Substance use disorder treatment retention and completion: a prospective study of horse-assisted therapy (HAT) for young adults.
Keeping substance use disorder patients actively engaged in treatment is a challenge. Horse-assisted therapy (HAT) is increasingly used as a complementary therapy, with claimed motivational and other benefits to physical and psychological health. This naturalistic study aimed to assess HAT's impact on the duration and completion of treatment for young substance users at Oslo University Hospital. Discharge and other data were derived from the Youth Addiction Treatment Evaluation Project (YATEP) database for patients (n = 108) admitted during an 18-month period. An intention-to-treat design, and univariate and multivariate analyses were used to compare those receiving treatment as usual (n = 43) with those who received treatment as usual plus HAT (n = 65). Despite a lack of randomization, the baseline characteristics of the two groups were similar. However, more HAT participants completed treatment (56.9 vs 14 %, p < 0.001), remained in treatment for longer (mean 141 vs 70 days, p < 0.001) and had a significantly higher chance of completing their treatment than those not given the HAT program. Excluding time in treatment, and after controlling for the potentially confounding influence of age, sex, education, number and severity of substances used, psychological distress and number of temporary exits, the adjusted odds ratio for treatment completion was 8.4 in the HAT group compared with those not participating in HAT (95 % CI 2.7-26.4, p < 0.001). The study found a statistically significant association between HAT participation and time in treatment, and between HAT participation and completion of treatment. This association does not infer causality. However, it adds supporting evidence for the development of an innovative therapy, and warrants investment in further research in relation to its inclusion in substance use disorder treatment.


Rifampicin-moxifloxacin interaction in tuberculosis treatment: a real-life study.
Rifampicin (RMP) has been reported to reduce moxifloxacin (MFX) levels, which may interfere with the effectiveness of MFX in treating tuberculosis (TB). To study the MFX-RMP interaction in patients receiving MFX with or without RMP as part of their anti-tuberculosis treatment regimen. Patients with pulmonary TB followed up by the Tuberculosis Out-patient Clinic of the Pulmonary Department, Aristotle University of Thessaloniki, Greece, who underwent treatment with MFX during the periods 1 May 2012-30 April 2014 and 1 January-31 March 2015, were included in the study. MFX levels were compared between 12 patients who were receiving RMP (Group 1) and 10 who were not (Group 2). The participants did not significantly differ in body mass index, days of MFX treatment or MFX dose/kg. Neither the peak concentration (Cmax) nor the 24 h area under the curve (AUC24) differed significantly between the two groups (Group 1, Cmax median 3.9 [range 1.9-4.5] mg/l; AUC24 29.1 [10-47.4] mg·h/l and Group 2, Cmax 4.1 [2-6.4] mg/l; AUC24 36.5 [14.6-54.2] mg·h/l). Although a decrease in MFX exposure was observed in the RMP-treated group, the effect was lower than previously reported in a real-life setting. The large variability observed in MFX pharmacokinetics in both groups may suggest the need for dose readjustment in some patients, regardless of RMP co-administration.


Purulent pericarditis as a complication of bacteraemic Enterococcus faecalis urinary tract infection.
Purulent pericarditis is a rare clinical entity in the modern antibiotic era. The most common portal of entry is thought to be direct extension from a primary lung source and is usually caused by Staphylococcus aureus, Streptococcus pneumoniae or Haemophilus influenzae We report the case of a man aged 69 years who presented with purulent pericarditis due to Enterococcus faecalis likely caused by haematogenous spread from a urinary tract source. Urgent pericardiocentesis was vital and restored his haemodynamic stability. He was treated for a total duration of 4 weeks with susceptible antibiotics. Echocardiography 3 weeks later showed persistent resolution of the pericardial effusion. This case shows that prompt diagnosis and drainage of the pericardial effusion are vital to achieve a positive outcome in purulent pericarditis. To the best of our knowledge, this is the first reported case of purulent pericarditis caused by E. faecalis from a urinary tract source.


Effect of EMG-triggered stimulation combined with comprehensive rehabilitation training on muscle tension in poststroke hemiparetic patients.
The aim of this study was to investigate the effect of electromyography stimulation (EMGS) combined with comprehensive rehabilitation training on muscle tension of paretic limb in poststroke hemiparetic patients. Forty poststroke hemiparetic patients were randomly divided into 2 groups (N.=20 each): control group that received conventional therapy and experimental group that underwent EMGS combined with comprehensive rehabilitation training in addition to conventional therapy. The outcome was assessed by Fugl-Meyer Score, functional ambulation category (FAC) Scale and integrated electromyography (iEMG) for both pretreatment and post-treatment. The results were analyzed using paired t-test and group t-test. No statistical significance was observed for Fugl-Meyer Score, FAC Score and iEMG values between control and experimental groups prior to the treatment (P>0.05). However, Fugl-Meyer and FAC scores were improved and iEMG values of gastrocnemius muscle were significantly decreased (P<0.05) in experimental group post-treatment. Thus, EMGS combined with comprehensive rehabilitation training show statistically significant interaction effect on Fugl-Meyer Score, FAC score and iEMG values (P<0.05), suggesting a positive effect of this combined therapy on functional recovery of post-stroke hemiparetic patients. The iEMG values in both groups were also consistent with the Fugl-Meyer and FAC scores. EMGS combined with comprehensive rehabilitation training can synergistically reduce muscle tension and relieve muscular spasticity of paretic limb in post-stroke patients. The iEMG proved to be a potential candidate for the evaluation of motor function in these patients.


Diagnostic Electron Microscopy of Retina.
The electron microscopy techniques were used in various fields as an analytical technique under in vitro conditions, which provides the sufficient resolution for better visualization and interpretation. This review gives a brief overview of the analytical application of transmission electron microscopy (TEM) and scanning electron microscopy (SEM) techniques and critical findings in different retinal pathologies. This review article aims to improvise understanding of retinal microstructures for clinicians which will help to improve the interpretation of the current advanced imaging techniques.


Lessons for Health From Insights into Environmental Crises.
The health of whole populations within nations and globally and the implications of climate change are two of the most important challenges facing humanity in the 21st century. Both are components of a complex global crisis that must be acknowledged and addressed. Here we draw the attention of health professionals to some emerging threats and insights from key works of environmentalists in the hope that these may catalyze reflection on the broader challenges facing human health at a time of deep planetary malaise.


Association of PTSD symptom groups with functional impairment and distress in trauma-exposed disaster survivors.
In the nearly a quarter of a century since the addition of the clinically significant distress/impairment criterion to the definition of PTSD in DSM-IV, little research has been done to examine the association of this criterion with symptom group criteria and with the numbing subgroup specifically. This study was conducted to examine these relationships in a large database of disaster survivors consistently studied across 12 different incidents of the full range of disaster typology. Analysis was conducted on a merged database representing 1187 trauma-exposed survivors of 12 different disasters studied systematically. DSM-IV-TR criteria for disaster-related PTSD were assessed with the Diagnostic Interview Schedule. PTSD Group C (avoidance/numbing) and numbing specifically were less common and more associated than other symptom groups with criterion F (distress/impairment). Consistently in multivariable models, group C and numbing were independently associated with criterion F. Group D (hyperarousal) was less strongly associated with criterion F. Neither group B (intrusion) nor avoidance were associated with criterion F. In this and other studies, group C and numbing specifically have been shown to be associated with criterion F, which is consistent with the demonstration that group C and the numbing component specifically are central to the psychopathology of PTSD. The addition of the distress/impairment requirement broadly across the psychiatric diagnoses in DSM-IV added little value to PTSD symptom criteria. Future revisions of diagnostic criteria may benefit by carefully considering these findings to possibly re-include a prominent numbing symptom section.


Functional reorganization and prediction of motor recovery after a stroke: A graph theoretical analysis of functional networks.
This study investigated the changes in the network topological configuration of the ipsilesional and contralesional hemispheres after a stroke and the indicators for the prediction of motor recovery using a graph theoretical approach in networks obtained from functional magnetic resonance imaging (fMRI). A longitudinal observational experiments (2 weeks and 1, 3, and 6 months after onset) were conducted on 12 patients after a stroke. We investigated the network reorganization during recovery in the ipsilesional and contralesional hemispheres by examining changes of graph indices related to network randomization. We predicted the recovery of motor function by examining the relationship between specific network measures and improved motor function scores. The ipsilesional hemispheric network showed active reorganization during recovery after a stroke. The randomness of the network significantly increased for 3 months post-stroke. We described an indicator for the prediction of the recovery of motor function from graph indices: the characteristic path length. As the path length of the ipsilesional network was lower immediately after onset, the better recovery could be expected after 3 months. This approach were helpful for understanding dynamic reorganizations of both hemispheric networks after a stroke and finding the implication for recovery.


[Shaping ability of multi-taper nickel-titanium files in simulated resin curved root canal].
To compare the shaping ability of ISO standard stainless steel K files and multi-taper ProTaper nickel-titanium files in simulated resin curved root canals. METHODS Thirty simulated resin root canals were randomly divided into three groups and prepared by stainless steel K files, hand ProTaper, rotary ProTaper, respectively. The amount of material removed from inner and outer wall and canal width after canal preparation was measured, while the canal curvature before and after canal preparation and canals aberrations were recorded. The stainless steel K files removed more material than hand ProTaper and rotary ProTaper at the outer side of apex and inner side of curvature (P < 0.05). The mean degree of straightening in stainless steel K files group was significantly bigger than in ProTaper group (P < 0.05). The canals prepared by ProTaper had no evident aberration. The shaping ability of ProTaper is better than stainless steel K files.


Safety of cardiac catheterization via peripheral vascular grafts.
There are few data concerning the complications and technical difficulties encountered when cardiac catheterization is performed using peripheral bypass grafts for vascular access. All cardiac catheterizations performed at our institution from January 1, 1984 to April 1, 1991 were retrospectively reviewed to assess the in-hospital clinical outcomes in patients who had arterial access for catheterization achieved via prosthetic graft puncture. Seventeen procedures had percutaneous puncture of a vascular graft from a total of 2,929 arterial catheterizations performed. The interval from graft placement to catheterization was 7.5 +/- 1.1 years. Arterial sheaths were employed in all cases and corresponded to the catheter size, with 5F systems used in 53% and 7F or larger systems used in the remaining patients. No intraprocedural or postprocedural complications were recognized. Technical difficulties were limited to the inability to selectively cannulate a nondominant right coronary artery in 1 patient. We conclude that percutaneous introduction of an arterial sheath and left heart catheterization via remotely implanted vascular bypass grafts is not associated with an increased risk of procedural complications or technical difficulties.


