication, modification and repair. Base pair opening is the first step of base flipping and the exact mechanism is still not well understood. We investigate sequence effects on base pair opening using extensive classical molecular dynamics simulations targeting the opening of 11 different canonical base pairs in two DNA sequences. Two popular biomolecular force fields are applied. To enhance sampling and calculate free energies, we bias the simulation along a simple distance coordinate using a newly developed adaptive sampling algorithm. The simulation is guided back and forth along the coordinate, allowing for multiple opening pathways. We compare the calculated free energies with those from an NMR study and check assumptions of the model used for interpreting the NMR data. Our results further show that the neighboring sequence is an important factor for the opening free energy, but also indicates that other sequence effects may play a role. All base pairs are observed to have a propensity for opening toward the major groove. The preferred opening base is cytosine for GC base pairs, while for AT there is sequence dependent competition between the two bases. For AT opening, we identify two non-canonical base pair interactions contributing to a local minimum in the free energy profile. For both AT and CG we observe long-lived interactions with water and with sodium ions at specific sites on the open base pair.


The Role of Oxidative Stress, Inflammation, and Advanced Glycation End Product in Skin Manifestations of Diabetes Mellitus.
Diabetes mellitus is a metabolic disorder caused by an increase in insulin resistance, a decrease in insulin production, or both of them, resulting in a high level of blood glucose or hyperglycemia. An uncontrolled state of DM may cause complications, namely skin disorder. One or more skin disorders are found amongst 74% of T2DM patients, with the highest percentage is dry skin (47%), followed by infection (10%), diabetic hand (5%), hair loss and diabetic dermopathy (each 4%). In DM, the state of hyperglycemia and production of advanced glycaemic end-products (AGEs) profoundly impact skin changes. In the pathological pathway, AGEs induce oxidative stress and inflammation. Nonetheless, AGEs level is higher in T2DM patients compared to non- T2DM people. This is caused by hyperglycemia and oxidative stress. Binding between AGEs and receptor of AGEs (RAGE) promotes pathway of oxidative stress and inflammation cascade via mitogen- activated protein kinases (MAPK), nuclear factor-k-light-chain-enhancer of activated β cells (NF-kβ), interleukin- 6 (IL-6), tumor necrosis factor-α (TNF-α), expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 2 (VCAM-2) pathway which furtherly effectuates DM complication including skin disorders.


Nonparallelism in MHCIIβ diversity accompanies nonparallelism in pathogen infection of lake whitefish (Coregonus clupeaformis) species pairs as revealed by next-generation sequencing.
Major histocompatibility (MHC) immune system genes may evolve in response to pathogens in the environment. Because they also may affect mate choice, they are candidates for having great importance in ecological speciation. Here, we use next-generation sequencing to test the general hypothesis of parallelism in patterns of MHCIIβ diversity and bacterial infections among five dwarf and normal whitefish sympatric pairs. A second objective was to assess the functional relationships between specific MHCIIβ alleles and pathogens in natural conditions. Each individual had between one and four alleles, indicating two paralogous loci. In Cliff Lake, the dwarf ecotype was monomorphic for the most common allele. In Webster Lake, the skew in the allelic distribution was towards the same allele but in the normal ecotype, underscoring the nonparallel divergence among lakes. Our signal of balancing selection matched putative peptide binding region residues in some cases, but not in others, supporting other recent findings of substantial functional differences in fish MHCIIβ compared with mammals. Individuals with fewer alleles were less likely to be infected; thus, we found no evidence for the heterozygote advantage hypothesis. MHCIIβ alleles and pathogenic bacteria formed distinct clusters in multivariate analyses, and clusters of certain alleles were associated with clusters of pathogens, or sometimes the absence of pathogens, indicating functional relationships at the individual level. Given that patterns of MHCIIβ and bacteria were nonparallel among dwarf and normal whitefish pairs, we conclude that pathogens driving MHCIIβ evolution did not play a direct role in their parallel phenotypic evolution.


Evaluation of the Widal tube agglutination test for the diagnosis of typhoid fever among children admitted to a rural hdospital in Tanzania and a comparison with previous studies.
The diagnosis of typhoid fever is confirmed by culture of Salmonella enterica serotype Typhi (S. typhi). However, a more rapid, simpler, and cheaper diagnostic method would be very useful especially in developing countries. The Widal test is widely used in Africa but little information exists about its reliability. We assessed the performance of the Widal tube agglutination test among febrile hospitalized Tanzanian children. We calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of various anti-TH and -TO titers using culture-confirmed typhoid fever cases as the "true positives" and all other febrile children with blood culture negative for S. typhi as the "true negatives." We found that 16 (1%) of 1,680 children had culture-proven typhoid fever. A single anti-TH titer of 1:80 and higher was the optimal indicator of typhoid fever. This had a sensitivity of 75%, specificity of 98%, NPV of 100%, but PPV was only 26%. We compared our main findings with those from previous studies. Among febrile hospitalized Tanzanian children with a low prevalence of typhoid fever, a Widal titer of > or = 1:80 performed well in terms of sensitivity, specificity, and NPV. However a test with improved PPV that is similarly easy to apply and cost-efficient is desirable.


Retraction: Oral leukoplakia, a clinical-histopathological study in 412 patients.
The authors detected some minor errors in the published manuscript (Rubert A, Bagán L, Bagán JV. Oral leukoplakia, a clinical-histopathological study in 412 patients. J Clin Exp Dent. 2020 Jun 1;12(6):e540-e546. doi: 10.4317/jced.57091. PMID: 32665812; PMCID: PMC7335600.) and have requested that the entire article be republished with these errors already rectified. A retrospective clinical-histopathological study was made of the evolution of oral leukoplakia over time, staging the disease according to the classification of van der Waal. A study was made of 412 patients with oral leukoplakia, analyzing the corresponding clinical factors and histopathological findings; assessing associations between the different clinical presentations and epithelial dysplasia; and evaluating the factors influencing malignant transformation of the lesions. Clinically, homogeneous presentations were seen to predominate (n = 336, 81.6%), while histologically most of the lesions exhibited no dysplastic changes (n = 271; 65.7%). Stage 1 of the van der Waal classification was the most common presentation (n = 214; 51.9%). The lesion malignization rate was 8.5%, and the factors associated to a significantly increased malignization risk were non-homogeneous OL lesions (p=0.00), lesion location in the tongue (p=0.00), and the presence of epithelial dysplasia (p=0.00). In our series of patients with oral leukoplakia, malignization was associated to the less common clinical presentations of the disease, i.e., non-homogeneous lesions, and the latter tended to exhibit high grade epithelial dysplasia. Key words:Oral leukoplakia, potentially malignant disorders, malignant transformation.


The association between the extent of lipidic burden and delta-fractional flow reserve: analysis from coronary physiological and near-infrared spectroscopic measures.
Vulnerable plaque features including lipidic plaque have been shown to affect fractional flow reserve (FFR). Given that formation and propagation of lipid plaque is accompanied by endothelial dysfunction which impairs vascular tone, the degree of lipidic burden may affect vasoreactivity during hyperemia, potentially leading to reduced FFR. Our aim is to elucidate the relationship of the extent of lipidic plaque burden with coronary physiological vasoreactivity measure. We analyzed 89 subjects requeuing PCI due to angiographically intermediate coronary stenosis with FFR ≤0.80. Near-infrared spectroscopy (NIRS) and intravascular ultrasound were used to evaluate lipid-core burden index (LCBI) and atheroma volume at both target lesion (maxLCBI4mm; maximum value of LCBI within any 4 mm segments) and entire target vessel (LCBIvessel: LCBI within entire vessel). In addition to FFR, delta-FFR was measured by difference of distal coronary artery pressure/aortic pressure (Pd/Pa) between baseline and hyperemic state. The averaged FFR and delta-FFR was 0.74 (0.69-0.77), and 0.17±0.05, respectively. On target lesion-based analysis, maxLCBI4mm was negatively correlated to FFR (ρ=-0.213, P=0.040), and it was positively correlated to delta-FFR (ρ=0.313, P=0.002). Furthermore, target vessel-based analysis demonstrated similar relationship of LCBIvessel with FFR (ρ=-0.302, P=0.003) and delta-FFR (ρ=0.369, P<0.001). Even after adjusting clinical characteristics and lesion/vessel features, delta-FFR (by 0.10 increase) was independently associated with maxLCBI4mm (β=57.2, P=0.027) and LCBIvessel (β=24.8, P=0.007) by mixed linear model analyses. A greater amount of lipidic plaque burden at not only "target lesion" alone but "entire target vessel" was associated with a greater delta-FFR. The accumulation of lipidic plaque materials at both local site and entire vessel may impair hyperemia-induced vasoreactivity, which causes a reduced FFR.


The Role of Mitochondrial Stress in Muscle Wasting Following Severe Burn Trauma.
Increased resting metabolic rate and skeletal muscle wasting are hallmarks of the pathophysiological stress response to severe burn trauma. However, whether these two responses occur independently in burn patients or are in fact related remains unclear. In light of recent evidence demonstrating that increased proteolysis in skeletal muscle of burned patients is accompanied by mitochondrial hypermetabolism, oxidative stress, and protein damage; in this article, we discuss the evidence for a role for the mitochondrion in skeletal muscle wasting following severe burn trauma. In particular, we focus on the role of mitochondrial superoxide production in oxidative stress and subsequent proteolysis, and discuss the role of the mitochondrion as a signaling organelle resulting in protein catabolism in other cellular compartments following severe burn trauma.


