Electroacupuncture and cognitive behavioural therapy for sub-syndromal depression among undergraduates: a controlled clinical trial.
Individuals with sub-syndromal depression (SSD) are at increased risk of incident depressive disorders; however, the ideal therapeutic approach to SSD remains unknown. To evaluate the effects of electroacupuncture (EA) and cognitive behavioural therapy (CBT), alone or in combination, on depressive symptoms. Undergraduate students with SSD were recruited and allocated to one of four groups based on their preferences: EA (n=6), CBT (n=10), EA+CBT (n=6), and untreated control (n=11) groups. Six weeks of treatment were provided in the first three groups. Clinical outcomes were measured using the 17-item Hamilton Depression (HAMD-17) rating scale, Center for Epidemiologic Depression (CES-D) scale, WHO Quality of Life-Brief version (WHOQOL-BREF) questionnaire, and clinical remission rate. All 33 subjects were included in an intent-to-treat analysis. Statistically significant improvements in HAMD-17, CES-D, and WHOQOL-BREF scores and a higher remission rate were found in the EA, CBT, and EA+CBT intervention groups compared with the control group (all p<0.05). No significant differences were found between the three intervention groups. HAMD-17 factor score analysis revealed that EA reduced sleep disturbance scores more than CBT or EA+CBT (p<0.05), and CBT reduced retardation scores more than EA (p<0.01). EA+CBT reduced anxiety/somatisation scores more than EA or CBT (p<0.05) and retardation scores more than EA (p<0.05). Early intervention may alleviate depressive symptoms in SSD. EA and CBT may have differential effects on certain symptoms. Combination therapy targeting both physical and psychological symptoms may represent an ideal strategy for SSD intervention. However, randomised trials with larger sample sizes are needed. ChiCTR-TRC-10000889; Results.


Paraquat neurotoxicity is distinct from that of MPTP and rotenone.
Paraquat, MPTP, and rotenone reproduce features of Parkinson's disease (PD) in experimental animals. The exact mechanisms by which these compounds damage the dopamine system are not firmly established, but selective damage to dopamine neurons and inhibition of complex I are thought to be involved. We and others have previously documented that the toxic metabolite of MPTP, MPP+, is transported into dopamine neurons through the dopamine transporter (DAT), while rotenone is not transported by DAT. We have also demonstrated the requirement for complex I inhibition and oxidative damage in the dopaminergic neurodegeneration produced by rotenone. Based on structural similarity to MPP+, it has been proposed that paraquat exerts selective dopaminergic toxicity through transport by the DAT and subsequent inhibition of mitochondrial complex I. In this study we report that paraquat is neither a substrate nor inhibitor of DAT. We also demonstrate that in vivo exposure to MPTP and rotenone, but not paraquat, inhibits binding of 3H-dihydrorotenone to complex I in brain mitochondria. Rotenone and MPP+ were both effective inhibitors of complex I activity in isolated brain mitochondria, while paraquat exhibited weak inhibitory effects only at millimolar concentrations. These data indicate that, despite the apparent structural similarity to MPP+, paraquat exerts its deleterious effects on dopamine neurons in a manner that is unique from rotenone and MPTP.


Atrazine exposure causes mitochondrial toxicity in liver and muscle cell lines.
Chronic exposure to atrazine and other pesticides is reported to cause metabolic disorders, yet information on effects of atrazine on expression of genes relevant to mitochondrial function is largely missing. In the present study, therefore, we investigated the expression of a battery of nuclear- and mitochondrial-encoded genes involved in oxidative phosphorylation (OXPHOS) in human liver (HepG2) and rat muscle (L6) cell lines due to short-term atrazine exposure. We have determined the EC50 values of atrazine for cytotoxicity and mitochondrial toxicity (mitotoxicity) in terms of adenosine triphosphate (ATP) content in HepG2 and L6 cells. Further, the mRNA expression of nuclear- and mitochondrial-encoded genes was analyzed using quantitative real-time polymerase chain reaction. The EC50 value of atrazine for mitotoxicity in HepG2 and L6 cells was found to be about 0.162 and 0.089 mM, respectively. Mitochondrial toxicity was indicated by reduction in ATP content following atrazine exposure. Atrazine exposure resulted in down-regulation of many OXPHOS subunits expression and affected biogenesis factors' expression. Most prominently, superoxide dismutase (SOD) and sirtuin 3 (SIRT3) expressions were up-regulated in HepG2 cells, whereas SIRT3 expression was alleviated in L6 cells, without significant changes in SOD levels. Mitochondrial transcription factor A (TFAM) and SIRT1 expression were significantly down-regulated in both cell lines. Results suggest that TFAM and SIRT1 could be involved in atrazine-induced mitochondrial dysfunction, and further studies can be taken up to understand the mechanism of mitochondrial toxicity. Further study can also be taken up to explore the possibility of target genes as biomarkers of pesticide toxicity.