Primary Ovarian Neuroendocrine Carcinoid Tumor Arising in a Mature Cystic Teratoma.
Primary ovarian neuroendocrine carcinoid tumors are extremely rare. However, their clinical course is good, and hence, fertility-sparing surgery is a feasible treatment option in cases of unilateral localized lesions. In this report, we present the case of a 20-year-old nulliparous woman who was diagnosed as having a primary ovarian neuroendocrine carcinoid tumor arising from a mature cystic teratoma. She underwent laparoscopic right ovarian cystectomy, and her postoperative recovery was uneventful. The patient has been under close observation over a 1-year follow-up period and has shown no evidence of tumor recurrence.


Gastrointestinal manifestations of AIDS.
Although gastrointestinal complications have decreased dramatically in patients with acquired immunodeficiency syndrome (AIDS) who received highly active antiretroviral therapy, these disorders still occur in those who do not seek healthcare, those with resistant virus, and those in developing countries where these drugs are not available. Opportunistic infections are the most frequent causes of gastrointestinal disease in patients with AIDS. A practical approach based on the character of the complaints and location of symptoms will help direct the most appropriate evaluation. In most patients, a diagnosis should be sought because effective antimicrobial therapy is available for most infections in these patients. When possible, improvement in immune function forms an integral part of the treatment regimen.


Alpha-Synuclein Disease Mutations Are Structurally Defective and Locally Affect Membrane Binding.
The intrinsically disordered human protein alpha-Synuclein (αS) has a prominent role in Parkinson's disease (PD) pathology. Several familial variants of αS are correlated with inherited PD. Disease mutations have been shown to have an impact on lipid membrane binding. Here, using electron paramagnetic resonance spectroscopy in combination with site-directed spin labeling, we show that familial PD-associated variants are structurally defective in membrane binding and alter the local binding properties of the protein.


Clozapine-induced eosinophilia: A case report.
Schizophrenia is a chronic neuropsychiatric illness defined by the appearance of positive, and negative symptoms and/or cognitive impairment. Antipsychotic drugs are predominantly used in the treatment of psychotic disorders, but not all patients with schizophrenia respond to every antipsychotic medication. Clozapine is one of the best atypical antipsychotics and is highly effective in treating treatment-resistant schizophrenia. Evidence suggests that clozapine appears to be effective in lowering the risk of suicide, extrapyramidal side effects, and relapse in patients with schizophrenia. Per contra, clozapine is not the first-line treatment due to its unalterable aftereffects such as agranulocytosis, metabolic syndrome, seizures, and rarely, eosinophilia. Eosinophilia can be life-threatening. Eosinophils infiltrate different tissues and cause inflammation in multiple organs causing end-organ damage. The current study aimed to report the incidence of eosinophilia associated with clozapine use in patients with schizophrenia. Literature on clozapine-induced eosinophilia is relatively scarce. Understanding the progression and management of clozapine-induced eosinophilia and its end-organ effects is imperative. While there is insufficient data about the guidelines in the management of clozapine-induced eosinophilia, this study contributes to understanding the patterns of the disease progression with clozapine dosage. A case study was done on a patient with schizophrenia and autistic spectrum disorder who was on clozapine. Data on how eosinophil levels varied with clozapine dosing was analyzed and documented. The evidence of clozapine dosage affecting eosinophil and C-reactive protein levels in this patient was summarized in a table and a narrative review.


A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics.
Novel chemotherapeutics with marked and selective antitumor activity are essential to develop, particularly those that can overcome resistance to established therapies. Iron (Fe) is critical for cell-cycle progression and DNA synthesis and potentially represents a novel molecular target for the design of new anticancer agents. The aim of this study was to evaluate the antitumor activity and Fe chelation efficacy of a new class of Fe chelators using human tumors. In this investigation, the ligands showed broad antitumor activity and could overcome resistance to established antitumor agents. The in vivo efficacy of the most effective chelator identified, di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone (Dp44mT), was assessed by using a panel of human xenografts in nude mice. After 7 weeks, net growth of a melanoma xenograft in Dp44mT-treated mice was only 8% of that in mice treated with vehicle. In addition, no differences in these latter animals were found in hematological indices between Dp44mT-treated mice and controls. No marked systemic Fe depletion was observed comparing Dp44mT- and vehicle-treated mice, probably because of the very low doses required to induce anticancer activity. Dp44mT caused up-regulation of the Fe-responsive tumor growth and metastasis suppressor Ndrg1 in the tumor but not in the liver, indicating a potential mechanism of selective anticancer activity. These results indicate that the novel Fe chelators have potent and broad antitumor activity and can overcome resistance to established chemotherapeutics because of their unique mechanism of action.


TGF beta 2 and TGF beta 3 are potent survival factors for midbrain dopaminergic neurons.
The vertebrate ventral midbrain contains 3-4 x 10(4) dopaminergic neurons that influence motor activity, emotional behavior, and cognition. Recently, glial cell line-derived neurotrophic factor (GDNF) was shown to be a potent survival factor for these dopaminergic neurons in culture. However, many midbrain dopaminergic neurons project to targets that do not express GDNF. We report here that transforming growth factors (TGFs) TGF beta 2 and TGF beta 3, which are distantly related to GDNF, also prevent the death of cultured rat embryonic midbrain dopaminergic neurons at picomolar concentrations. Furthermore, we find that TGF beta 2, TGF beta 3, and GDNF are expressed sequentially as local and target-derived trophic factors and that subpopulations of dopaminergic neurons projecting to distinct targets have access to only one of these factors. These findings are consistent with the idea that GDNF, TGF beta 2, and TGF beta 3 are physiological survival factors for developing midbrain dopaminergic neurons and may have applications as therapeutics for Parkinson's disease, a neurodegenerative disorder of dopaminergic neurons.


Solitary intradural extramedullary lymphoma of the cervical spine.
The authors report on the case of a 64-year-old man with solitary intradural extramedullary non-Hodgkin lymphoma of the cervical spine. The lesion mimicked the appearance of meningioma on MR imaging. Positron emission tomography showed increased accumulation of fluorine-18-labeled fluorodeoxyglucose only in the cervical lesion. Serum levels of C-reactive protein and soluble interleukin-2 receptor were mildly elevated. At surgery, the intradural tumor in the subarachnoid space was totally extirpated. Based on histopathological findings, diffuse, large B-cell type non-Hodgkin lymphoma was diagnosed. Postoperatively, the patient was treated with 2 courses of chemotherapy by intrathecal injection of methotrexate, cytarabine, and prednisolone and 4 courses of intravenous rituximab, an antibody binding to CD20 on the surface of B cells. All preoperative symptoms completely resolved after surgery. Two years postoperatively, the patient was faring well with no evidence of local recurrence or new lesions at any other site. To the best of the authors' knowledge, this case is the first reported instance of solitary intradural extramedullary non-Hodgkin lymphoma of the cervical spine.


[Organisational issues in implementing clinical trials in primary care].
To identify health professionals concerns on the organisational issues of a randomised clinical trial. A qualitative cross-sectional, descriptive study. Primary Care Area 11, Madrid, Spain. Twenty-four doctors and nurses from 4 primary care teams. Three planning meetings with researchers. Design of an anonymous self-administered questionnaire to collect researchers' perceptions on design, method, and organisation during the implementation of a clinical trial. The prestige of being involved in a multi-centre nationwide project, the training sessions offered, a primary care research topic, a working team model of doctor and nurse, and the support provided by team from the 11th Area, were the main organisational incentives. Lack of time, increased clinic workload, and methodological difficulties are discouraging issues. 79.2% (19/24) of the researchers returned the questionnaire. 94.7% (18/19) considered themselves highly motivated. 84.2% (16/19) of researchers, the time required to complete recruitment was reasonable. The 57.9% (13/19) spent 20-25 minutes collecting data at the interview. Cooperation between doctors and nurses had been effective for 68.4% (13/19) of researchers. 89.4% (17/18) considered that support from the Area 11 organisers was useful. Organisational barriers for implementation are: complexity of data collection at the recruitment interview, design and methodological issues too unrealistic for a primary care setting, and lack of time and extra workload at consultations. The factors that make organisation easier are: having a high level of motivation, sharing workload with other professionals, and support provided by organisers of the trial.


Manual Dexterity in Schizophrenia-A Neglected Clinical Marker?
Impaired manual dexterity is commonly observed in schizophrenia. However, a quantitative description of key sensorimotor components contributing to impaired dexterity is lacking. Whether the key components of dexterity are differentially affected and how they relate to clinical characteristics also remains unclear. We quantified the degree of dexterity in 35 stabilized patients with schizophrenia and in 20 age-matched control subjects using four visuomotor tasks: (i) force tracking to quantify visuomotor precision, (ii) sequential finger tapping to measure motor sequence recall, (iii) single-finger tapping to assess temporal regularity, and (iv) multi-finger tapping to measure independence of finger movements. Diverse clinical and neuropsychological tests were also applied. A patient subgroup (N = 15) participated in a 14-week cognitive remediation protocol and was assessed before and after remediation. Compared to control subjects, patients with schizophrenia showed greater error in force tracking, poorer recall of tapping sequences, decreased tapping regularity, and reduced degree of finger individuation. A composite performance measure discriminated patients from controls with sensitivity = 0.79 and specificity = 0.9. Aside from force-tracking error, no other dexterity components correlated with antipsychotic medication. In patients, some dexterity components correlated with neurological soft signs, Positive and Negative Syndrome Scale (PANSS), or neuropsychological scores. This suggests differential cognitive contributions to these components. Cognitive remediation lead to significant improvement in PANSS, tracking error, and sequence recall (without change in medication). These findings show that multiple aspects of sensorimotor control contribute to impaired manual dexterity in schizophrenia. Only visuomotor precision was related to antipsychotic medication. Good diagnostic accuracy and responsiveness to treatment suggest that manual dexterity may represent a useful clinical marker in schizophrenia.


Is psychotherapy good for your health?
This is a dedicated review of the evidence for the relation of having a period of psychotherapy and then comparing it with a measure of improved physical health. We aimed to make it the first intended-to-be-complete review of this type. Three inter-related types of studies were examined: Type 1: reduction in physical illnesses through psychotherapy, especially for the patient's survival time during the interval between diagnosis and an end point, Type 2: reduction in pain in relation to receiving psychotherapy, and Type 3: reduction in costs of treatment in relation to receiving psychotherapy. To find the relevant studies on these topics, we performed a literature search using both Psychinfo and Medline databases. An average of the effect sizes under each type was taken to calculate the mean effect size along with its confidence interval. Our results (1) on survival time for the combined severe patients, did not reach even the lowest significant level of effect size, although the low severity patients seemed to fit the hypothesis better, but the other two reduction topics, (2) and (3), clearly did achieve it.