Proteinases of Legionella: phenylalanineaminopeptidase of L. pneumophila.
Phenylalanineaminopeptidase was isolated and purified from the culture filtrate of Legionella pneumophila by affinity chromatography on O-tert-butyl-L-threonyl-L-phenylalanyl-L-prolylglycyl-aminosilo chrom and by gel-filtration; a 401-fold purification with a yield of 18% was achieved. The enzyme was a metalloenzyme with a molecular weight of 35000 and a pI of 5.8. It was stable at pH 7-9 and had an activity optimum in the range of pH 8-9.5 with L-phenylalanine p-nitroanilide as substrate. Enzyme activity was highest towards the latter compound, substantially lower towards L-leucine p-nitroanilide and only marginal towards other p-nitroanilides. Besides phenylalanineaminopeptidase, a metalloproteinase and a serine proteinase were also detected in L. pneumophila culture filtrate.


A 10-year study of homosexually transmitted infection.
A 10-year survey is presented of male cases of homosexually acquired infection seen between 1962 and 1971 at Charing Cross Hospital (West London Branch). Tables showing the number of cases of syphilis, gonorrhea, and other conditions in homosexual and heterosexual males and in females are considered. Tables of other relevant data are also presented. The reasons underlying the changes illustrated, including the Act legalizing homosexual practices between consenting adult males, which became effective in 1968, are discussed. Certain pathological conditions apparently connected with homosexual practices, such as serum hepatitis, local rectal disease, and mucous colitis, are included and also some relevant manifestations of herpes genitalis and genitral warts. Homosexually acquired infection in prisoners is described. Some of the psychiatric effects of homosexuality on clinic patients and also their fears of treatment at clinics are considered, as well as the behavioral differences in response to infection between exclusively homosexuals, bi-sexuals, and married homosexuals.


Implicit need for achievement predicts attenuated cortisol responses to difficult tasks.
The present research tested the hypothesis that the implicit need for achievement (n Achievement) predicts attenuated cortisol (C) responses to difficult tasks, because it represents a propensity to view difficulty as a cue to mastery reward. In two studies, n Achievement was assessed through content-coding of imaginative stories and salivary C was assessed both at baseline and post-task. In Study 1 (N = 108 US students), n Achievement predicted an attenuated C response to a one-on-one competition in the laboratory, regardless of whether participants won or lost. In Study 2 (N = 62 German students), n Achievement predicted an attenuated C response to the Trier Social Stress Test (Kirschbaum, Pirke, & Hellhammer, 1993), but not to a non-stressful control task. In Study 2 only, the attenuating effect of n Achievement was moderated by gender, with only men showing the effect. Across both studies, the average effect size of the association between n Achievement and C responses to difficult tasks was r = -.28. These findings point to a role of n Achievement in emotion regulation.


Efficacy and Safety of Corneal Transplantation Using Corneas from Foreign Donors versus Domestic Donors: A Prospective, Randomized, Controlled Trial.
Purpose. To assess the efficacy and safety of corneal transplantation using corneas from foreign donors. Methods. One hundred and eight patients needing therapeutic penetrating keratoplasty were randomly divided into 2 groups (54 cases/group): foreign group using foreign donor corneas and domestic group using domestic donor corneas. Clinical outcome and incidence of postoperative complications were compared between groups. Results. No significant difference with respect to the therapeutic outcome and postoperative Best Corrected Visual Acuity (BCVA) and neovascularization by final follow-up was observed between the two groups. The graft thickness in the foreign group was statistically higher than the domestic group at 1 month postoperatively, but not at 3, 6, and 12 months postoperatively. Corneal endothelial cell density in the domestic group was statistically higher than in the foreign group at 3, 6, and 12 months postoperatively. Corneal epithelial abnormalities in the foreign group were significantly higher than that in domestic group. The primary graft failure, incidence of graft survival, and postoperative complications such as immunologic rejection, graft infection, and secondary glaucoma were not significantly different between the two groups. Conclusions. Corneal transplantations using foreign donor corneas are as effective and safe as those using domestic donor corneas.


[Health Technology Assessment: conceptual framework and international perspective].
The increasing concerns of nations to improve efficiency, access and quality of health care, have encouraged a more appropriate use of health interventions. Thus, the interest of clinicians and decision-makers has shifted towards evidence-based medicine, comparative effectiveness research and health technology assessment (HTA). Although these concepts should not be understood as synonyms, they converge on common characteristics: a systematic approach to evidence, the focus on relevant outcomes for the patient, and the notion that policy-making for a group of patients will affect others. As a consequence, concerns not only involve efficiency and effectiveness, but also transparency, clinical practice and opportunity costs. This paper introduces the concept and processes of HTA in the first and second sections. Section three reviews the evolution of HTA in developed and Latin-American countries, analyzing the aspects that influence the structure and scope of HTA. The last section concludes with reflections on the challenges to implement HTA in Chile.


FISHing for answers: the use of molecular cytogenetic techniques in adolescent medicine practice.
Chromosomal abnormalities are common causes of a variety of diseases, cancers, and malformation syndromes. Identification of chromosomal aberrations is important for counseling families about prognosis and reproductive risks with future pregnancies. However, limited resolution leads to the inability to detect small deletions, small insertions or duplications, and complex chromosomal rearrangements. Fluorescence-based assays, which have become possible because of sophisticated cloning technologies and improved sensitivity of antibody conjugates, enable the detection of subtle chromosomal changes beyond the resolution of classic cytogenetics. Such techniques have greatly expanded the diagnostic armamentarium available in the investigation of adolescents with mental retardation, malformations and many other disorders.


Pancreatic guidewire placement for achieving selective biliary cannulation during endoscopic retrograde cholangio-pancreatography.
To investigate the frequency and risk factors for acute pancreatitis after pancreatic guidewire placement (P-GW) in achieving cannulation of the bile duct during endoscopic retrograde cholangio-pancreatography (ERCP). P-GW was performed in 113 patients in whom cannulation of the bile duct was difficult. The success rate of biliary cannulation, the frequency and risk factors of post-ERCP pancreatitis, and the frequency of spontaneous migration of the pancreatic duct stent were investigated. Selective biliary cannulation with P-GW was achieved in 73% of the patients. Post-ERCP pancreatitis occurred in 12% (14 patients: mild, 13; moderate, 1). Prophylactic pancreatic stenting was attempted in 59% of the patients. Of the 64 patients who successfully underwent stent placement, three developed mild pancreatitis (4.7%). Of the 49 patients without stent placement, 11 developed pancreatitis (22%: mild, 10; moderate, 1). Of the five patients in whom stent placement was unsuccessful, two developed mild pancreatitis. Univariate and multivariate analyses revealed no pancreatic stenting to be the only significant risk factor for pancreatitis. Spontaneous migration of the stent was observed within two weeks in 92% of the patients who had undergone pancreatic duct stenting. P-GW is useful for achieving selective biliary cannulation. Pancreatic duct stenting after P-GW can reduce the incidence of post-ERCP pancreatitis, which requires evaluation by means of prospective randomized controlled trials.


Biphasic effect of gonadotropin releasing hormone on progestin secretion by rat granulosa cells.
The effect of an agonistic gonadotropin releasing hormone (GnRH)-analog (D-Ala6, des-Gly10-NH2-GnRH-ethylamide, GnRHa) on granulosa cell steroidogenesis in the presence or absence of follicle-stimulating hormone (FSH) or luteinizing hormone (LH) was studied. Granulosa cells, isolated from preovulatory follicles of pregnant mare's serum gonadotropin (PMSG)-treated immature rats or from the less mature follicles of untreated immature rats, were cultured for a period of 72 h with daily changes of medium, and progesterone and its metabolite, 20 alpha-dihydro-progesterone (20 alpha-OHP), were assayed in the medium. In granulosa cells from preovulatory follicles, LH and FSH caused a much greater stimulation of steroidogenesis than did GnRHa. There appeared to be no interaction between GnRHa and FSH during the first 10 h, but at 24 h and later the presence of GnRHa clearly inhibited the steroidogenic response to LH and FSH. Steroidogenesis in granulosa cells from immature rats was considerably lower and the effects of GnRHa and FSH alone less pronounced. In these cells, FSH-stimulated progesterone secretion was inhibited by GnRHa only at 72 h. In contrast, 20 alpha-OHP secretion in the same cultures was potentiated by the combined presence of FSH and GnRHa. In conclusion, it seems as though the effects of GnRHa on granulosa cell steroidogenesis varies with exposure time, the initial response being stimulatory and the later inhibitory. Furthermore, the response is also to some extent determined by the maturational stage of the granulosa cells.


Real-time monitoring of superoxide generation and cytotoxicity in neuroblastoma mitochondria induced by 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline.
The potential neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) has recently been suggested to be a causative factor in the clinical development of parkinsonian symptoms after long-term exposure to precursor compounds such as the hypnotic chloral hydrate. TaClo is known to cause cell death in dopaminergic neuronal cells, however, the pathway and mechanisms remain undefined. This study reports for the first time that TaClo promotes cytotoxicity in SH-SY5Y neuroblastoma cells within 2 hours of initial exposure. TaClo also caused superoxide production from isolated mitochondria, which was comparable in response time and magnitude to production elicited by more established respiratory inhibitors such as rotenone and antimycin A. These findings present new evidence in support of TaClo-induced neuronal death via superoxide signalling and oxidative stress.