Production and functional activity of a recombinant von Willebrand factor-A domain from human complement factor B.
Factor B is a five-domain 90 kDa serine protease proenzyme which is part of the human serum complement system. It binds to other complement proteins C3b and properdin, and is activated by the protease factor D. The fourth domain of factor B is homologous to the type A domain of von Willebrand Factor (vWF-A). A full-length human factor B cDNA clone was used to amplify the region encoding the vWF-A domain (amino acids 229-444 of factor B). A fusion protein expression system was then used to generate it in high yield in Escherichia coli, where thrombin cleavage was used to separate the vWF-A domain from its fusion protein partner. A second vWF-A domain with improved stability and solubility was created using a Cys(267)-->Ser mutation and a four-residue C-terminal extension of the first vWF-A domain. The recombinant domains were investigated by analytical gel filtration, sucrose density centrifugation and analytical ultracentrifugation, in order to show that both domains were monomeric and possessed compact structures that were consistent with known vWF-A crystal structures. This expression system and its characterization permitted the first investigation of the function of the isolated vWF-A domain. It was able to inhibit substantially the binding of (125)I-labelled factor B to immobilized C3b. This demonstrated both the presence of a C3b binding site in this portion of factor B and a ligand-binding property of the vWF-A domain. The site at which factor D cleaves factor B is close to the N-terminus of both recombinant vWF-A domains. Factor D was shown to cleave the vWF-A domain in the presence or absence of C3b, whereas the cleavage of intact factor B under the same conditions occurs only in the presence of C3b.


Repetitively assaultive psychiatric patients: fifteen-year analysis of the Assaulted Staff Action Program (ASAP) with implications for emergency services.
Research has demonstrated that psychiatric patient's assaults on emergency services personnel providing onsite, prehospital care represent a serious and ongoing nationwide concern. Embedded within these patient assailants is a small group of repeat offenders who present a serious increased risk for assault. This study examined the demographic and clinical variables of repeat offenders over a 15-year period. Included in the sample were patients who were transferred from correctional facilities to mental health facilities and then to the community. The results indicated that older male patients with schizophrenia and younger patients with personality disorders were the more likely to re-offend. The risk of assault was greatly increased if these patients had histories of violence toward others, personal victimization, and substance use disorder. Correction patients did not appear to present any additional risk per se. The significance of the findings and the implications for emergency services personnel are presented.


Fc epsilon receptor, a specific differentiation marker transiently expressed on mature B cells before isotype switching.
The expression of Fc epsilon R on human lymphocytes was studied with the anti-Fc epsilon R mAbs. Fc epsilon R was expressed on most mu+,delta+ circulating B cells, whereas T cells did not express Fc epsilon R even in patients with hyper-IgE syndrome. B cells with gamma, alpha, or epsilon phenotype did not express Fc epsilon R, moreover its expression could not be induced, suggesting that the Fc epsilon R expression was correlated with isotype switching. mu+delta+ B cells in bone marrow did not express Fc epsilon R, but PHA-sup (supernatant from PHA-stimulated cell cultures) could induce its expression, and the addition of IgE augmented this induction. Recombinant IL-2, IL-1, IFN-gamma or -beta, or purified B cell differentiation factor (BSF-2 B cell-stimulatory factor 2) could not induce Fc epsilon R expression in bone marrow B cells. IFN-gamma inhibited the Fc epsilon R expression induced by PHA-sup, suggesting that the human counterpart of BSF-1 may be responsible for Fc epsilon R expression in bone marrow B cells. B cells from patients with common variable immunodeficiency and ataxia telangiectasia did not express Fc epsilon R, but PHA-sup could induce its expression, indicating that circulating B cells of these patients are at a differentiation stage similar to B cells in bone marrow. The study showed that Fc epsilon R is a B cell-specific differentiation marker, the expression of which is restricted to a defined stage of B cell differentiation.


Intravenous diazepam for direct-current cardioversion.
The induction of anaesthesia with intravenous diazepam is a valuable contribution to the simpler use of cardioversion and is the method of choice because it is readily available for elective cardioversion. Fifty-six cardioversion procedures were carried out by this method in an African hospital. No special premedication or drug preparation was used. There were no hazards apart from transient apnoea in two patients and persisting amnesia in one patient.