Tools for assessing outcomes in studies of chronic cough: CHEST guideline and expert panel report.
Since the publication of the 2006 American College of Chest Physicians (CHEST) cough guidelines, a variety of tools has been developed or further refined for assessing cough. The purpose of the present committee was to evaluate instruments used by investigators performing clinical research on chronic cough. The specific aims were to (1) assess the performance of tools designed to measure cough frequency, severity, and impact in adults, adolescents, and children with chronic cough and (2) make recommendations or suggestions related to these findings. By following the CHEST methodologic guidelines, the CHEST Expert Cough Panel based its recommendations and suggestions on a recently published comparative effectiveness review commissioned by the US Agency for Healthcare Research and Quality, a corresponding summary published in CHEST, and an updated systematic review through November 2013. Recommendations or suggestions based on these data were discussed, graded, and voted on during a meeting of the Expert Cough Panel. We recommend for adults, adolescents (≥ 14 years of age), and children complaining of chronic cough that validated and reliable health-related quality-of-life (QoL) questionnaires be used as the measurement of choice to assess the impact of cough, such as the Leicester Cough Questionnaire and the Cough-Specific Quality-of-Life Questionnaire in adult and adolescent patients and the Parent Cough-Specific Quality of Life Questionnaire in children. We recommend acoustic cough counting to assess cough frequency but not cough severity. Limited data exist regarding the performance of visual analog scales, numeric rating scales, and tussigenic challenges. Validated and reliable cough-specific health-related QoL questionnaires are recommended as the measurement of choice to assess the impact of cough on patients. How they compare is yet to be determined. When used, the reporting of cough severity by visual analog or numeric rating scales should be standardized. Previously validated QoL questionnaires or other cough assessments should not be modified unless the new version has been shown to be reliable and valid. Finally, in research settings, tussigenic challenges play a role in understanding mechanisms of cough.


Protective effect of L‑carnitine against oxidative stress injury in human ovarian granulosa cells.
Granulosa cells (GCs) are important for supporting and nourishing oocytes during follicular development and maturation. Oxidative stress (OS) injury of GCs can lead to decreased responsiveness of follicles to follicular stimulating hormone (FSH), which will accelerate ovarian senescence and adversely affect oocyte and embryo quality. Since L-carnitine has been previously reported to exert strong antioxidant activity, the present study aimed to explore the possible effects of L-carnitine on OS injury and FSH receptor (FSHR) expression in ovarian GCs, results of which may be of significance for GCs protection. In the present study, OS was induced in vitro in KGN cells by treatment with H2O2. KGN cells were cultured and divided into the following four groups: Blank, OS, and 40 and 80 µmol/l L-carnitine pre-treatment groups. In the OS group, cells showed nuclear pyknosis, mitochondria swelled irregularly whilst featuring fractured cristae. In addition, cell viability, ROS levels, superoxide dismutase levels, glutathione levels, malondialdehyde levels, the mitochondrial membrane potential and FSHR expression, as determined by Cell Counting Kit-8 (CCK-8), 2,7-dichloro-dihydrofluorescein diacetate, spectrophotometry, ELISA, spectrophotometry, JC-1 and western blot analyses, respectively, were all significantly different in the OS group compared with those in the control group. However, malonaldehyde levels, reactive oxygen species levels and the apoptosis rate according to flow cytometry were all significantly increased compared with those in the control. Compared with those in the OS group, the morphology of cells and mitochondria in the L-carnitine pre-treatment groups were improved, whilst cell viability and the expression of FSHR were significantly increased but oxidative stress injury was decreased. The present results suggest that L-carnitine can protect the cells from OS damage induced by H2O2, enhance antioxidant activity whilst suppressing the apoptosis of GCs, in addition to preserving FSHR expression in GCs under OS. Therefore, the present study revealed that the introduction of L-carnitine in clinical medicine or dietary supplement may protect GCs, improve follicular quality and female reproductive function.


Diffusion-limited friendship network: a model for six degrees of separation.
A dynamic model of a society is studied where each person is an uncorrelated and noninteracting random walker. A dynamical random graph represents the acquaintance network of the society whose nodes are the individuals and links are the pairs of mutual friendships. This network exhibits a different percolationlike phase transition in all dimensions. On introducing simultaneous death and birth rates in the population, we show that the friendship network shows the six degrees of separation for ever after where the precise value of the network diameter depends on the death/birth rate. A susceptible-infected-susceptible-type model of disease spreading shows that this society always remains healthy if the population density is less than certain threshold value.


[Effect of interleukin-6 and interleukin-12 on immune response to hepatitis B vaccination in infants of HBsAg-positive mothers].
Objective: To explore the effect of interleukin-6 (IL-6) and Interleukin-12 (IL-12) on immune response to hepatitis B vaccination in infants of HBsAg-positive mothers. Methods: A total of 91 neonates whose mothers were HBsAg-positive were included and followed up for 12 months. HBV DNA and HBV serological markers in the peripheral blood of the neonates and infants were detected with fluorescence quantitative polymerase chain reaction (FQ-PCR) and chemiluminescence immunoassay (CLIA), and the levels of IL-6 and IL-12 in the peripheral blood of the neonates and infants were detected with enzyme-linked immunosorbent assay (ELISA). Results: The non-/hypo-response rate to hepatitis B vaccination was 35.16% (32/91) in the 91 infants. In the neonatal period and infantile period, the level of IL-6 in non-/hypo-response group was lower than that in high-response group, while the level of IL-12 was higher than that in high-response group, and there was significant difference (P<0.01). From the neonatal period to the infantile period, the level of IL-6 increased, while the level of IL-12 descended in both groups, and there was significant difference (P<0.01). Furthermore, the level of anti-HBs of infants was positively correlated with the level of IL-6 (r(s)=0.70, 0.79, P<0.01), and was negatively correlated with the level of IL-12 (r(s)=-0.71, -0.72, P<0.01) in the neonatal period and the infantile period. From the neonatal period to the infantile period, the increased level of IL-6 was positively associated with the level of anti-HBs (r(s)= -0.74, P<0.01), while the decreased level of IL-12 was negatively associated with the level of anti-HBs (r(s)=-0.42, P<0.01). The level of IL-6 was negatively correlated with the level of IL-12 in the neonatal period and the infantile period (r(s)=-0.68, -0.70, P<0.01). Conclusions: IL-6 might promote the immune response to hepatitis B vaccination in infants whose mothers were HBsAg-positive, while IL-12 might inhibit the immune response. IL-6 and IL-12 would affect the immune response to hepatitis B vaccination in infants of HBsAg-positive mothers at the same time.


[Thyroid dysgenesis in mother and daughter].
A case of congenital hypothyroidism with lingual thyroid in a woman and her daughter is presented. The scarcity of familial cases of thyroid malformations leads to discuss the genetic factors involved.


Airway Collapsibility during Drug-Induced Sleep Endoscopy Relates with Clinical Features of Obstructive Sleep Apnea.
Increased pharyngeal collapsibility leads to obstructive sleep apnea (OSA). Positive airway pressure titration during drug-induced sleep endoscopy (DISE-PAP) provides objective collapsibility metrics, the pharyngeal opening pressure (PhOP), and active pharyngeal critical pressure (PcritA ). We examined the interrelationships between risk factors of OSA, airway collapsibility measures, and clinical manifestations of the disease. This is a cross-sectional analysis of consecutive OSA patients undergoing DISE-PAP. Nasal PAP was increased stepwise until inspiratory flow limitation was abolished, signifying PhOP. PcritA was derived from the resulting titration pressure-flow relationships. Clinical data including demographics, anthropometrics, sleep studies, and patient-symptom questionnaires were obtained from the electronic medical record. Multivariate regression was used to evaluate the relationship between risk factors, airway collapsibility, and clinical data. On average, the 164 patients meeting inclusion criteria were middle-aged (54.2 ± 14.7 years), overweight/obese (BMI 29.9 ± 4.5 kg/m2 ), male (72.6%), White (79.3%) and had severe OSA (AHI 32.0 ± 20.5 events/hour). Mean PhOP was 7.5 ± 3.3 cm H2 O and mean PcritA was 0.80 ± 3.70 cm H2 O. Younger age (Standardized β = -0.191, p = 0.015) and higher BMI (Standardized β = 0.176, p = 0.028) were associated with higher PhOP, but not PcritA . PhOP and PcritA were both associated with AHI, supine AHI, and SpO2 nadir. Higher PhOP was associated with higher snoring scores (Standardized β = 0.246, p = 0.008), but not other patient-reported outcomes. Objective assessment of passive and active airway mechanics during DISE relates with clinical risk factors for OSA. Quantitative measures of collapsibility provide accessible and meaningful data, enhancing the standard sleep surgery evaluation. 4 Laryngoscope, 2023.


"A Group of Fellow Travellers Who Understand": Interviews With Autistic People About Post-diagnostic Peer Support in Adulthood.
Receiving a diagnosis of autism in adulthood can be a life changing event, impacting identity, relationships, and mental health. A lack of post-diagnostic support has been highlighted by autistic adults, their allies, clinicians, and service providers. It can be a source of distress for autistic adults, reinforcing feelings of social isolation and rejection. Peer support could be a cost-effective, flexible, and sustainable model to provide community-based support for autistic adults. However, there is little research on the value of peer support, despite calls from the autistic community. This qualitative study explored autistic experiences and needs post-diagnosis, identifying specific ways that peer support may benefit them, and exploring the limitations of peer support. Twelve autistic adults who had all received an autism diagnosis in adulthood completed a semi-structured interview focussing on the diagnostic experience, post-diagnostic support needed and provided, engagement with the autistic community, and post-diagnostic peer support. Thematic analysis of interview transcripts resulted in four themes: (1) Mismatch in support needed and provided; (2) Community connection; (3) Flexible and personalised support; and (4) Sustainability. Participants indicated that peer support may be a useful mechanism to support autistic adults' post-diagnosis and offers unique opportunities not available through other support channels. Though informal peer support exists, it could be more sustainable and effective if well-supported and funded.