Learning-induced bidirectional plasticity of intrinsic neuronal excitability reflects the valence of the outcome.
Long-term memory is supported not only by modulation of synaptic strength, but also by modifications in intrinsic neuronal properties. Learning-induced enhancement of neuronal excitability has been shown in the hippocampus and the piriform cortex, where it lasts for days and is involved in maintaining the learned skills. The basolateral amygdala (BLA) is suggested to encode positive and negative significance of information, thus forming a unique experimental setting to monitor bidirectional changes as a function of the valence change. In rodents, olfaction is a major modality that guides goal-directed behavior. Here, we show that intrinsic neuronal excitability in BLA pyramidal neurons is differentially modified by positive and negative olfactory learning and explore the cellular mechanisms of such bidirectional intrinsic neuronal plasticity. Learning of complex olfactory-discrimination task, in which success was rewarded with drinking water, resulted with enhanced intrinsic excitability. Such enhancement is mediated by reduction in the slow potassium current. In contrast, olfactory fear conditioning, in which the animal learned to associate the odor with an electric shock, resulted in decreased intrinsic excitability, mediated by activation of the µ-opioid-sensitive potassium current. We suggest that positive and negative changes in BLA excitability contribute to the encoding of opposite odor-value behaviors.


A molecular phylogeny of the bivalve mollusks.
A phylogenetic reconstruction based on 506 nucleotides near the 5' end of the 18S subunit of ribosomal DNA (rDNA) in 2 gastropod, 3 chiton and 28 bivalve mollusks supported the monophyly and sister group relationship of the subclasses Heterodonta and Palaeoheterodonta but could not confidently establish either the monophyly or the phylogenetic relationships of the morphologically well defined subclasses Pteriomorphia, Protobranchia, and Anomalodesmata. When both gastropods and chitons were included in the analysis, one or the other invariably emerged within Bivalvia. Some evidence indicates that this apparent polyphyly may be the consequence of unequal rates of evolution and of rapid changes in the protobranch and anomalodesmatan lineages. The taxa usually included in Pteriomorpha emerge as a grade rather than a clade, although in a sequence that differs from morphologically based phylogenies.


Spontaneous and antigen-induced production of HIV-inhibitory beta-chemokines are associated with AIDS-free status.
The beta-chemokines RANTES, macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta suppress infection by macrophage-tropic strains of HIV and simian immunodeficiency virus (SIV) by binding and down-regulating the viral coreceptor, CCR5. Accordingly, we have examined whether higher levels of CCR5 ligands are associated with a more favorable clinical status in AIDS. A cross-sectional study of 100 subjects enrolled in the Multicenter AIDS Cohort Study at the Baltimore site was conducted to measure chemokine production and lymphocyte proliferation by peripheral blood mononuclear cells (PBMC). Statistical analyses of the data revealed that the production of HIV-suppressive beta-chemokines by HIV antigen-stimulated PBMC was significantly higher in HIV-positive subjects without AIDS compared with subjects with clinical AIDS. Increased chemokine production was also correlated with higher proliferative responses to HIV antigens. Both parameters were significantly lower in the AIDS versus non-AIDS group. Notably, significantly higher levels of MIP-1alpha were also observed with unstimulated PBMC from seronegative subjects at risk for HIV infection released as compared with seropositive and non-Multicenter AIDS Cohort Study seronegative subjects. The association of chemokine production with antigen-induced proliferative responses, more favorable clinical status in HIV infection, as well as with an uninfected status in subjects at risk for infection suggests a positive role for these molecules in controlling the natural course of HIV infection.


25 Years of Session Rating of Perceived Exertion: Historical Perspective and Development.
The session rating of perceived exertion (sRPE) method was developed 25 years ago as a modification of the Borg concept of rating of perceived exertion (RPE), designed to estimate the intensity of an entire training session. It appears to be well accepted as a marker of the internal training load. Early studies demonstrated that sRPE correlated well with objective measures of internal training load, such as the percentage of heart rate reserve and blood lactate concentration. It has been shown to be useful in a wide variety of exercise activities ranging from aerobic to resistance to games. It has also been shown to be useful in populations ranging from patients to elite athletes. The sRPE is a reasonable measure of the average RPE acquired across an exercise session. Originally designed to be acquired ∼30 minutes after a training bout to prevent the terminal elements of an exercise session from unduly influencing the rating, sRPE has been shown to be temporally robust across periods ranging from 1 minute to 14 days following an exercise session. Within the training impulse concept, sRPE, or other indices derived from sRPE, has been shown to be able to account for both positive and negative training outcomes and has contributed to our understanding of how training is periodized to optimize training outcomes and to understand maladaptations such as overtraining syndrome. The sRPE as a method of monitoring training has the advantage of extreme simplicity. While it is not ideal for the precise recording of the details of the external training load, it has large advantages relative to evaluating the internal training load.


MicroRNA-152 specifically targets kinesin family member 14 to suppress the advancement of bladder cancer cells via PI3K/AKT pathway.
Kinesin family member 14 (KIF14) overexpression has been linked to tumor progression and metastasis in different malignancies, but its precise molecular mechanism in bladder cancer (BLCA) remains unclear. The expression of KIF14 in BLCA and its relationship with clinical outcomes were assessed. Functional investigations on KIF14 were conducted using CCK-8, Transwell experiment, colony formation, scratch motility assays, and flow cytometry. We examined the downstream route of KIF14 and identified its upstream regulatory factor through luciferase reporter experiments and bioinformatics tools. Our findings demonstrated that increased KIF14 expression was associated with poor survival prognosis in BLCA patients. Deletion of KIF14 affected cell cycle progression, induced apoptosis, and inhibited cell growth, migration, and invasion. GSEA analysis revealed a strong association between KIF14 expression and the PI3K/AKT signaling pathway. Further research showed that KIF14 deletion decreased the levels of p-PI3K, p-AKT, FOXM1, and CCNB1. We also found that has-miR-152-3p (miR-152) suppressed BLCA cell growth by post-transcriptionally regulating KIF14 expression. Our findings suggest that targeting KIF14 could alter the PI3K/AKT and FOXM1-CCNB1 axis, leading to growth inhibition, cell cycle arrest, and induction of apoptosis in BLCA cells. Additionally, miR-152 directly regulates KIF14 expression at the post-transcriptional level. Overall, KIF14 represents a promising therapeutic target for BLCA clinical therapy.


Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation.
Inhibiting lipogenesis prevents hepatic steatosis in rodents with insulin resistance. To determine if reducing lipogenesis functions similarly in humans, we developed MK-4074, a liver-specific inhibitor of acetyl-CoA carboxylase (ACC1) and (ACC2), enzymes that produce malonyl-CoA for fatty acid synthesis. MK-4074 administered to subjects with hepatic steatosis for 1 month lowered lipogenesis, increased ketones, and reduced liver triglycerides by 36%. Unexpectedly, MK-4074 increased plasma triglycerides by 200%. To further investigate, mice that lack ACC1 and ACC2 in hepatocytes (ACC dLKO) were generated. Deletion of ACCs decreased polyunsaturated fatty acid (PUFA) concentrations in liver due to reduced malonyl-CoA, which is required for elongation of essential fatty acids. PUFA deficiency induced SREBP-1c, which increased GPAT1 expression and VLDL secretion. PUFA supplementation or siRNA-mediated knockdown of GPAT1 normalized plasma triglycerides. Thus, inhibiting lipogenesis in humans reduced hepatic steatosis, but inhibiting ACC resulted in hypertriglyceridemia due to activation of SREBP-1c and increased VLDL secretion.


Kinematic constraints on glacier contributions to 21st-century sea-level rise.
On the basis of climate modeling and analogies with past conditions, the potential for multimeter increases in sea level by the end of the 21st century has been proposed. We consider glaciological conditions required for large sea-level rise to occur by 2100 and conclude that increases in excess of 2 meters are physically untenable. We find that a total sea-level rise of about 2 meters by 2100 could occur under physically possible glaciological conditions but only if all variables are quickly accelerated to extremely high limits. More plausible but still accelerated conditions lead to total sea-level rise by 2100 of about 0.8 meter. These roughly constrained scenarios provide a "most likely" starting point for refinements in sea-level forecasts that include ice flow dynamics.


A Pilot In Vivo Study of Flexible Fully Polymeric Nerve Cuff Electrodes.
Recent trends in the field of bioelectronics have been focused on the development of electrodes that facilitate safe and efficient stimulation of nervous tissues. Novel conducting polymer (CP) based materials, such as flexible and fully polymeric conductive elastomers (CEs), constitute a promising alternative to improve on the limitations of current metallic devices. This pilot study demonstrates the performance of tripolar CE-based peripheral nerve cuffs compared to current commercial tripolar platinum-iridium (PtIr) nerve cuffs in vivo. CE and metallic cuff devices were implanted onto rodent sciatic nerves for a period of 8 weeks. Throughout the entire study, the CE device demonstrated improved charge transfer and electrochemical safety compared to the PtIr cuff, able to safely inject 2 to 3 times more charge. In comparison to the commercial control, the CE cuff was able to record in the in vivo setting with reduced noise and produced smaller voltages at all simulation levels. CE technologies provide a promising alternative to metallic devices for the development of bioelectronics with enhanced chronic device functionality.