Host and viral determinants of the outcome of exposure to HCV infection genotype 4: a large longitudinal study.
The objective of this study was to characterize the factors that influence the outcome of exposure to hepatitis C virus (HCV) genotype 4 (HCV-G4) and the course of recent infection. In this longitudinal study, we prospectively assessed the clinical, genetic, virological, and immunological parameters and retrospectively determined single-nucleotide polymorphisms at interleukin-28B (IL-28B) rs12979860 in a well-characterized large cohort recently exposed to HCV-G4. A total of 136 subjects with acute HCV (new viremia, seroconversion, and HCV-specific T-cell responses) were identified. Forty-eight subjects (35%) had spontaneous viral clearance and 88 subjects developed chronic HCV of which 42 subjects were treated with pegylated interferon monotherapy, with a sustained virologic response (SVR) rate of 88%. Twenty-six subjects developed HCV-specific T-cell immune responses without detectable viremia or seroconversion. IL-28B-CC (odds ratio (OR) 14.22; P<0.0001), multispecific T-cell responses (OR=11.66; P<0.0001), >300 IU/l alanine aminotransferase (ALT) decline within 4 weeks (OR=6.83; P<0.0001), jaundice (OR=3.54; P=0.001), female gender (OR=2.39; P=0.007), and >2.5 log10 HCV-RNA drop within 8 weeks (OR=2.48; P=0.016) were independently associated with spontaneous clearance. ALT normalization and undetectable HCV-RNA predicted SVR. Exposed apparently uninfected participants had a higher frequency of IL-28B-CC than patients with unresolved acute HCV (P<0.001). IL-28B-CC was associated with multispecific T-cell response (r(2)=0.0.835; P<0.001). IL-28B-CC genotype, multispecific HCV T-cell responses, rapid decline in ALT, and viral load predict spontaneous clearance and response to acute HCV-G 4 therapy. IL-28B-CC genotype correlates with developing early multispecific T-cell responses. These findings have important implications for predicting the outcome of HCV exposure and acute infection and identifying patients likely to benefit from therapy.


Attitudes to animal euthanasia do not correlate with acceptance of human euthanasia or suicide.
Several reasons have been suggested for the elevated risk of suicide experienced by those in the veterinary profession. The current study aimed to investigate possible links between veterinarians' attitudes to 'convenience' or non-justified animal euthanasia and attitudes towards human euthanasia and suicide. Veterinary students and graduates had a negative attitude towards convenience animal euthanasia, but their attitudes changed over time (pre-clinical studies, clinical studies and recently graduated). A greater tolerance to euthanasia was displayed in the later years of study and post qualification - primarily by males. Attitudes towards both human euthanasia and suicide, however, remained stable over time and indicated on average a neutral stance. No correlations were found between attitudes to convenience euthanasia and either human euthanasia or suicide, suggesting a tolerance to convenience euthanasia of animals does not lead to desensitisation in valuing human life and a changed attitude to human euthanasia or suicide, or vice versa. Attitudes to human euthanasia and suicide were predictably correlated, perhaps suggesting an overarching attitude towards control over human death. The results of the current study throw into question the argument that it is the changes in attitudes to animal life that affect veterinarian's attitudes to human life and contribute to the high suicide rate.


Nano-Structuration of WO3 Nanoleaves by Localized Hydrolysis of an Organometallic Zn Precursor: Application to Photocatalytic NO2 Abatement.
WO3 is a known photocatalytic metal oxide frequently studied for its depollution properties. However, it suffers from a high recombination rate of the photogenerated electron/holes pair that is detrimental to its performance. In this paper, we present a new chemical method to decorate WO3 nanoleaves (NLs) with a complementary metal oxide (ZnWO4) in order to improve the photocatalytic performance of the composite material for the abatement of 400 ppb NO2 under mild UV exposure. Our strategy was to synthesize WO3·2H2O nanoleaves, then, to expose them, in water-free organic solution, to an organometallic precursor of Zn(Cy)2. A structural water molecule from WO3·2H2O spontaneously decomposes Zn(Cy)2 and induces the formation of the ZnO@WO3·H2O nanocomposite. The material was characterized by electronic microscopy (SEM, TEM), TGA, XRD, Raman and solid NMR spectroscopies. A simple thermal treatment under air at 500 °C affords the ZnWO4@WO3 nanocomposite. The resulting material, additionally decorated with 1% wt. Au, presents a remarkable increase (+166%) in the photocatalytic abatement of NO2 under UV compared to the pristine WO3 NLs. This synthesis method paves the way to the versatile preparation of a wide range of MOx@WO3 nanocomposites (MOx = metal oxide).