Effects of upper eyelid blepharoplasty on ocular surface sensation and tear production.
To evaluate the effect of upper eyelid surgery on ocular surface sensation and tear production. Prospective, interventional, consecutive case series. Patients undergoing upper eyelid blepharoplasty or blepharoptosis repair were evaluated with measurements of their corneal sensation and tear production using a Cochet-Bonnet esthesiometer and the Schirmer 1 test without anesthesia, respectively. Measurements were obtained preperatively, and at 1 day and 1 month postoperatively. Eleven patients (21 eyes) were enrolled in the study. There was a significant decrease in corneal sensation between the baseline and postperative day 1 (p < 0.01) and a significant increase between day 1 and month 1 after surgery (p < 0.01). There was no statistically significant difference in corneal sensation between the baseline and postoperative 1 month measurement (p > 0.05). There was no significant difference in tear production between baseline and postoperative day 1 (p > 0.05). There was a statistically significant increase in tear production between baseline and postoperative month 1 (p < 0.05). There was no significant correlation between corneal sensitivity and Schirmer 1 test preoperatively, at postoperative day 1, or at postoperative month 1 after surgery. Upper eyelid surgery results in a temporary decrease in ocular surface sensation that returns to baseline after 1 month. Patients with pre-existing ocular surface dysfunction should consider aggressive treatments with lubricating drops and ointment, punctual occlusion, or anti-inflammatory therapy to accommodate the temporary effects on ocular surface sensation that result from upper eyelid surgery.


Relation of bone mineral density to vitamin D receptor gene polymorphism and lifestyle factors in Japanese female workers aged 22-44 years: a cross-sectional study.
Bone mineral density (BMD) reflects both genetic and lifestyle factors. The aim of this cross-sectional study was to investigate the influence of vitamin D receptor (VDR) gene polymorphism and lifestyle factors on BMD in premenopausal female workers. The subjects were 162 premenopausal female employees aged 22-44 y who worked at a large-scale integrated manufacturing facility in Japan. BMD was measured at the nondominant radius by dual energy X-ray absorptiometry. Lifestyle information was obtained by a questionnaire at the same time and genomic DNA was isolated from peripheral leukocytes. BMD was positively correlated with age, weight, and body mass index (BMI). The genotype frequencies of VDR gene polymorphism detected by TaqI analysis were 77.2, 22.8, and 0.0% for TT, Tt, and tt, respectively. Analysis of covariance with adjustment for age and BMI showed that the mean BMD was significantly lower in subjects with the Tt genotype than in those with the TT genotype. Subjects who drank alcohol also showed a significantly lower BMD if they had the Tt genotype than if they had the TT genotype. According to multiple linear regression analysis, the independent determinants of BMD were age, BMI, and VDR gene polymorphism. Our data show that BMD is negatively correlated with the Tt genotype of the VDR gene, but positively correlated with age and BMI. These findings suggest that analysis of VDR gene polymorphism may be useful for identifying individuals who are susceptible to osteoporosis so that early preventive measures can be provided.


Crack nucleation using combined crystal plasticity modelling, high-resolution digital image correlation and high-resolution electron backscatter diffraction in a superalloy containing non-metallic inclusions under fatigue.
A crystal plasticity finite-element model, which explicitly and directly represents the complex microstructures of a non-metallic agglomerate inclusion within polycrystal nickel alloy, has been developed to study the mechanistic basis of fatigue crack nucleation. The methodology is to use the crystal plasticity model in conjunction with direct measurement at the microscale using high (angular) resolution-electron backscatter diffraction (HR-EBSD) and high (spatial) resolution-digital image correlation (HR-DIC) strain measurement techniques. Experimentally, this sample has been subjected to heat treatment leading to the establishment of residual (elastic) strains local to the agglomerate and subsequently loaded under conditions of low cyclic fatigue. The full thermal and mechanical loading history was reproduced within the model. HR-EBSD and HR-DIC elastic and total strain measurements demonstrate qualitative and quantitative agreement with crystal plasticity results. Crack nucleation by interfacial decohesion at the nickel matrix/agglomerate inclusion boundaries is observed experimentally, and systematic modelling studies enable the mechanistic basis of the nucleation to be established. A number of fatigue crack nucleation indicators are also assessed against the experimental results. Decohesion was found to be driven by interface tensile normal stress alone, and the interfacial strength was determined to be in the range of 1270-1480 MPa.


Integrative analysis of DNA methylation and gene expression reveals key molecular signatures in acute myocardial infarction.
Acute myocardial infarction (AMI) has been one of the most fatal diseases among all types of heart diseases due to its rapid onset and high rates of fatality. Understanding accurately how multi-omics molecular features change at the early stage of AMI is crucial for its treatment. Currently, the changes involved in DNA methylation modification and gene expression of multiple genes have remained unexplored. We used the RNA-seq and MeDIP-seq on heart tissues from AMI mouse models at series of time points (Sham, AMI 10-min, 1-h, 6-h, 24-h and 72-h), to comprehensively describe the transcriptome and genome-wide DNA methylation changes at above time points. We identified 18814, 18614, 23587, 26018 and 33788 differential methylation positions (DMPs) and 123, 135, 731, 1419 and 2779 differentially expressed genes (DEGs) at 10-min, 1-h, 6-h, 24-h and 72-h AMI, respectively, compared with the sham group. Remarkably, the 6-h AMI with the drastic changes of DEGs and a large number of enriched functional pathways in KEGG may be the most critical stage of AMI process. The 4, 9, 40, 26, and 183 genes were further identified at each time point, based on the negative correlation (P < 0.05) between the differential mRNA expression and the differential DNA methylation. The mRNA and the promoter methylation expressions of five genes (Ptpn6, Csf1r, Col6a1, Cyba, and Map3k14) were validated by qRT-PCR and BSP methods, and the mRNA expressions were further confirmed to be regulated by DNA methylation in cardiomyocytes in vitro. Our findings profiled the molecular variations from the perspective of DNA methylation in the early stage of AMI and provided promising epigenetic-based biomarkers for the early clinical diagnosis and therapeutic targets of AMI.


[Comparison of sexual behavior patterns in small laboratory animals].
It is known that in the reproductive systems, aged-related changes are prominent. Similarly, in normal nonhuman primates and other mammals such as rats, various sexual activities of male and female decline with aging. The purpose of the present study was to clarify the pattern of sexual behavior in matured mice, voles, Syrian hamsters, rats, guinea pigs, rabbits and house musk shrews of both sexes, and to select the appropriate animals for studies of aged-related changes in sexual behavior. There were species differences among laboratory animals in the pattern of sexual behavior. In summary, hamsters and rats ejaculated about three times during 30 min, while mice did once during 10 hrs. The former animals showed the intromission and ejaculation within a few min and 10 min, respectively, the latter did the ejaculation a few hrs after introduction of a heat female. In female animals, rats displayed receptive and proceptive behaviors, while hamsters and guinea pigs did only receptive behavior. From the above results, rats of both sexes may be recommended for studies of aged-related changes in sexual behavior.


Evidence for mother-to-child transmission of human T lymphotropic virus type II.
Serologic analysis of the children of 2 married human T lymphotropic virus type II (HTLV-II)-infected prostitutes demonstrated antibodies to HTLV-II in an 8-year-old boy whose only recognizable risk for HTLV-II infection was breast-feeding during his first 4 years of life. Limited sequence analysis of isolates infecting the mother and child demonstrated 100% identical sequences in the long terminal repeat (LTR65-297; 236 bp), pol4762-4919 (157 bp), and env5523-6003 (480 bp) regions (both isolates were subtype a), suggesting mother-to-child transmission. In contrast, isolates obtained from 2 other prostitutes from the same geographic region had sequences different from those of the first woman and her child, and the second and third women were infected with HTLV-II subtype b. Although vertical transmission of HTLV-II in this 8-year-old child cannot be conclusively ascertained, the probability is overwhelming that infection occurred through breast-feeding for an extended period of time.


Magnetic resonance imaging of pacemakers and implantable cardioverter-defibrillators without specific absorption rate restrictions.
The purpose of the current study is to evaluate the safety profile of patients with pacemakers or implantable cardioverter-defibrillators (ICDs) undergoing a medically necessary magnetic resonance imaging (MRI) scan without limitation on peak specific absorption rate (SAR). Recent series suggest that MRI scanning can be performed safely in select patients with pacemakers or ICDs. These studies, though, limited peak SAR. One-hundred and three patients with a total of 240 leads underwent a total of 127 scans of any body landmark using usual protocols with standard peak SAR settings for the scan. No patient was pacemaker dependent. Thresholds were obtained immediately before and after the scan. For all scans, the median (25th and 75th percentiles) peak SAR was 2.5 (1.3, 3.2) W/kg whereas the median scan time was 1650 (1236, 2099) s. Pre- and post-scan pacing thresholds were unchanged [0.7 (0.5, 0.8) vs. 0.6 (0.5, 0.8) V at 0.5 ms, P=NS], though the sensed amplitudes [6.7 (2.9, 11.5) vs. 6.1 (2.9, 11.2) mV, P<0.0001] and pacing impedances [500 (440, 609) vs. 491 (437, 593) Omega, P<0.0001] both decreased significantly. The current series suggests that MRI scans may be performed safely in appropriately selected patients up to a peak SAR of 3.2 W/kg. Furthermore, peak SAR level poorly predicts the safety profile of patients with pacemakers or ICDS who are exposed to an MRI environment.


[Arab surgery and cancer: definitions and treatments].
The present paper presents the study of a set of cancers collected by medieval doctors, especially Arabic surgeons, in order to identify their knowledge about carcinoma, how they defined the disease and, most importantly, what type of treatment they applied. The paper is organised in three sections: in section 1, we focus on the terminology used to refer to carcinoma. In section 2, we offer a description of the symptoms specific to each type of cancer. Finally, in section 3, we describe the surgical and pharmacological treatments, followed by diet-related remedies. We analysed texts by al-Zahrāwī, Ibn Sīnā, Ibn al-Quff and al-Safra.