Antiepileptic drug prescribing patterns in Iraq and Afghanistan war veterans with epilepsy.
We examined patterns of antiepileptic drug (AED) use in a cohort of Iraq/Afghanistan war veterans (IAVs) who were previously identified as having epilepsy. We hypothesized that clinicians would be more likely to prescribe newer AEDs and would select specific AEDs to treat seizures based on patient characteristics including gender and comorbidities. From the cohort of IAVs previously identified with epilepsy between fiscal years 2009 and 2010, we selected those who received AEDs from the Veterans Health Administration in FY2010. Regimens were classified as monotherapy or polytherapy, and specific AED use was examine overall and by gender. Multivariable logistic regression examined associations of age; gender; race/ethnicity; medical, psychiatric, and neurological comorbidities; and receipt of neurology specialty care associated with the six most commonly used AEDs. Among 256,284 IAVs, 2123 met inclusion criteria (mean age: 33years; 89% men). Seventy-two percent (n=1526) received monotherapy, most commonly valproate (N=425) and levetiracetam (n=347). Sixty-one percent of those on monotherapy received a newer AED (levetiracetam, topiramate, lamotrigine, zonisamide, oxcarbazepine). Although fewer women than men received valproate, nearly 90% (N=45) were of reproductive age (≤45years). Antiepileptic drug prescribing patterns were associated with posttraumatic stress disorder, bipolar disorder, cerebrovascular disease, dementia/cognitive impairment, headache, and receipt of neurological specialty care (all p<0.01). In this cohort of veterans with epilepsy, most received AED monotherapy and newer AEDs. Prescribing patterns were different for men and women. The patterns observed between AEDs and neurological/psychiatric comorbidities suggest that clinicians are practicing rational prescribing.


Discriminative stimulus characteristics of BMY 14802 in the pigeon.
Pigeons were trained to discriminate intramuscular injections of 5.6 mg/kg BMY 14802, a drug that has relatively high affinity for sigma binding sites, from saline in a two-key operant procedure. Many compounds that displace sigma binding failed to produce BMY 14802-like discriminative stimulus effects; these included (+)-SKF 10,047, (+)3-PPP, DTG and MR 2035; the typical antipsychotic haloperidol; the putative antipsychotics tiospirone, cinuperone and rimcazole; and the uncompetitive NMDA antagonist phencyclidine. In addition, MR 2035 and tiosperone failed to antagonize the discriminative stimulus effects of BMY 14802. The selective D2 antagonist eticlopride and the norepinephrine uptake blocker and antidepressant desmethylimipramine also failed to evoke substantial BMY 14802-appropriate responding. In contrast to sigma ligands and other reference compounds, the 5-HT1A agonists buspirone, 8-OH-DPAT and spiroxatrine dose-dependently produced BMY 14802-like discriminative stimulus effects. The limited-efficacy 5-hydroxytryptamine (HT)1A agonist NAN 190 did not produce BMY 14802-like discriminative effects; however, it did competitively antagonize the stimulus effects of BMY 14802 and the BMY 14802-like stimulus effects of (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin. Other serotonergic compounds failed to produce substantial BMY 14802-appropriate responding; such as 5-HT1 agonist I-5-HTP; 5-HT1A/1B agonist RU24969; 5-HT1B/1C agonist m-CPP; 5-HT1C/2 agonist quipazine; 5-HT1C/2 antagonists, metergoline and the atypical antipsychotic clozapine; and 5-HT3 antagonist ondansetron. Also, metergoline, ondansetron and pirenpirone failed to antagonize the stimulus effects of BMY 14802. These results indicate that the discriminative stimulus effects of BMY 14802 are serotonergically mediated primarily by 5-HT1A receptors rather than by sigma sites.


Resistance of growth hormone secretion to somatostatin in men with type I diabetes mellitus.
The effect of continuous infusions of somatostatin (SRIF) on growth hormone (GH) secretion induced by GH-releasing hormone (GHRH) bolus was compared in a dose-response manner between diabetic subjects in poor glycemic control and nondiabetic subjects to address the hypothesis that altered pituitary responsiveness to SRIF contributes to the hypersecretion of GH in diabetes mellitus in humans. Studies were conducted with a modification of the euglycemic clamp technique to minimize fluctuations in glucose and insulin. Suppression of GHRH-induced GH secretion was demonstrable in diabetic subjects only at a SRIF dose 15-fold higher than that at which suppression could be detected in nondiabetic subjects. The calculated 50% inhibitory dose (ID50) in diabetic subjects was 4-fold higher than that in nondiabetic subjects (P = 0.03). In diabetic subjects after 2 wk of intensive insulin management, the change in the dose-response curve persisted despite significant decrements in glycosylated hemoglobin and increments in plasma insulinlike growth factor I. The increment in plasma SRIF predicted at the SRIF ID50 from concentrations measured during the SRIF infusions in nondiabetic subjects would result in hypophyseal portal SRIF concentrations in the physiological range reported in recent animal studies, whereas those for the ID50 in diabetic subjects would be approximately 1.5-2.5 times the upper limit of that range. These studies indicate that pituitary resistance to the action of SRIF occurs in men with insulin-dependent (type I) diabetes at physiological concentrations of the hormone and is therefore highly likely to contribute to the hypersecretion of GH in diabetes.


Aging in the natural world: comparative data reveal similar mortality patterns across primates.
Human senescence patterns-late onset of mortality increase, slow mortality acceleration, and exceptional longevity-are often described as unique in the animal world. Using an individual-based data set from longitudinal studies of wild populations of seven primate species, we show that contrary to assumptions of human uniqueness, human senescence falls within the primate continuum of aging; the tendency for males to have shorter life spans and higher age-specific mortality than females throughout much of adulthood is a common feature in many, but not all, primates; and the aging profiles of primate species do not reflect phylogenetic position. These findings suggest that mortality patterns in primates are shaped by local selective forces rather than phylogenetic history.


Identification and localization of gibberellins in maturing seeds of the cucurbit Sechium edule, and a comparison between this cucurbit and the legume Phaseolus coccineus.
Twenty known gibberellins (GAs) have been identified by combined capillary gas chromatography-mass spectrometry in extracts from less than 10 g fresh weight of maturing seeds of the cucurbit Sechium edule Sw. The GAs are predominantly 3- and-or 13-hydroxylated. This is the first reported identification of non-conjugated 13-hydroxylated GAs in a cucurbit. Gibberellin A8 and gibberellin A8-catabolite are the major GAs in terms of quantity and are largely accumulated in the testa. The catabolites of 2β-hydroxylated GAs are α,β-unsaturated ketones which no longer possess of a γ-lactone. They were hitherto known only in legumes. The presence of GA8-catabolite as a major component of Sechium seeds indicates that the distribution of these GA-catabolites may be more widespread than previously envisaged. The localization of known GAs in maturing seeds of the legume Phaseolus coccineus L. was found to resemble closely that in Sechium. Gibberellin A8, a putative conjugate of GA8 and GA8-catabolite are accumulated in the testa. The localization in the testa of end-products of the GA-biosynthetic pathway, which was first observed in maturing seeds of Pisum sativum, and is now described in Phaseolus and Sechium, may be a general feature of seed development.


Atmospheric dry deposition of polychlorinated dibenzo-p-dioxins and dibenzofurans in the vicinity of municipal solid waste incinerators.
This study focuses on the atmospheric dry deposition flux of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in the vicinity of the two municipal solid waste incinerators (MSWIs) located in southern Taiwan. PCDD/Fs in ambient air were taken and analyzed for seventeen 2,3,7,8-substituted PCDD/Fs during November 2004 and July 2005. Results show that the mean concentrations of PCDD/Fs in the ambient air near MSWI-GS and MSWI-RW were 0.090 and 0.097pg I-TEQ/Nm(3), respectively. Dry deposition fluxes of total PCDD/Fs were 18.0 and 23.5pg I-TEQ/(m(2)d) in the ambient air near MSWI-GS and MSWI-RW, respectively, which were considerably higher than that measured in Guangzhou, China. Annual dry deposition fluxes of total PCDD/Fs in the ambient air near MSWI-GS and MSWI-RW were 189 and 217ng/(m(2)year), respectively, which were also much higher than dry deposition of total PCDD/Fs to the Atlantic Ocean. The results of the present study strongly suggest that exposure to PCDD/Fs in this area should be reduced. In addition, parametric sensitivity shows that dry deposition flux of PCDD/Fs is most sensitive to dry deposition velocity of the particle-phase, followed by air temperature and concentration of total suspended particulate but least sensitive to dry deposition velocity of the gas-phase.


Efficacy and safety of memantine in Lewy body dementia.
Lewy body dementia (LBD) is a progressive brain disease manifest as dementia and parkinsonism, along with psychotic and autonomic disorders. Although studies in recent years have demonstrated the positive effects of cholinesterase inhibitors in LBD, the search for therapeutic agents with other mechanisms of action remains relevant. An open, controlled, 16-week study was performed with the aim of evaluating the efficacy and safety of memantine in patients with clinically diagnosed LBD (criteria of McKeith et al., 1999). The study included 23 patients (mean age 69.2 +/- 5.9 years), who were divided into two groups: 14 patients received memantine at a dose of 20 mg/day and nine patients constituted the control group. Efficacy was evaluated using a battery of quantitative neurospychological tests, clinical scales for assessment of fluctuations in mental states, scales for assessment of behavioral and psychotic disorders, and the general clinical impression scale. The results demonstrated that memantine had positive effects on the patients' general status and cognitive functions (increases on the mini mental state examination by 1.5 points), mainly because of improvements in attention and control functions. There were also reductions in the severity of fluctuations in mental state, aggressivity, lack of spontaneity, and disinhibition. The severity of psychotic and motor disorders did not change significantly. Tolerance of the agent was good, only two patients withdrawing from the study because of episodes of confusion during the dose titration period.


Impaired lipid clearance in patients with previous acute pancreatitis.
Fasting serum triglycerides were measured in 52 patients who had sustained an attack of pancreatitis (gall stone related 33, alcoholism six) at least six months earlier. Several patients (23%) had raised fasting serum triglycerides, with a type IV phenotype in all but one patient. The 40 patients with normal fasting serum triglycerides received an oral load of 100 g sunflower oil to compare their clearance of dietary triglycerides with that of a control group of 54 subjects. The clearance of ingested triglycerides was significantly impaired in the patients - irrespective of the presumed aetiological factor, or clinical condition associated with pancreatitis - compared with the clearance in controls. A triglyceride tolerance test is the only way to detect those patients in whom a future attack of pancreatitis may be precipitated by a diet rich in fat, or endogenous over production of triglycerides as after an alcoholic debauch.


Body composition assessment in athletes: a systematic review.
Body composition represents an unbreakable unity of the human body basic structure elements and involves a relative representation of the various constituent elements of the human total body weight. It is well known that body composition changes under the influence of continuous physical activity, and, therefore, it is one of the major components of fitness, and general health of the athletes. Therefore, this topic has become a major field of interest for many exercise and sport scientists as well as clinicians who specialize not only in different training methods but also in the prevention of and rehabilitation from major injuries. To date, having considered issues of accuracy, repeatability and utility, there is no universally applicable criterion or 'gold standard' methodology for body composition assessment in athletes. The main objective of this review was to give a short overview of methods for body composition analysis in athletes and to show and compare the latest data on their usefulness and reliability in order to find the best solution for practical everyday work.


Getting off the carousel: Exploring the wicked problem of curriculum reform.
Making substantial changes to the form and delivery of medical education is challenging. One reason for this may be misalignment between existing conceptualizations of curricula and curriculum reform in medical education, with the former perceived as 'complex' yet the latter as linear. Reframing curriculum reform as a process-driven, complex entity may enhance the possibility of change. To explore the utility of this approach, we carried out an exploratory case study of curriculum reform in a real-life context. We used a qualitative case study approach. Data were collected from 17 interviews with senior faculty involved in curriculum reform in one medical school plus document analysis of approximately 50 documents and files, to provide background, context, and aid triangulation. Data coding and analysis was initially inductive, using thematic analysis. After themes were identified, we applied the 'wicked problem' framework to highlight aspects of the data. This paper focuses on two main analytic themes. First, that multiple players hold different views and values in relation to curriculum reform, resulting in various influences on the process and outcomes of reform. Second, 'solutions' generate consequences which go beyond the anticipated advantages of curriculum reform. This is the first empirical study of curriculum reform in medical education which uses the wicked problem framework to conceptually illuminate the complex processes which occur in relation to reform. Those involved in reform must be reflective and attentive to the possibility that persistent and emerging challenges may be a result of wicked problems.


Pharmaceutical citizenship in an era of universal access to hepatitis C treatment: Situated potentials and limits.
Until recently, the only medical treatment available for the hepatitis C virus (HCV) was interferon-based therapy, a notoriously long and arduous treatment with limited success. However, in December 2015, the Australian Government announced a scheme of 'universal access' to new, highly effective direct-acting antiviral therapies (DAAs). This article draws on in-depth interviews with community actors engaged in national and state-based drug user and viral hepatitis advocacy to trace how universal access to curative medicines affords revised notions of citizenship and social inclusion among people who inject drugs and others affected by HCV. To inform our analysis, we draw on and combine critical perspectives from the biological citizenship literature, particularly pharmaceutical citizenship, along with work on the concepts of 'publics and counterpublics'. We ask: what kinds of emergent HCV communities or publics are being enacted through our participant accounts in response to the new DAA-era of universal access, and what forms of citizenship and inclusion (or non-citizenship and exclusion) do they postulate? Some accounts indeed enacted treatment as an individual, sometimes collective, 'good': a citizenship potential. However, a number of accounts enacted situated limits to a straightforward actualisation of this potential, performing a model of public health governance that prioritised viral cure whilst rendering injecting drug use and its attendant social disadvantages an absent presence. Reconceptualising HCV treatment within a counterpublic health sensibility would, by engaging with the everyday health needs and aspirations of people living with HCV in conditions of social disadvantage, create space for new social inclusions and citizenships.


Citrobacter rodentium virulence in mice associates with bacterial load and the type III effector NleE.
Severe disease caused by Shiga toxin-producing Escherichia coli (STEC) has been associated with a pathogenicity island, O-Island 122, which encodes the type III secretion system-effector NleE. Here we show that full virulence of the related attaching and effacing mouse pathogen Citrobacter rodentium requires NleE. Relative to wild-type bacteria, nleE-mutant C. rodentium are attenuated for colonisation in mice in both single and mixed infections. Examination of the ability of nleE-mutant bacteria to induce pathologic change in vivo revealed that nleE-mutant bacteria induce significantly less pathologic change than wild-type bacteria in susceptible mice. Consistent with these results, mice infected with nleE-mutant bacteria exhibit delayed mortality. These results suggested that pathologic change during attaching and effacing pathogen infection may associate with the degree of pathogen colonisation. Using mutants of 23 type III secretion genes, including the type III effectors nleC, nleD, nleE and nleF, the association of pathologic change with the ability of these mutants to colonise mice was examined. The induction of in vivo disease correlates strongly with the degree of colonisation, suggesting that the colonisation advantage type III secretion genes afford the bacteria, contribute to, and are required for, full virulence.


The pathophysiology of pulmonary hypertension in congenital heart disease.
Congenital heart disease with increased pulmonary blood flow commonly leads to the development of pulmonary hypertension and increased vascular reactivity. These serious sequelae are associated with the following two major categories of congenital heart defects: those resulting in increased pulmonary blood flow and increased pulmonary arterial pressure and those resulting in increased pulmonary venous pressure. Recent evidence that the pulmonary vascular endothelium is an important determinant of vascular tone has led to the hypothesis that endothelial injury, secondary to congenital heart disease with increased pulmonary blood flow, disrupts these regulatory mechanisms and thereby plays a role in the development of pulmonary hypertension and its associated increased vascular reactivity. In many animal models, endothelial dysfunction is a precursor for smooth muscle dysfunction, and there is an apparent progression from endothelial dysfunction to smooth muscle dysfunction as vascular changes progress. We established a chronic model of pulmonary hypertension with increased pulmonary blood flow in young lambs by placing a systemic-to-pulmonary shunt in utero. In this model, we found significant physiologic and molecular alternations of both the nitric oxide (NO) and endothelin signaling pathways, two important mechanisms by which the endothelium regulates pulmonary vascular tone. These alterations occur extremely early and precede severe anatomic changes. Early endothelial damage may contribute to the development of pulmonary hypertension and its associated enhanced pulmonary vascular reactivity.


The behaviour of recent isolates of human respiratory coronavirus in vitro and in volunteers: evidence of heterogeneity among 229E-related strains.
Strains of human coronavirus (HCV) isolated between 1974 and 1976 have been studied in vitro and in volunteers. All strains caused colds in volunteers, and those cultivable in tissue culture (TC) produced significantly more coryza and less sore throat than strains growing only in organ culture (OC). The TC strains were serologically related to 229E, but these isolates produced colds with a frequency and severity that contrasted with the effects of 229E itself. Tests on volunteers' preinfection sera showed that the prevalence of antibody to 229E had increased during the period 1961-1979 and that during 1977-1979 only 11% of subjects had no neutralising antibody against 229E. Susceptibility to the 229E-related isolates PR and TO was associated with low preinfection serum neutralising antibody against the homologous virus, and paired sera frequently showed fourfold or greater antibody rises, most commonly against the homologous strain. Volunteers infected with TO were immune when reinoculated with the same strain approximately 1 year later, but other similar volunteers were at least partly susceptible to infection with a heterologous 229E-related virus after similar time intervals. Although the strains of HCV that were grown in tissue culture were all related to the prototype 229E, they appeared not to be identical with it, and this heterogeneity is probably a significant factor in the epidemiology of HCV infections.


Health in China. The healthcare market.
It is now about 15 years since the introduction of the market into health care in China. This produced fundamental changes in the way that health care is financed and resulted in the disappearance of universal free basic health care. Responsibility for provision of health services has been devolved to the provincial and county governments, and healthcare providers have been given considerable financial independence. A fee for service system has been introduced, and several different payment mechanisms are now in operation. The new financing and pricing structures are responsible for greater inequity of access to services and more inefficient use of resources. These problems are widely acknowledged, and a range of solutions is being developed and tested. Since the introduction of the reforms the measurable health status of the population has not declined, probably as a result of overall improved socioeconomic conditions and a continued emphasis on prevention.