Real-life study of dual therapy based on dolutegravir and ritonavir-boosted darunavir in HIV-1-infected treatment-experienced patients.
Dual therapy based on dolutegravir and ritonavir-boosted darunavir (DTG/DRV/r) is a combination of well-known drugs with a high genetic barrier to HIV resistance. A retrospective analysis of all HIV-1 infected treatment-experienced patients who switched to DTG/DRV/r from May 2014 till March 2017 in 4 Polish centres-results of a 48-week treatment. The study group consisted of 59 men and 17 women. Median baseline parameters were: age- 42.7 years, CD4 cells count- 560.5 cells/μl, CD4 cells nadir- 150 cells/μl, number of prior antiretroviral regimens- 3. The introduction of dual therapy was primarily due to virologic failure (30 patients), adverse events on previous regimens (17 patients) and therapy simplification (27 patients). At week 48 the treatment was continued in 70/76 of patients and the median CD4 cells count increased from 560.5 to 641.0 cells/μl. The therapy was discontinued in six patients (1 -virologic failure, 1 -decrease of estimated glomerular filtration rate (eGFR), 1 -myalgia, 3 -lost to follow-up). At week 48 six patients had detectable viremia, but only in one patient viremia was higher than 200 copies/ml. At week 48 the level of serum total cholesterol of the investigated subjects was statistically significantly higher than at the moment of dual therapy introduction (185.8 mg/dl vs. 174.8 mg/dl- p<0.05). However, in patients previously not treated with TDF, there were no changes in lipid parameters during therapy. Proteinuria was observed in 13.2% of patients before the switch to dual therapy and in 7.1% of patients at week 48. The investigated dual therapy was effective and safe. The observed increase in lipid parameters only concerned the patients who had used a TDF-based regimen prior to analysed dual treatment.


CD1 stimulation of human T cell lines induces a rapid increase in the intracellular free Ca2+ concentration and the production of IL-2.
The effect of a battery of CD1 mAb on intracellular free Ca2+ concentration and IL-2 production has been examined on different T cell lines in this study. Both 0249F and NU-T2 two CD1b specific mAb tested, induced a rapid increase in the intracellular Ca2+ concentration on HPBALL T cells whereas only one (L161) among three different CD1c mAb (L161, 10C3, and M241) produced a similar effect. In contrast the addition of four different CD1a mAb directed against two different epitopic groups of this molecule were uneffective in modifying the intracellular Ca2+. Both L161 and 0249F also induced a comparable increase in the intracellular Ca2+ concentration on MOLT 4 and JURKAT, two other T cell lines of similar phenotype. The effect of L161 mAb on the IL-2 production of the IL-2 producing T cell line JURKAT was also examined. The association of the latter with PMA strongly induced the production of IL-2 on this cell model while either L161 or PMA alone had no effect. Although the natural ligand and the function of CD1 molecules are still unknown, the accumulation of these data strongly suggest that CD1b and CD1c might represent two activatory pathways for immature T cells operating before the classical CD2 and CD3 activation pathways.


PROPRANOLOL PHARMACOKINETICS AND HEMODYNAMIC INDICES IN ANTIORTHOSTATIC HYPOKINESIA.
Purpose of the work was to study pharmacokinetics of beta adrenoblocker propranolol, and hemodynamic indices in volunteers for simulation of some effects of microgravity The study involved 8 essentially healthy subjects and the head-down tilt (-80) bedrest model reproducing the effects of microgravity (BD). This was designed as three series of investigations, i.e. before BD, on BD day-2 and on the first day of BD completion. Propranolol concentration in blood plasma was determined using high performance liquid chromatography with fluorescence detection. Hemodynamic indices including heart rate (HR), stroke volume, cardiac output, cardiac index and total peripheric resistance were measured using integral rheography; average blood pressure (BPav) Was assessed by Korotkovs method. Statistical deviations in propranolol pharmacokinetics were found in none of the three series. The most characteristic reactions to propranolol were BPav reductions in all series and HR decreases 2 hours after intake in the first and second series. These deviations were not pathologic but physiological variations typical of healthy people. Therefore, propranolol can be advised for rational pharmacotherapy of acute cardiovascular diseases in piloted space missions.


Animal escapology I: theoretical issues and emerging trends in escape trajectories.
Escape responses are used by many animal species as their main defence against predator attacks. Escape success is determined by a number of variables; important are the directionality (the percentage of responses directed away from the threat) and the escape trajectories (ETs) measured relative to the threat. Although logic would suggest that animals should always turn away from a predator, work on various species shows that these away responses occur only approximately 50-90% of the time. A small proportion of towards responses may introduce some unpredictability and may be an adaptive feature of the escape system. Similar issues apply to ETs. Theoretically, an optimal ET can be modelled on the geometry of predator-prey encounters. However, unpredictability (and hence high variability) in trajectories may be necessary for preventing predators from learning a simple escape pattern. This review discusses the emerging trends in escape trajectories, as well as the modulating key factors, such as the surroundings and body design. The main ET patterns identified are: (1) high ET variability within a limited angular sector (mainly 90-180 deg away from the threat; this variability is in some cases based on multiple peaks of ETs), (2) ETs that allow sensory tracking of the threat and (3) ETs towards a shelter. These characteristic features are observed across various taxa and, therefore, their expression may be mainly related to taxon-independent animal design features and to the environmental context in which prey live - for example whether the immediate surroundings of the prey provide potential refuges.


Prescription Opioid Use among Adults with Mental Health Disorders in the United States.
The extent to which adults with mental health disorders in the United States receive opioids has not been adequately reported. We performed a cross-sectional study of a nationally representative sample of the noninstitutionalized U.S. adult population from the Medical Expenditure Panel Survey. We examined the relationship between mental health (mood and anxiety) disorders and prescription opioid use (defined as receiving at least 2 prescriptions in a calendar year). We estimate that among the 38.6 million Americans with mental health disorders, 18.7% (7.2 million of 38.6 million) use prescription opioids. Adults with mental health conditions receive 51.4% (60 million of 115 million prescriptions) of the total opioid prescriptions distributed in the United States each year. Compared with adults without mental health disorders, adults with mental health disorders were significantly more likely to use opioids (18.7% vs 5.0%; P < .001). In adjusted analyses, having a mental health disorder was associated with prescription opioid use overall (odds ratio, 2.08; 95% confidence interval, 1.83-2.35). The 16% of Americans who have mental health disorders receive over half of all opioids prescribed in the United States. Improving pain management among this population is critical to reduce national dependency on opioids.


Robust Trajectory Tracking Control for Variable Stiffness Actuators With Model Perturbations.
Variable Stiffness Actuators (VSAs) have been introduced to develop new-generation compliant robots. However, the control of VSAs is still challenging because of model perturbations such as parametric uncertainties and external disturbances. This paper proposed a non-linear disturbance observer (NDOB)-based composite control approach to control both stiffness and position of VSAs under model perturbations. Compared with existing non-linear control approaches for VSAs, the distinctive features of the proposed approach include: (1) A novel modeling method is applied to analysis the VSA dynamics under complex perturbations produced by parameter uncertainties, external disturbances, and flexible deflection; (2) A novel composite controller integrated feedback linearization with NDOB is developed to increase tracking accuracy and robustness against uncertainties. Both simulations and experiments have verified the effectiveness of the proposed method on VSAs.


Time-specific Components of Pupil Responses Reveal Alternations in Effort Allocation Caused by Memory Task Demands During Speech Identification in Noise.
Daily communication may be effortful due to poor acoustic quality. In addition, memory demands can induce effort, especially for long or complex sentences. In the current study, we tested the impact of memory task demands and speech-to-noise ratio on the time-specific components of effort allocation during speech identification in noise. Thirty normally hearing adults (15 females, mean age 42.2 years) participated. In an established auditory memory test, listeners had to listen to a list of seven sentences in noise, and repeat the sentence-final word after presentation, and, if instructed, recall the repeated words. We tested the effects of speech-to-noise ratio (SNR; -4 dB, +1 dB) and recall (Recall; Yes, No), on the time-specific components of pupil responses, trial baseline pupil size, and their dynamics (change) along the list. We found three components in the pupil responses (early, middle, and late). While the additional memory task (recall versus no recall) lowered all components' values, SNR (-4 dB versus +1 dB SNR) increased the middle and late component values. Increasing memory demands (Recall) progressively increased trial baseline and steepened decrease of the late component's values. Trial baseline increased most steeply in the condition of +1 dB SNR with recall. The findings suggest that adding a recall to the auditory task alters effort allocation for listening. Listeners are dynamically re-allocating effort from listening to memorizing under changing memory and acoustic demands. The pupil baseline and the time-specific components of pupil responses provide a comprehensive picture of the interplay of SNR and recall on effort.


Management of pelvic organ prolapse.
Quality of life is adversely affected by pelvic organ prolapse, the prevalence of which is increasing because of the persistently growing older population. Today, the tension-free vaginal mesh kit has grown in popularity owing to its comparable cure rate to traditional reconstructive surgery and the feasibility of an early return to normal life. However, significant debate remains over the long-term cure rate and the safety of tension-free vaginal mesh in the United States. The U.S. Food and Drug Administration recommends obtaining informed consent about the safety and cure rate when the patient chooses surgery using the tension-free vaginal mesh kit or meshes before surgery. The goal of surgery for pelvic organ prolapse is the restoration of anatomic defects. This review article provides an overview of basic surgical techniques and the results, advantages, and disadvantages of surgery for pelvic organ prolapse.


Aging dynamics in the polymer glass of poly(2-chlorostyrene): Dielectric susceptibility and volume.
Aging dynamics was investigated in the glassy states of poly(2-chlorostyrene) by measuring the complex electrical capacitance during aging below the glass transition temperature. The variations with time and temperature of the ac dielectric susceptibility and volume could be determined by simply measuring the variation in the complex electrical capacitance. Isothermal aging at a given temperature for several hours after an intermittent stop in constant-rate cooling is stored in the deviations of both the real and imaginary parts of the complex ac dielectric susceptibility and volume. During cooling after isothermal aging, the deviation of the ac dielectric susceptibility from the reference value decreases and almost vanishes at room temperature. By contrast, the deviation in volume induced during isothermal aging remains almost constant during cooling. The simultaneous measurement of ac dielectric susceptibility and volume clearly revealed that the ac dielectric susceptibility exhibits a full rejuvenation effect, whereas the volume does not show any rejuvenation effects. We discuss a plausible model that can reproduce the present experimental results.


Total synthesis of (-)-(6S,7S,8S,9R,10S,2'S)-membrenone-A and (-)-(6S,7S,8S,9R,10S)- membrenone-B and structural assignment of membrenone-C.
[reaction: see text] (-)-(6S,7S,8S,9R,10S,2'S)-Membrenone-A and (-)-(6S,7S,8S,9R,10S)-membrenone-B were prepared in 11 steps (3% and 2.4% overall yield, respectively). Key steps included a tin(II)-mediated aldol followed by a syn selective reduction, giving the C7-C9 stereocenters, a second chain extending aldol coupling, and a p-TsOH-promoted cyclization/dehydration giving the common gamma-dihydropyrone precursor. We have thus established that synthetic (-)-(6S,7S,8S,9R,10S,2'S)-membrenone-A, (-)-(6S,7S,8S,9R,10S)-membrenone-B, and (-)-(6S,7S,8S,9R,10S)-membrenone-C are the enantiomers of the natural products.