Transfusion triggers: a systematic review of the literature.
Most clinical practice guidelines recommend restrictive red blood cell (RBC) transfusion practices with the goal of minimizing transmission of blood-borne pathogens. The purpose of this review is to compare clinical outcomes in patients randomized to restrictive versus liberal transfusion thresholds (triggers). We conducted a search of OVID Medline, Current Contents, the Cochrane Library, and bibliographies of published studies. Our search strategies used a combination of key-word terms as text and MeSH headings relating to transfusion triggers. We included trials if the comparison groups were assigned on the basis of a clear transfusion trigger or threshold, and the study was randomized with a concurrent control group. Eligibility of studies was assessed by 2 independent raters, with disagreements resolved by consensus. Disagreements not resolved by consensus were referred to a third party for review. Two raters assessed the methodologic quality of the trials modified from the methods of Schultz. The main study outcomes probability of receiving an RBC transfusion, volume of RBCs transfused, hematocrit levels, mortality, and length of hospital stay. Ten trials, which reported outcomes for a total of 1,780 patients, were included. Five studies were in surgical patients, 3 were in the setting of acute blood loss and trauma, and 2 involved intensive care unit patients. Transfusion triggers varied between 7 and 10 g/dL (most often they were 8 or 9 g/dL). Being randomized to a restrictive transfusion trigger group had the following average effects: the probability of receiving an RBC transfusion was reduced by 42% (relative risk, 0.58; 95% confidence interval [CI] 0.47, 0.71), the volume of RBCs was reduced by 0.93 units (95% CI 0.36, 1.5 units), and hematocrit values were 5.6 % lower (95% CI 3.5, 7.7%). Mortality, rates of cardiac events, morbidity, and length of hospital stay were unaffected. The limited published evidence supports the use of restrictive transfusion triggers in patients who are free of serious cardiac disease. However, most of the data on clinical outcomes were generated by a single trial. The effects of conservative transfusion triggers on functional status, morbidity, and mortality, particularly in patients with cardiac disease, need to be tested in further large clinical trials. In countries with inadequate screening of donor blood, the data may constitute a stronger basis for avoiding transfusion with allogeneic RBCs.


Neutron reflectometry studies of the adsorbed structure of the amelogenin, LRAP.
Amelogenins make up over 90% of the protein present during enamel formation and have been demonstrated to be critical in proper enamel development, but the mechanism governing this control is not well understood. Leucine-rich amelogenin peptide (LRAP) is a 59-residue splice variant of amelogenin and contains the charged regions from the full protein thought to control crystal regulation. In this work, we utilized neutron reflectivity (NR) to investigate the structure and orientation of LRAP adsorbed from solutions onto molecularly smooth COOH-terminated self-assembled monolayer (SAM) surfaces. Sedimentation velocity (SV) experiments revealed that LRAP is primarily a monomer in saturated calcium phosphate (SCP) solutions (0.15 M NaCl) at pH 7.4. LRAP adsorbed as ∼32 Å thick layers at ∼70% coverage as determined by NR. Rosetta simulations of the dimensions of LRAP in solution (37 Å diameter) indicate that the NR determined z dimension is consistent with an LRAP monomer. SV experiments and Rosetta simulations show that the LRAP monomer has an extended, asymmetric shape in solution. The NR data suggests that the protein is not completely extended on the surface, having some degree of structure away from the surface. A protein orientation with the C-terminal and inner N-terminal regions (residues ∼8-24) located near the surface is consistent with the higher scattering length density (SLD) found near the surface by NR. This work presents new information on the tertiary and quaternary structure of LRAP in solution and adsorbed onto surfaces. It also presents further evidence that the monomeric species may be an important functional form of amelogenin proteins.


Malvidin and Its Mono- and Di-Glucosides Forms: A Study of Combining Both In Vitro and Molecular Docking Studies Focused on Cholinesterase, Butyrylcholinesterase, COX-1 and COX-2 Activities.
Malvidin, one of the six most prominent anthocyanins found in various fruits and vegetables, may possess a wide range of health-promoting properties. The biological activity of malvidin and its glycosides is not entirely clear and has been relatively less frequently studied compared to other anthocyanins. Therefore, this study aimed to determine the relationship between the structural derivatives of malvidin and their anti-cholinergic and anti-inflammatory activity. The study selected malvidin (Mv) and its two sugar derivatives: malvidin 3-O-glucoside (Mv 3-glc) and malvidin 3,5-O-diglucoside (Mv 3,5-diglc). The anti-inflammatory activity was assessed by inhibiting the enzymes, specifically COX-1 and COX-2. Additionally, the inhibitory effects on cholinesterase activity, particularly acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), were evaluated. Molecular modeling was also employed to examine and visualize the interactions between enzymes and anthocyanins. The results revealed that the highest inhibitory capacity at concentration 100 µM was demonstrated by Mv 3-glc in relation to AChE (26.3 ± 3.1%) and BChE (22.1 ± 3.0%), highlighting the crucial role of the glycoside substituent at the C3 position of the C ring in determining the inhibitory efficiency of these enzymes. In addition, the glycosylation of malvidin significantly reduced the anti-inflammatory activity of these derivatives compared to the aglycone form. The IC50 parameter demonstrates the following relationship for the COX-1 enzyme: Mv (12.45 ± 0.70 µM) < Mv 3-glc (74.78 ± 0.06 µM) < Mv 3,5-diglc (90.36 ± 1.92 µM). Similarly, for the COX-2 enzyme, we have: Mv (2.76 ± 0.16 µM) < Mv 3-glc (39.92 ± 3.02 µM) < Mv 3.5-diglc (66.45 ± 1.93 µM). All tested forms of malvidin exhibited higher activity towards COX-2 compared to COX-1, indicating their selectivity as inhibitors of COX-2. Theoretical calculations were capable of qualitatively replicating most of the noted patterns in the experimental data, explaining the impact of deprotonation and glycosylation on inhibitory activity. It can be suggested that anthocyanins, such as malvidins, could be valuable in the development of treatments for inflammatory conditions and Alzheimer's disease and deserve further study.


Refracture of proximal fifth metatarsal (Jones) fracture after intramedullary screw fixation in athletes.
This study details six instances of refracture of clinically and radiographically healed fractures of the base of the fifth metatarsal after intramedullary screw fixation. Four professional football players, one college basketball player, and one recreational athlete underwent intramedullary screw fixation of fifth metatarsal fractures. The athletes were released to full activities an average of 8.5 weeks (range, 5.5 to 12) after fixation, when healing was clinically and radiographically documented. Three football players developed refracture within 1 day of return to full activity. The other three athletes refractured at 2.5, 4, and 4.5 months after return to activity. Two football players underwent repeat fixation with larger screws and returned to play in the same season. The college basketball player underwent bone grafting and returned to play in subsequent seasons. The other three athletes underwent nonoperative management and healed uneventfully over 6 to 8 weeks. On the basis of this series, we recommend that 1) screw fixation using a large-diameter screw should be given careful consideration for patients with large body mass for whom early return to activity is important; 2) functional bracing, shoe modification, or an orthosis should be considered for return to play; 3) if refracture occurs, exchange to a larger screw may allow return to play in the same season; and 4) alternative imaging should be considered to help document complete healing.


Cadmium spiked soil modulates root organic acids exudation and ionic contents of two differentially Cd tolerant maize (Zea mays L.) cultivars.
Our earlier work described that the roots of two maize cultivars, grown hydroponically, differentially responded to cadmium (Cd) stress by initiating changes in medium pH depending on their Cd tolerance. The current study investigated the root exudation, elemental contents and antioxidant behavior of the same maize cultivars [cv. 3062 (Cd-tolerant) and cv. 31P41 (Cd-sensitive)] under Cd stress. Plants were maintained in a rhizobox-like system carrying soil spiked with Cd concentrations of 0, 10, 20, 30, 40 and 50 μmol/kg soil. The root and shoot Cd contents increased, while Mg, Ca and Fe contents mainly decreased at higher Cd levels, and preferentially in the sensitive cultivar. Interestingly, the K contents increased in roots of cv. 3062 at low Cd treatments. The Cd stress caused acidosis of the maize root exudates predominantly in cv. 3062. The concentration of various organic acids was significantly increased in the root exudates of cv. 3062 with applied Cd levels. This effect was diminished in cv. 31P41 at higher Cd levels. Cd exposure increased the relative membrane permeability, anthocyanin (only in cv. 3062), proline contents and the activities of peroxidases (POD) and superoxide dismutase (SOD). The only exception was the catalase activity, which was diminished in both cultivars. Root Cd contents were positively correlated with the secretion of acetic acid, oxalic acid, glutamic acid, citric acid, and succinic acid. The antioxidants like POD and SOD exhibited a positive correlation with the organic acids under Cd stress. It is likly that a high exudation of dicarboxylic organic acids improves nutrient uptake and activities of antioxidants, which enables the tolerant cultivar to acclimatize in Cd polluted environment.


Normal reference interval for thyrotropin response to thyroliberin: dependence on age, sex, free thyroxin index, and basal concentrations of thyrotropin.
We measured the thyrotropin response (delta TSH) to 200 micrograms of thyroliberin in 131 subjects without thyroid dysfunction or other disease and with basal values for thyroid function that were within the normal reference intervals for our laboratory. By univariate and multivariate statistical methods we found delta TSH to be significantly influenced by the basal concentration of thyrotropin (TSH0) and the free thyroxin index (FT4I). When the effects of variations in TSH0 and FT4I were eliminated, delta TSH in men under 40 years of age did not differ from that in women. A decrease in delta TSH with increasing age was found in men but not in women. Thus a reference interval for delta TSH should consider TSH0, FT4I, and, in men, age. On the basis of multiple linear regression analysis, we constructed a formula for delta TSH reference intervals that takes into account individual values for TSH0 and FT4I. The formula should be applicable for women, regardless of age, up to 77 years and for men under 40 years. For older men a correction for the age-related decrease in delta TSH must be applied.


Evaluation of 5-hydroxyindoloacetic acid excretion in urine in patients with small intestine neuroendocrine neoplasm and carcinoid syndrome treated with somatostatin analogues.
The assessment of hormonal function of neuroendocrine neoplasm (NEN) is an important stage in the diagnosis and monitoring of these diseases treatment. Objective of this study was to analyze the results of urinary excretion of 5-hydroxyindoloacetic acid (5-HIAA) in patients with carcinoid syndrome treated with somatostatin analogues, depending on the histologic maturity, degree of liver involvement and stage of the disease. The final group comprised of 41 patients. All patients were subject to surgical removal of the primary site. Presence of hepatic metastases was determined in all patients. All patients were treated with somatostatin analogues. The 5-HIAA urine excretion was determined using the ELISA immunoenzymatic method. The mean excretion of 5-HIAA in patients with histological maturity grade G1 was 45.64 mg/24h, while in the group G2 the mean excretion was 108.41 mg/24h and was higher than in the group G1 (p=0.003). In the analysis of 5-HIAA value depending on the degree of liver involvement, the mean value of 5-HIAA excretion in patients with 10% liver involvement was 38.99 mg/24h, whereas in patients with 25% liver involvement this value was considerably higher and amounted 131.00 mg/24h (p< 0.001). In patients with disease progression the mean excretion was 117.37 mg/24h compared to the group of patients with stabilization of the disease, where the mean value was lower and amounted to 39.39 mg/24h (p<0.001). Assessment of 5-HIAA excretion in patients with carcinoid syndrome is of considerable significance in the diagnostics and monitoring of the treatment.


Application of irradiation as an immunosuppressive agent.
The concept of using total lymphoid irradiation (TLI) for immunosuppression is based on the prolonged and profound immunosuppressive effects observed after TLI in the treatment of patients with Hodgkin's disease. Pre-operative TLI of allograft recipients has been shown to be immunosuppressive when used alone or together with chemical immunosuppression. Fractionated TLI and allogeneic bone marrow injections produce stable chimaerism without graft-versus-host disease in inbred mice, rats and mongrel dogs and transplantation tolerance of skin and cardiac grafts in rats. In the primate, TLI and bone marrow injection result in significant tolerance of liver and kidney allografts. In 1959 sublethal whole-body irradiation was used as an immunosuppressive agent for the first successful related-human renal allografts between non-identical twins. Despite the dangers of myelosuppression, recent clinical experience has shown TLI to be a useful immunosuppressant for organ transplantation, allowing decreased dosage of concomitant immunosuppressive drugs.


Case report of abdominal left upper quadrant collection secondary to fish bone perforation.
We present an unusual case of an intra-abdominal collection which evidenced a rare etiology and raises diagnostic particularities. Fish bones ingestion is frequent, but seldom followed by complications. Those are often reported at specific sites. This case report emphasizes the unusual presentation and site localization of a colonic perforation by a small fish bone, in the context of limited radiological accuracy at the diagnostic phase. A 37 year old male was admitted to the gastroenterology ward with upper and left sided abdominal pain associated with fever and marked fatigue. His medical history was marked by a sleeve gastrectomy in 2010 for obesity. Abdominal signs and elevated acute inflammatory syndrome on blood tests were followed by computer tomography which revealed a pericolic mass near the left splenic flexure. The pain and fever increased in intensity, so a laparotomy was proposed. Intraoperatively, a tumor-like lesion was found and a resection with oncologic limits was performed. Microscopic examination of the specimen revealed a fish bone, but only after surgery did the patient confirm that he had eaten fish meal the week before. The post-operative period was uneventful. Fish bones remain some of the most frequently ingested alimentary foreign bodies; they may cause atypical clinical presentations, frequently omitted by the patients themselves if symptoms appear delayed. They could also lead to possible high-risk complications which need to be addressed by surgeons.


Problem-solving training for family caregivers of persons with traumatic brain injuries: a randomized controlled trial.
To test the hypothesis that a problem-solving training program would lower depression, health complaints, and burden, and increase well-being reported by community-residing family caregivers of persons with traumatic brain injuries (TBIs). Randomized controlled trial. General community. Of the 180 people who expressed interest in the study, 113 did not meet eligibility criteria. A consenting sample of family caregivers were randomized into a problem-solving training group (4 men, 29 women; average age, 51.3y) or an education-only control group (34 women; average age, 50.8y). Care recipients included 26 men and 7 women in the intervention group (average age, 36.5y) and 24 men and 10 women in the control group (average age, 37.2y). Problem-solving training based on the D'Zurilla and Nezu social problem-solving model was provided to caregivers in the intervention group in 4 in-home sessions and 8 telephone follow-up calls over the course of their year-long participation. Control group participants received written educational materials and telephone calls at set intervals throughout their 12 months of participation. Caregiver depression, health complaints, well-being, and social problem-solving abilities. Hierarchical linear models revealed caregivers receiving problem-solving training reported significant decreases in depression, health complaints, and in dysfunctional problem-solving styles over time. No effects were observed on caregiver well-being, burden, or constructive problem-solving styles. Problem-solving training provided in the home appears to be effective in alleviating distress and in decreasing dysfunctional problem-solving styles among family caregivers of persons with TBI. Methodologic limitations and the implications for interventions and future research are discussed.


The "mortality ascent": Hourly risk of death for hemodynamically unstable trauma patients at Level II versus Level I trauma centers.
Severely injured trauma patients have higher in-hospital mortality at Level II versus Level I trauma centers (TCs). To better understand these differences, we sought to determine if there were any periods during which hemodynamically unstable trauma patients are at higher risk of death at Level II versus Level I TCs within the first 24 hours postadmission. Trauma patients aged 18 years to 64 years, with Injury Severity Score of 15 or greater, systolic blood pressure less than 90 mm Hg at admission, and treated at Level II or Level I TCs, were identified using the 2007 to 2012 National Trauma Data Bank. Burn patients, transfers, and patients dead on arrival were excluded. Log-binomial regression models, adjusted for patient- and hospital-level confounders, were used to compare mortality at Level II versus Level I TCs over the first 24 hours postadmission. Of 13,846 hemodynamically unstable patients, 4,212 (30.4%) were treated at 149 Level II TCs, and 9,634 (69.6%) at 116 Level I TCs. Within the first 24 hours, 3,059 (22.1%) patients died. In risk-adjusted models, mortality risk was significantly elevated at Level II versus Level I TCs during the 24 hours postadmission (relative risk, 1.08; 95% confidence interval, 1.01-1.16). Hourly mortality risk was significantly different between Level II and Level I TCs during 4 hours to 7 hours postadmission, with a maximal difference at 7 hours (relative risk, 1.70; 95% confidence interval, 1.23-2.36) and comparable mortality risk beyond 7 hours postadmission. The 4-hour to 7-hour time window postadmission is critical for hemodynamically unstable trauma patients. Variations in available treatment modalities may account for higher relative mortality at Level II TCs during this time. Further investigation to elucidate specific risk factors for mortality during this period may lead to reductions in in-hospital mortality among hemodynamically unstable trauma patients. Therapeutic/care management, level IV.


Molecular simulation of 8-styrylxanthines.
Regarding theophylline as representative xanthine derivative, it was shown that the net charges of various semiempirical quantum chemistry methods are transferable by scaling. PM3 should be preferred for calculation of xanthine derivatives. Molecular modelling indicated that there is a conformational similarity of the lead structure of xanthine and adenosine derivatives. The substituents bound to the C8 of xanthine and to the C2 of adenosine derivatives are involved in the discrimination into adenosine A2 antagonists and agonists. The A2 affinity of xanthines is mainly determined by the type of N7 substitution (hydrogen/methyl), the lipophilic substituent constant related to the C8 substituents, and the dipole moment of the molecules. To simulate chemically the A1 affinity, a further term (lowest unoccupied molecular orbital energy) must be added. In addition, hydrogen-bonding forces were hypothesized using a newly synthesized 3,6-diaminocarbazole derivative as synthetic adenosine pseudoreceptor.


[Pregnancy induced hypertension risk factors in diabetes mellitus pregnant women].
Relation between gestational diabetes mellitus and pregnancy-induced hypertension increases significantly the maternal and perinatal morbidity and mortality risk. The purpose of this study was to investigate the risk factors for pregnancy-induced hypertension in women with gestational diabetes mellitus. In this case-control study, were compared a total of 90 women with gestational diabetes mellitus according to absence (controls, n = 60) or presence (cases, n = 30) of pregnancy-induced hypertension in terms of demographic data, previous reproductive history, maternal and neonatal characteristics. Odds ratios and 95 percent confidence intervals were calculated to estimate the effects of individual factors on the risk of pregnancy-induced hypertension. In our study, the body mass index in cases was greater than controls (35.70 +/- 8.7 vs. 31.17 +/- 5.2). In addition, pregnancy-induced hypertension in a previous pregnancy was the only factor associated with an increased risk of recurrent hypertension (OR = 4.52, IC95%: 1.02-20.03). Women with gestational diabetes mellitus and pregnancy-induced hypertension in a previous pregnancy require more surveillance for to prevent or achieve an early diagnosis and treatment of hypertension, and if the woman is overweight, she should be offered advice on life style adjustment for to avoid maternal and perinatal complications.