Electronic properties of supracrystals of Au nanocrystals: influence of thickness and nanocrystallinity.
Well-defined superlattices of colloidal nanocrystals, called supracrystals, are expected to have interesting physical properties. While the electronic properties of thin supracrystals have been extensively studied in the planar configuration, little is known about electron transport through micrometer-thick supracrystals. Here, we investigate the electronic properties of supracrystals made of Au nanocrystals with diameters of 5, 6, 7 and 8 nm using scanning tunneling microscopy/spectroscopy at low temperatures. The current-voltage characteristics show power-law dependences with exponents varying strongly with supracrystal thicknesses from 30 nm to a few microns. The crystallinity of these nanocrystals, called nanocrystallinity, is exclusively single domain for 5 nm nanocrystals and a mixture of single and polycrystalline phase for 6, 7 and 8 nm nanocrystals. We observed that supracrystals made of 5 nm nanocrystals have a different behavior than supracrystals made of 6, 7 and 8 nm nanocrystals and this might be related to the nanocrystallinity. These results help us to better understand the electron transport mechanism in such miniscule structures built from a bottom-up approach.


Effect of heat stress on age at first calving of Japanese Black cows in Okinawa.
Calving records from birth certificates of cows were analyzed to investigate the effect of heat stress on age at first calving (AFC) of Japanese Black cows. The data set covered 20 years (1990-2009) of calving records. Total number of records was 9279. Daily weather information from weather stations in the vicinity of the farms was used. Temperature-humidity index (THI) fitted to a linear model covered 30 days pre-insemination to 61 days post-insemination. Statistical analysis was conducted with procedures of SAS/STAT. Preliminary analysis showed that THI of the lowest temperature and humidity was most conducive to AFC. Covariance analysis, including main effect of sire, farm and year of insemination and covariates of THI on days showed that regression coefficients of THI on day -7, day -2 and day +31 were statistically significant. The estimated piecewise regression line showed different responses of AFC to THI on days: roof-shasped downward trend on day -7, hockey-stick shaped upward trend on day -2 and day +31. The difference among the estimated regression lines may be caused by direct and indirect factors on reproduction: indirect effect of reduced feed intake, failure of conception at previous insemination, direct effect of heat stress on oocyte and embryo development.


Computer-aided diagnosis for CT colonography.
CT colonography, or virtual colonoscopy, is a promising alternative screening tool for colon cancer. Computer-aided diagnosis (CAD) for CT colonography has the potential to increase radiologists' diagnostic performance in the detection of polyps and to reduce variability of the diagnostic accuracy among readers. Technical developments have advanced CAD for CT colonography substantially during the last several years. This paper describes the key techniques used for CAD for detection of polyps and masses in CT colonography, the current detection performance, and challenges and the future of CAD.


Ethics consultation as moral engagement.
I will begin by presenting some doubts about what might be called the "received view" of the role of the moral expert as a health care consultant. Then I will review the literature on moral experts and moral expertise and proceed to apply the results of that review to the notion that there are some who are expert in ethical decision making in health care. I will try to show that certain conclusions that can be drawn from this rather circumscribed topic have implications for the very conception of the relationship between moral theory and clinical ethics.


Model-based quality management of groundwater resources - catchment area Liedern, Germany.
Strategies of groundwater protection in agricultural dominated areas are mainly based on a general reduction of the input of nutrients like nitrate. However, preventive measures in different parts of the catchment may provide very different effects on raw water quality. Exemplified on the case study 'Liedern' (BEW GmbH Bocholt, Germany) it is shown that hydrogeochemical processes along the flow path and in the well strongly affect the results of agricultural measures in terms of modality and efficiency. Thus, a reduction of fertilization in the vicinity of the well gallery leads to a decrease of nitrate concentration in the raw water. Whereas agricultural measures in the eastern part of the catchment do not influence nitrate, but cause a reduction of the iron concentration and rate of incrustation in the wells after 18 years. In this study we present a management tool that enables assessment of future trends in raw water quality. The tool is based on a reactive transport model which considers land use dynamics as an instrument to influence groundwater/raw water quality. A thermodynamic equilibrium approach is applied for modelling hydrogeochemical processes between aqueous, solid and gaseous phases. Kinetically controlled reactions like the microbial degradation of organic carbon are expressed by multiplicative Michaelis-Menten equations.


Effects of simulated weightlessness on bone mineral metabolism.
Space flight and bedrest result in a negative calcium balance and osteopenia. The mechanisms underlying these events are not well understood. In particular, it is not clear whether systemic or local factors are preeminent in mediating the effects of gravity on bone mineral content. Using a rat model that unweights only the hindlimbs, we determined whether the osteopenia induced in these rats was generalized or restricted to the unweighted limbs, and whether changes in intestinal calcium transport contributed to the alterations in bone calcium content. In this model, the hindquarters were elevated using the tail at an approximately 40 degrees angle for up to 15 days. The tibia and lumbar vertebra from experimental rats contained substantially less calcium than the same bones from pair-fed controls; at 15 days, the tibia was 86.2 +/- 2.5% of the control value (mean +/- SE), and the vertebra was 75.5 +/- 3.5% of control value (mean +/- SE). However, these differences were found only for the unweighted bones; the mandible and humerus showed no differences between experimental and pair-fed control rats. When calcium uptake by bone was evaluated after 45Ca administration, we observed an initial decrease in uptake at 5 days only in the tibia [percentage of control value, 60.5 +/- 5.5, (mean +/- SE)] and vertebra (percentage of control value, 74.3 +/- 3.7) when experimental animals were compared to pair-fed controls; there was no decrease in the humerus and mandible. However, after 10 days of unweighting , calcium uptake in the tibia and vertebra of experimental animals returned to control levels and by 15 days exceeded control levels (the tibia was 125.8 +/- 5.8% of the control value and the vertebra was 136.2 +/- 9.6% of the control value) despite the progressive decrease in total bone calcium compared to that in pair-fed controls. At no time could we demonstrate a difference in duodenal calcium transport between experimental and control animals. These data suggest that in this model, which simulates certain aspects of weightlessness, changes in local factors within the unweighted bones may have a greater impact on bone mass and turnover than changes in systemic factors that regulate overall bone mineral homeostasis.


The Parkinson disease protein α-synuclein inhibits autophagy.
Parkinson disease (PD) is the most common movement disorder affecting people. It is characterized by the accumulation of the protein α-synuclein in Lewy body inclusions in vulnerable neurons. α-Synuclein overexpression caused by gene multiplications is sufficient to cause this disease, suggesting that α-synuclein accumulation is toxic. Here we review our recent study showing that α-synuclein inhibits autophagy. We discuss our mechanistic understanding of this phenomenon and also speculate how a deficiency in autophagy may contribute to a range of pleiotropic features of PD biology.


Label-Free Sensing of Human 8-Oxoguanine DNA Glycosylase Activity with a Nanopore.
Human 8-oxoguanine DNA glycosylase (hOGG1) plays a significant role in maintaining the genomic integrity of living organisms for its capability of repairing DNA lesions. Accurate detection of hOGG1 activity would greatly facilitate the screening and early diagnosis of diseases. In this work, we report a nanopore-based sensing strategy to probe the hOGG1 activity by employing the enzyme-catalytic cleavage reaction of DNA substrate. The hOGG1 specifically catalyzed the removal of the 8-hydroxyguanine (8-oxoG) and cleaved the DNA substrates immobilized on magnetic beads, thereby releasing the output DNA which would quantitatively produce the signature current events when subjected to α-hemolysin (α-HL) nanopore test. The approach enables the sensitive detection of hOGG1 activity without the need of any labeling or signal amplification route. Furthermore, the method can be applied to assay the inhibition of hOGG1 and evaluate the activity of endogenous hOGG1 in crude cell extracts. Importantly, since DNAs with specific sequences are the catalytic substrates of a wide variety of enzymes, the proposed strategy should be universally applicable for probing the activities of different types of enzymes with nanopore sensors.


[Leeches in the intensive care unit: nursing care].
Leeches have been used in medicine since ancient times. Leeches or Hirudos were used to treat multiple diseases, since the bleeding they induce was related to purification. This practice subsequently fell into disuse until the 1980s when leeches again began to be applied in the treatment of venous congestion and in plastic and reconstructive surgery, especially in the USA and Germany. The use of leeches is not yet widespread in Spain. One of the Spanish hospitals pioneering this practice is the University Hospital Joan XXIII de Tarragona, where leeches are employed in the Maxillofacial Service among patients with microvascularized grafts. The present article describes the therapeutic use of leeches (Hirudo medicinalis), as well as the nursing care and complications in patients undergoing this treatment. The aim is to ensure that this new technique is used with maximal safety and quality.


TGF-beta and TNF-alpha cooperatively induce mesenchymal transition of lymphatic endothelial cells via activation of Activin signals.
Lymphatic systems play important roles in the maintenance of fluid homeostasis and undergo anatomical and physiological changes during inflammation and aging. While lymphatic endothelial cells (LECs) undergo mesenchymal transition in response to transforming growth factor-β (TGF-β), the molecular mechanisms underlying endothelial-to-mesenchymal transition (EndMT) of LECs remain largely unknown. In this study, we examined the effect of TGF-β2 and tumor necrosis factor-α (TNF-α), an inflammatory cytokine, on EndMT using human skin-derived lymphatic endothelial cells (HDLECs). TGF-β2-treated HDLECs showed increased expression of SM22α, a mesenchymal cell marker accompanied by increased cell motility and vascular permeability, suggesting HDLECs to undergo EndMT. Our data also revealed that TNF-α could enhance TGF-β2-induced EndMT of HDLECs. Furthermore, both cytokines induced the production of Activin A while decreasing the expression of its inhibitory molecule Follistatin, and thus enhancing EndMT. Finally, we demonstrated that human dermal lymphatic vessels underwent EndMT during aging, characterized by double immunostaining for LYVE1 and SM22α. These results suggest that both TGF-β and TNF-α signals play a central role in EndMT of LECs and could be potential targets for senile edema.