Transmasculine Voice Modification: A Case Study.
This case study measured the effects of manual laryngeal therapy on the fundamental frequency (fo), formant frequencies, estimated vocal tract length, and listener perception of masculinity of a 32-year-old transmasculine individual. The participant began testosterone therapy 1.5 years prior to the study. Two therapy approaches were administered sequentially in a single session: (1) passive circumlaryngeal massage and manual laryngeal reposturing, and (2) active laryngeal reposturing with voicing. Acoustic recordings were collected before and after each treatment and 3 days after the session. Speaking fo decreased from 124 Hz to 120 Hz after passive training, and to 108 Hz after active training. Estimated vocal tract length increased from 17.0 cm to 17.3 cm after passive training, and to 19.4 cm after active training. Eight listeners evaluated the masculinity of the participant's speech; his voice was rated as most masculine at the end of the training session. All measures returned to baseline at follow-up. Overall, both acoustic and perceptual changes were observed in one transmasculine individual who participated in manual laryngeal therapy, even after significant testosterone-induced voice changes had already occurred; however, changes were not maintained in the follow-up. This study adds to scant literature on effective approaches to and proposed outcome measures for voice masculinization in transmasculine individuals.


Laboratory risk indicator for necrotising fasciitis (LRINEC) score for the assessment of early necrotising fasciitis: a systematic review of the literature.
Introduction Early operative debridement of necrotising fasciitis is a major outcome determinant. Identification and diagnosis of such patients can be clinically difficult. The Laboratory Risk Indicator for Necrotising Fasciitis (LRINEC) score first published in 2004 is based on routinely performed parameters and offers a method for identifying early cases. No literature review has yet been performed on the application of such a score. Methods A systematic review of English-language literature was performed from 2004 to 2014 to identify articles reporting use of LRINEC score and the incidence of necrotising fasciitis. We performed a critical review of PubMed, Medline and Embase in line with the PRISMA statement. A meta-analysis was performed with a random effects model and 95% confidence interval. Suitable correlation coefficient and receiver operating characteristic (ROC) curves were also calculated. Results After application of inclusion criteria, 16 studies with 846 patients were included. The mean LRINEC score in patients with necrotising fasciitis was 6.06. Two papers reported LRINEC score in patients without necrotising fasciitis with a mean 2.45. All six studies with a reported coefficient of variance were < 1; Pearson correlation coefficient was r = 0.637 (P = 0.011). An ROC curve showed an area under the curve of 0.927. Conclusions The LRINEC score is a useful clinical determinant in the diagnosis and surgical treatment of patients with necrotising fasciitis, with a statistically positive correlation between LRINEC score and a true diagnosis of necrotising fasciitis.


An ultrastructural study of GABA-immunoreactive neurons and terminals in the septum of the rat.
The fine structure and types of contact made by GABAergic elements in the septal nuclei were studied at the electronmicroscopic level by means of peroxidase immunocytochemistry, using anti-GABA antibodies. Observations were made on normal and colchicine-injected rats. GABA-immunoreactivity was distributed within somata, dendrites, axonal varicosities and terminals, and myelinated axons. The peroxidase reaction product was diffuse in the cytoplasm; cytoplasmic organelles were generally devoid of immunoreactivity, while showing a strong reaction on the outer surface of their membrane. GABA-immunoreactive (GABA-I) neurons were small (10 microns on average) to medium (20 microns) in size, with round or multipolar cell bodies. Additionally, labeled large (30 microns) cells were observed within the myelinated fibers of the medial septal nucleus after intraseptal administration of colchicine. No difference in the ultrastructural features and distribution of the immunoreactivity of the 2 kinds of cell was noticed, except for a higher number of synaptic contacts on large neurons of the medial septum. GABA-I cells of the medial and lateral nuclei received synapses on their soma and dendrites, made by both immunonegative and GABA-I terminals. Nonimmunoreactive boutons contacting GABA-I cell bodies were of 2 types: those containing small, clear synaptic vesicles and those that additionally contained large dense vesicles. Synaptic vesicles of GABA-I boutons were rarely labeled internally, but showed varying electron densities. Synapses made by GABA-I boutons on GABA-I or unlabeled somata and dendrites were always of symmetrical type. Synapses made by non-GABA-I boutons on GABA-I cells were either symmetrical or asymmetrical.


Identification of a high-affinity network of secretagogin-binding proteins involved in vesicle secretion.
Secretagogin is a hexa EF-hand Ca(2+)-binding protein expressed in neuroendocrine, pancreatic endocrine and retinal cells. The protein has been noted for its expression in specific neuronal subtypes in the support of hierarchical organizing principles in the mammalian brain. Secretagogin has previously been found to interact with SNAP25 involved in Ca(2+)-induced exocytosis. Here, the cellular interaction network of secretagogin has been expanded with nine proteins: SNAP-23, DOC2alpha, ARFGAP2, rootletin, KIF5B, β-tubulin, DDAH-2, ATP-synthase and myeloid leukemia factor 2, based on screening of a high content protein array and validation and quantification of binding with surface plasmon resonance and GST pulldown assays. All targets have association rate constants in the range 10(4)-10(6) M(-1) s(-1), dissociation rate constants in the range 10(-3)-10(-5) s(-1) and equilibrium dissociation constants in the 100 pM to 10 nM range. The novel target SNAP23 is an essential component of the high affinity receptor for the general membrane fusion machinery and an important regulator of transport vesicle docking and fusion. Complementary roles in vesicle trafficking are known for ARFGAP2 and DOC2alpha in regulating fusion of vesicles to membranes, kinesin 5B and tubulin for transport of vesicles in the cell, while rootletin builds up the rootlet believed to function as a scaffold for vesicles. The identification of a discrete network of interacting proteins that mediate secretion and vesicle trafficking suggests a regulatory role for secretagogin in these processes.


Genome instability in Alzheimer disease.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Autosomal dominant, familial AD (fAD) is very rare and caused by mutations in amyloid precursor protein (APP), presenilin-1 (PSEN-1), and presenilin-2 (PSEN-2) genes. The pathogenesis of sporadic AD (sAD) is more complex and variants of several genes are associated with an increased lifetime risk of AD. Nuclear and mitochondrial DNA integrity is pivotal during neuronal development, maintenance and function. DNA damage and alterations in cellular DNA repair capacity have been implicated in the aging process and in age-associated neurodegenerative diseases, including AD. These findings are supported by research using animal models of AD and in DNA repair deficient animal models. In recent years, novel mechanisms linking DNA damage to neuronal dysfunction have been identified and have led to the development of noninvasive treatment strategies. Further investigations into the molecular mechanisms connecting DNA damage to AD pathology may help to develop novel treatment strategies for this debilitating disease. Here we provide an overview of the role of genome instability and DNA repair deficiency in AD pathology and discuss research strategies that include genome instability as a component.


Membrane Cholesterol in Skeletal Muscle: A Novel Player in Excitation-Contraction Coupling and Insulin Resistance.
Membrane cholesterol is critical for signaling processes in a variety of tissues. We will address here current evidence supporting an emerging role of cholesterol on excitation-contraction coupling and glucose transport in skeletal muscle. We have centered our review on the transverse tubule system, a complex network of narrow plasma membrane invaginations that propagate membrane depolarization into the fiber interior and allow nutrient delivery into the fibers. We will discuss current evidence showing that transverse tubule membranes have remarkably high cholesterol levels and we will address how modifications of cholesterol content influence excitation-contraction coupling. In addition, we will discuss how membrane cholesterol levels affect glucose transport by modulating the insertion into the membrane of the main insulin-sensitive glucose transporter GLUT4. Finally, we will address how the increased membrane cholesterol levels displayed by obese animals, which also present insulin resistance, affect these two particular skeletal muscle functions.


Diagnosis and treatment patterns for patients with leptomeningeal metastasis from solid tumors across Europe.
Leptomeningeal metastases are a late manifestation of systemic cancer which affects up to 10% of patients with solid tumors. Prognosis is poor, and overall survival at 1 year is only approximately 10%. Management depends mainly on general and neurological condition, primary tumor, and patterns of metastasis, notably absence or presence of concurrent systemic or solid brain metastases. Here we set out to characterize current practice patterns of diagnosis and treatment of patients with leptomeningeal metastasis in Europe. We prepared a web-based survey including 25 simple or multiple choices questions on best practice supplemented by eight case vignettes with various diagnosis and management options. The survey was sent to the membership of the European Association of Neuro-Oncology and the European Organisation for Research and Treatment of Cancer Brain Tumor Group. Between April 7, 2016 and August 8, 2016, 224 colleagues from 26 countries initiated the survey, 115 colleagues completed the whole survey. There were major differences both in the general diagnostic and therapeutic approach, e.g., regarding the use of cerebrospinal fluid (CSF) flow studies, intra-CSF chemotherapy, various types of radiotherapy, and even more so when selecting decisions on diagnostic and therapeutic measures for single case vignettes. Diagnosis and treatment decisions for patients with leptomeningeal metastasis from solid tumors vary widely across Europe. Standardization of diagnosis and evaluation tools as well as controlled studies to improve the level of evidence for all therapeutic approaches to LM are required.