Detection of Campylobacter jejuni and Campylobacter coli in foods by enrichment culture and polymerase chain reaction enzyme-linked immunosorbent assay.
A polymerase chain reaction (PCR) assay based on a solution hybridization format with colorimetric end-point detection (PCR ELISA) was investigated for the specific detection of Campylobacter jejuni and Campylobacter coli in food samples following enrichment culture. One hundred fifteen samples of raw meat and offal (poultry, porcine, ovine, and bovine), raw shellfish, and artificially contaminated milk were enriched in blood-free Campylobacter Enrichment Broth for 48 h. Enrichment cultures were subcultured to Campylobacter blood-free selective agar plates, and presumptive isolates were identified by phenotypic methods. DNA was extracted from 1-ml aliquots of the enrichment cultures using a rapid extraction method, and the DNA was used as the template in a PCR ELISA. A comparison of the PCR ELISA with the enrichment culture and subculture to selective agar method showed that the results of 112 of the 115 samples tested were in agreement by both methods. Seventy-one of the various food samples were positive in the PCR ELISA, and 70 samples were positive by culture. The PCR ELISA had a sensitivity of 99% and a specificity of 96%, with a positive predictive value of 97% and a negative predictive value of 98%. The PCR ELISA is a rapid, sensitive, and specific method for the detection of C. jejuni and C. coli in foods following enrichment culture and significantly reduces the time required for their detection.


Head injuries in country and city. A study of hospital separations in South Australia.
The incidence of head injury in South Australia was estimated from hospital separation (discharges, transfers and deaths) data for 1980 and 1981. The rate of hospital separation of patients with head injury in these years was high by international standards, and was 33% greater for country residents than for residents of the Adelaide metropolitan area. Marked differences in separation rates were observed between different age, sex and occupational groups. On the basis of indirect measures of injury severity, the injury severity threshold for admission to hospital with head injury appeared to be similar in country and city hospitals. An attempt was made to estimate the number of people seriously disabled by head injury each year. The findings raise questions about the concentration of acute surgical and long-term rehabilitation services in the city, at the expense of country areas; they also provide a starting point for further, analytical studies of head injury.


Transdermal delivery of biopharmaceuticals: dream or reality?
The skin being the largest organ of the body presents a potential route for administration of drugs. Passive transdermal products such as gels, creams and patches deliver drugs effectively across the skin. However, this approach is limited to lipophilic molecules with low molecular weights. Passive transdermal delivery of proteins and peptides which are hydrophilic with high molecular weights is negligible. This led to the development of various ways of surmounting the skin barrier so as to make this route feasible for peptide and protein delivery. The current article reviews various active transdermal technologies with special emphasis on microneedle mediated delivery. Microneedles, especially dissolvable microneedles present an excellent platform for protein and peptide delivery. Significant advances have been made in the past decade in this area. Published literature shows a broad spectrum of molecules being delivered successfully via microneedles. However, success in clinic will give a boost to all the efforts and advances made in this field so far.


[Intraoperative Electrophysiological Monitoring for Neurosurgery].
Both motor evoked potential (MEP) and somatosensory evoked potential (SEP) have been used for the purpose of preventing postoperative neurological complications in patients undergoing neurosurgery. Although not completely, they can detect insufficient cerebral blood flow during aneurysm surgery and carotid surgery and prevent functional deterioration during tumor resection. Regarding MEP, there are several points to be considered for maximizing the potential of MEP. First, suprathreshold stimulus should be used because supramaximal stimulus may be too strong, resulting in false negative responses. Second, direct cortical stimulation in addition to transcranial stimulation may be useful for stimulating the target area precisely. Third, subcortical stimulation can provide decisive information during tumor resection. Although there is no such thing as 100% accuracy in electrophysiological monitoring, a multimodal electrophysiological monitoring system may contribute to decrease neurological deficits. Irreversible neurological deficits could be prevented by early detection of the changes in the amplitude and by prompt intervention to correct deteriorating condition. Therefore, it is important for anesthesiologists to select suitable anesthetics for the monitoring, maintain the depth of anesthesia, and discuss the patient management with surgeons.


Requisite role of VEGF receptors in angiogenesis of hepatocellular carcinoma: a comparison with angiopoietin/Tie pathway.
Tumor vascularity is an independent predictor of prognosis in HCC patients, however, the growth factors governing the angiogenesis remain obscure. Multiple mRNA species of angiogenesis-related growth factors/receptors and CD31 were evaluated in 38 hepatocellular carcinomas (HCCs) and surrounding livers (SL) by a highly sensitive RNase protection assay. Significant increases in VEGF, VEGFR3, endoglin and CD31 mRNA expressions were noted in HCC rather than in SL. Only VEGFR1 had significant correlation with CD31 expression. VEGFRs and CD31 overexpressed in tumors with portal vein invasion and only VEGFR3- and CD31-positive patients had significantly shorter disease-free survival. Tie1 and Tie2 were overexpressed in large HCCs. The VEGF and Tie receptors expressed differentially in 28 tumors. The VEGF receptors might play the major role in HCC angiogenesis and prognosis. The differential expression of receptors might prove valuable in selected subsets of patients for tailored antiangiogenic therapy in HCC patients.


PET/CT imaging fibroblast activation protein in initial colorectal cancer: compared to 18 F-FDG PET/CT.
In this study, the potential advantage of FAPI over 18 F-labelled deoxyglucose ( 18 F-FDG) in evaluation of the initial staging colorectal cancer (CRC) was investigated. Thirty-two patients with histopathologically confirmed primary CRC were included in our study. They all underwent both 18 F-FDG and FAPI PET/CT. Lesion detectability and tracer uptakes, mainly quantified by maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR), were compared for paired lesions between both modalities using the Wilcoxon signed-rank test and paired t-test. Thirty-five CRC lesions in 32 patients were diagnosed. The sensitivity of FAPI PET/CT in diagnosis of the CRC lesions was 100% while 93.8% of 18 F-FDG PET/CT. FAPI and 18 F-FDG had a similar uptake in CRC lesion (mean SUVmax: 14.3 ± 8.6 vs. 15.4 ± 9.8, P = 0.604), but lesions contained mucus and/or signet-ring cell carcinoma seemed to have a trend of higher FAPI uptake although there was no statistical difference (mean SUVmax: 12.7 ± 5.6 vs. 8.5 ± 4.1, P = 0.152) and higher TBR (13.4 ± 6.2 vs. 4.9 ± 2.2, P = 0.004) than those of 18 F-FDG. For regional lymph node metastases, both FAPI and FDG PET/CTs showed high sensitivity (7/8 vs. 7/8), specificity (7/8 vs. 6/8) and accuracy (14/16 vs. 13/16) (all P > 0.05). For distant metastasis, FAPI PET/CT depicted more positive lesions in distant lymph node (46 vs. 26), liver (13 vs. 7) and peritoneum (107 vs. 45) than 18 F-FDG PET/CT. FAPI PET/CT also had a higher peritoneal cancer index score (median 11 vs 4; P < 0.001) than 18 F-FDG PET/CT in evaluation of peritoneal metastases. FAPI PET/CT showed high sensitivity in detection of primary CRC and superiority to 18 F-FDG PET/CT in detection of metastases to distant lymph node, liver and peritoneum.


Two-year changes in health and functional status among elderly Medicare beneficiaries in HMOs and fee-for-service.
To compare two-year changes in health and functional status among a national sample of elderly Medicare beneficiaries in risk-based HMOs and in fee-for-service. Medicare Current Beneficiary Survey (MCBS) for 1995 to 1998. MCBS is a longitudinal, in-person survey of a nation ally representative sample of the Medicare population. Respondents are asked once a year about health and functional status. Noninstitutionalized respondents in the fall 1995 and fall 1996 rounds of MCBS for whom follow-up data were available two years later were included. Of the sample, 1,126 members were in HMOs and 3,449 were in fee-for-service at baseline. Ordered logistic regression and binary logistic regression were used to examine the association of HMO membership at baseline with each measure of health or functional status at follow-up, controlling for baseline health and functioning and other variables. No significant differences were found between HMO and fee-for-service respondents with respect to two-year changes in health and functional status, either for the full sample or for subsets of chronically ill respondents. there was little ef f ct on the findings when the analysis was restricted to persons who remained in the same care system (HMO or fee-for-service) between baseline and follow-up. Separate analyses of the 1995-97 and 1996-98 cohorts revealed some in consistencies between the cohorts with respect to patterns of change in health and functioning. There was no consistent evidence of an "HMO effect " on the health and functioning of enrollees over a two-year period.


Coagulation challenges after severe injury with hemorrhagic shock.
During the past 50 years, there have been huge changes in the approach to coagulopathic bleeding following the treatment of traumatic hemorrhagic shock (HS). Treatment during the 1960s consisted primarily of physiologic saline (balanced electrolyte solution [BES]) and whole blood supported with sodium bicarbonate for acidosis. Subsequent coagulopathy was assumed to be caused by lack of the labile factors (FV and FVIII) which were then replaced by fresh whole blood. The decade of 1970s saw the implementation of component therapy by the American Blood Banking Association so that HS was treated with BES and packed red blood cells (RBC). A new paradigm had to be learned to determine when and how much fresh frozen plasma (FFP) was needed to restore all coagulation factors. By the end of 1970s, most trauma centers were supplementing BES and RBC with FFP in patients with severe injuries requiring massive transfusion of more than one circulating blood volume. By the 1980s, the use of FFP skyrocketed, creating a crisis for the American Blood Banking Association. This led to a National Institute of Health Consensus Development Conference which concluded that FFP should be given to only those patients who had a documented coagulopathy as evidenced by a prolongation of the prothrombin time and the partial thromboplastin time. Restriction of FFP replacement to patients with proven coagulopathy after treatment for HS led to postoperative bleeding which was sometimes fatal. During the 1990s, uncontrolled clinical studies and rigorously controlled animal studies showed that FFP should be administered before the onset of proven coagulopathy with prolongation of the prothrombin time and partial thromboplastin time. Later during the 1990s, recombinant-activated factor VII (FVIIa) was purported to provide quicker hemostasis in patients treated with HS. The efficacy of FVIIa supplementation is still being assessed. During the 2010s, the military surgeons promoted the use of a hemostatic regimen which consists of platelets, RBC, and FFP in a 1:1:1 ratio. This recommendation is still being assessed with different authors reporting benefits and detriments. Throughout these years, an unusual entity of disseminated intravascular coagulation (DIC) was known to complicate the resuscitation of seriously injured patients with HS. This syndrome was typically seen after treatment of HS and was associated with abnormal bleeding plus respiratory failure and renal failure thought to be caused by a combination of micro- and macrothromboses. The early studies suggested that the best therapy for breaking this viscous cycle of bleeding and intravascular coagulation was by infusing fresh whole blood. The theoretical benefits of administering heparin to prevent the thrombosis and epsilon-aminocaproic acid to enhance lysis have not proven beneficial. DIC is also seen in association with toxic exposures, including snake bites. Epsilon-aminocaproic acid may be beneficial in that setting. Many of the intricate understandings of DIC remain elusive and are still being studied.


Annotation of gene sequence and protein structure of brinjal EDS1.
Enhanced Disease Susceptibility1 (EDS1) is a nucleo-cytoplasmic protein, known to be a key regulator of plant basal defense and effector-triggered immunity. Sequence of a single copy brinjal EDS1 gene (SmEDS1) was mined from draft brinjal genome assembly. The extracted sequence was found to be incomplete and polished with the help of transcriptome sequence data. Full-length SmEDS1 gene is 4.5kb long having three exons that coded for 1.8kb mRNA. SmEDS1 protein is a 602 amino acid long protein consisting of Lipase3 and EP domain regions. Predicted tertiary structure of SmEDS1 using homology modelling had a mass of 68.8kD and was made of 10 strands, 26 alpha helices, five 310 helices and 43 beta turns. Phylogenetic analysis based on protein sequence grouped the species in clades defined by botanical family suggesting that EDS1 protein has evolved through the speciation process. Phylogenetic tree based on EDS1 structures grouped Solanum species of American origin (tomato, wild tomato and potato) together but brinjal EDS1 (Asiatic origin) occupied a unique position. In silico information generated in this study is expected to be the first step toward cloning and expression analysis of SmEDS1 gene.


Safety of meningococcal polysaccharide-protein conjugate vaccine in pregnancy: a review of the Vaccine Adverse Event Reporting System.
We characterized reports to the Vaccine Adverse Event (AE) Reporting System (VAERS) of pregnant women who received meningococcal polysaccharide-protein conjugate vaccine Menactra (MenACWY-D; Sanofi Pasteur Inc., Swiftwater, PA). We searched VAERS for reports of pregnant women who received MenACWY-D from Jan. 1, 2005 through Dec. 31, 2011. We conducted clinical review of reports and available medical records. Of 103 identified reports, 38 (36.7%) did not describe any AE. No maternal or infant deaths were reported. The most frequent pregnancy-specific AE was spontaneous abortion in 17 (16.5%) reports. Urinary tract infections and fever with vomiting were the most frequent nonpregnancy-specific AEs found in 4 (3.9%) and 3 (2.9%) reports, respectively. We identified 1 report with a major congenital anomaly (aqueductal stenosis and severe ventriculomegaly). Our comprehensive review of reports to VAERS in pregnant women after MenACWY-D did not identify any concerning patterns in maternal, infant, or fetal outcomes.


[Study for lateralization of hemispheric cerebral blood flow by argon method with catheterization into the bilateral internal jugular bulbs].
Only 24 patients with chronic ischemic cerebrovascular lesions, which had been lateralized to either hemisphere of the cerebrum, were analyzed by argon desaturation method measuring bilateral hemispheric blood flows. Their ages varied from 10 to 72 years with a mean of 49 years. Fifteen patients (62.5%) had localized ischemic lesions in the left cerebral hemispheres and remaining 9 patients (37.5%) had in the right hemispheres. The clinical symptom of each patient was lateralized due to localized ischemic focus. Bilateral transfemoral catheterization of the internal jugular bulbs was successfully performed. Each hemispheric blood flow was calculated by argon desaturation method using mass spectrometry based on Fick's principle. Half of the patients, 12 cases revealed lateralization over 20% significant differences of its values. 8 patients (66.7%) were reduced significantly in the left hemispheres and 4 patients were contralaterally. Finally 9 patients revealed that CBF values at the affected side was significantly reduced with no anatomical differences among sinus systems. It is probably that CBF value at the affected side reflects its ischemic lesion more than that at the non-affected side. Several authors reported no predominant lateralization between bilateral sinus draining systems. Based on possibility of "laminar flow" in the confluence, CBF value at the affected side is more important. So further investigations are needed for the future.


Computational Simulation of the Activation Cycle of Gα Subunit in the G Protein Cycle Using an Elastic Network Model.
Agonist-activated G protein-coupled receptors (GPCRs) interact with GDP-bound G protein heterotrimers (Gαβγ) promoting GDP/GTP exchange, which results in dissociation of Gα from the receptor and Gβγ. The GTPase activity of Gα hydrolyzes GTP to GDP, and the GDP-bound Gα interacts with Gβγ, forming a GDP-bound G protein heterotrimer. The G protein cycle is allosterically modulated by conformational changes of the Gα subunit. Although biochemical and biophysical methods have elucidated the structure and dynamics of Gα, the precise conformational mechanisms underlying the G protein cycle are not fully understood yet. Simulation methods could help to provide additional details to gain further insight into G protein signal transduction mechanisms. In this study, using the available X-ray crystal structures of Gα, we simulated the entire G protein cycle and described not only the steric features of the Gα structure, but also conformational changes at each step. Each reference structure in the G protein cycle was modeled as an elastic network model and subjected to normal mode analysis. Our simulation data suggests that activated receptors trigger conformational changes of the Gα subunit that are thermodynamically favorable for opening of the nucleotide-binding pocket and GDP release. Furthermore, the effects of GTP binding and hydrolysis on mobility changes of the C and N termini and switch regions are elucidated. In summary, our simulation results enabled us to provide detailed descriptions of the structural and dynamic features of the G protein cycle.


Ni(II) Sensing by RcnR Does Not Require an FrmR-Like Intersubunit Linkage.
E. coli RcnR (resistance to cobalt and nickel regulator) is a homotetrameric DNA binding protein that regulates the expression of a Ni(II) and Co(II) exporter (RcnAB) by derepressing expression of rcnA and rcnB in response to binding Co(II) or Ni(II). Prior studies have shown that the cognate metal ions, Ni(II) and Co(II), bind in six-coordinate sites at subunit interfaces and are distinguished from noncognate metals (Cu(I), Cu(II), and Zn(II)) by coordination number and ligand selection. In analogy with FrmR, a formaldehyde-responsive transcriptional regulator in the RcnR/CsoR family, the interfacial site allows the metal ions to "cross-link" the N-terminal domain of one subunit with the invariant Cys35 residue in another, which has been deemed to be key to mediating the allosteric response of the tetrameric protein to metal binding. Through the use of mutagenesis to disconnect one subunit from the metal-mediated cross-link, X-ray absorption spectroscopy (XAS) as a structural probe, LacZ reporter assays, and metal binding studies using isothermal titration calorimetry (ITC), the work presented here shows that neither the interfacial binding site nor the coordination number of Ni(II) is important to the allosteric response to binding of this cognate metal ion. The opposite is found for the other cognate metal ion, Co(II), with respect to the interfacial binding site, suggesting that the molecular mechanisms for transcriptional regulation by the two ions are distinct. The metal binding studies reveal that tight metal binding is maintained in the variant. XAS is further used to demonstrate that His33 is not a ligand for Co(II), Ni(II), or Zn(II) in WT-RcnR. The results are discussed in the context of the overall understanding of the molecular mechanisms of metallosensors.


Regulation of HLA-DR peptide occupancy by histone deacetylase inhibitors.
Numerous molecular effects have been attributed to histone deacetylase inhibitors (HDACI's), including the induction of major histocompatibility (MHC) genes. Here we report that one FDA approved HDACI, Vorinostat, and a second HDACI currently in clinical trials, Entinostat, reduce the ratio of class II associated invariant peptide (CLIP) to the MHC class II molecule, HLA-DR, indicating an increase in the non-CLIP peptides bound to HLA-DR. The HDACI effects are apparent with immortalized B-cells, HLA-DR constitutive melanoma cells and with melanoma cells expressing HLA-DR due to transformation with an expression vector for the HLA-DR gene co-activator, CIITA. Entinostat treatment leads to upregulation of Cathepsin L1, and the HLA-DR peptidome of the Entinostat treated cells is consistent with increased Cathepsin L1 mediated proteolysis. These results indicate that HDACI treatments may alter the HLA-DR peptidome of cells in patients and provide a way to identify novel immunogens for vaccinations and the study of autoantigens.


Advances in Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma.
Stereotactic Body Radiation Therapy (SBRT) is an emerging effective treatment for hepatocellular carcinoma (HCC) associated with acceptable rates of toxicity in appropriately selected patients. Despite often being reserved for patients unsuitable for other local treatments, prospective and retrospective studies have demonstrated excellent long-term control. SBRT may be used as a stand-alone treatment, or as an adjunct to other HCC therapies. Based on available data, SBRT appears to complement existing local liver therapies. Randomized and nonrandomized comparative studies are required to better determine the optimal role of SBRT in HCC treatment.


Pituitary Carcinoma in a Patient with an SDHB Mutation.
We present the first case of pituitary carcinoma occurring in a patient with a succinate dehydrogenase subunit B (SDHB) mutation and history of paraganglioma. She was initially treated for a glomus tumour with external beam radiotherapy. Twenty-five years later, she was diagnosed with a non-functioning pituitary adenoma, having developed bitemporal hemianopia. Recurrence of the pituitary lesion (Ki-67 10% and p53 overexpressed) occurred 5 years after her transsphenoidal surgery, for which she underwent two further operations followed by radiotherapy. Histology showed large cells with vacuolated clear cytoplasm with positive immunostaining for steroidogenic factor 1 (SF1) and negative staining for pituitary hormones. Four years after the pituitary radiotherapy, two metastatic deposits were identified: a foramen magnum lesion and an intradural extra-medullary cervical lesion at the level of C3/C4. There was also significant growth of the primary pituitary lesion with associated visual deterioration. A biopsy of the foramen magnum lesion, demonstrating cells with vacuolated, clear cytoplasm and positive SF1 staining confirmed a pituitary carcinoma, for which she was commenced on temozolomide chemotherapy. There was dramatic clinical improvement after three cycles and reduction in the size of the lesions was observed following six cycles of temozolomide, and further shrinkage after 10 cycles. The plan is for a total of 12 cycles of temozolomide chemotherapy. SDH mutation-related pituitary tumours have an aggressive phenotype which, in this case, led to metastatic disease. SF1 immunostaining was helpful to identify the tissue origin of the metastatic deposit and to confirm the pituitary carcinoma.