Iron lactate-induced osteomalacia in association with osteoblast dynamics.
Osteomalacia was induced in rats fed a diet containing 50,000 ppm (5%) iron lactate for 13 weeks. The histopathology and histomorphometrical dynamics of osteoblasts under this condition were examined. Bone histomorphometry of the proximal tibial metaphysis revealed that the osteoblast surface, osteoid volume, osteoid surface and labeled surface ratio, which are the parameters of bone formation had increased. The blood chemistry revealed the greatest elevation in the osteocalcin level; however, the parathyroid hormone (PTH) secretion and inorganic phosphorus level were very low. From the serum biochemical, histopathological and histomorphometrical findings, the bone lesion in iron lactate-overloaded rats was considered to be similar to low turnover osteomalacia showing decreased trabeculae in secondary spongiosa and increased lamellar osteoid. Furthermore, an iron-positive reaction was detected at the interface between osteoid and mineralized bone. In the bone lesions induced by chronic iron overload, osteoblast recruitment exceeded that of mineralization or, alternatively, the iron within osteoblasts along the trabecular bone suppressed the remodeling and led to an increase in osteoid thickness.


Sex-specific effects of intranasal oxytocin on autonomic nervous system and emotional responses to couple conflict.
Unhappy couple relationships are associated with impaired individual health, an effect thought to be mediated through ongoing couple conflicts. Little is known, however, about the underlying mechanisms regulating psychobiological stress, and particularly autonomic nervous system (ANS) reactivity, during negative couple interaction. In this study, we tested the effects of the neuropeptide oxytocin on ANS reactivity during couple conflict in a standardized laboratory paradigm. In a double-blind, placebo-controlled design, 47 heterosexual couples (total n = 94) received oxytocin or placebo intranasally prior to instructed couple conflict. Participants' behavior was videotaped and salivary alpha-amylase (sAA), a measure of sympathetic activity, and emotional arousal were repeatedly measured during the experiment. Oxytocin significantly reduced sAA during couple conflict in women, whereas men showed increases in sAA levels (sex × group interaction: B = -49.36, t = -2.68, P = 0.009). In men, these increases were related to augmented emotional arousal (r = 0.286, P = 0.028) and more positive behavior (r = 0.291, P = 0.026), whereas there was no such association in women. Our results imply sex-specific effects of oxytocin on sympathetic activity, to negative couple interaction, with the neuropeptide reducing sAA responses and emotional arousal in women while increasing them in men.


The Importance of Being Familiar: The Role of Semantic Knowledge in the Activation of Emotions and Factual Knowledge from Music in the Semantic Variant of Primary Progressive Aphasia.
The role of semantic knowledge in emotion recognition remains poorly understood. The semantic variant of primary progressive aphasia (svPPA) is a degenerative disorder characterized by progressive loss of semantic knowledge, while other cognitive abilities remain spared, at least in the early stages of the disease. The syndrome is therefore a reliable clinical model of semantic impairment allowing for testing the propositions made in theoretical models of emotion recognition. The main goal of this study was to investigate the role of semantic memory in the recognition of basic emotions conveyed by music in individuals with svPPA. The performance of 9 individuals with svPPA was compared to that of 32 control participants in tasks designed to investigate the ability: a) to differentiate between familiar and non-familiar musical excerpts, b) to associate semantic concepts to musical excerpts, and c) to recognize basic emotions conveyed by music. Results revealed that individuals with svPPA showed preserved abilities to recognize familiar musical excerpts but impaired performance on the two other tasks. Moreover, recognition of basic emotions and association of musical excerpts with semantic concepts was significantly better for familiar than non-familiar musical excerpts in participants with svPPA. Results of this study have important implications for theoretical models of emotion recognition and music processing. They suggest that impairment of semantic memory in svPPA affects both the activation of emotions and factual knowledge from music and that this impairment is modulated by familiarity with musical tunes.


Epilepsia partialis continua associated with the p.Arg403Cys variant of the DNM1L gene: an unusual clinical progression with two episodes of super-refractory status epilepticus with a 13-year remission interval.
Dynamin-1-like (DNM1L) is a gene located on chromosome 12p11.21 that encodes for dynamin-related protein (DRP1), a GTPase involved in mitochondrial and peroxisomal fusion, which plays a pivotal role in brain development. The missense variant, p.Arg403Cys, is clinically associated with childhood-onset super-refractory status epilepticus, with either subsequent poor neurological outcome or death (described in 13 patients). We present a 20-year-old girl carrying this mutation with a history of two episodes of super-refractory focal myoclonic status epilepticus which manifested as epilepsia partialis continua (EPC) with a 13-year interval, during which she displayed moderate intellectual disability, social and school reintegration, without complete control of myoclonic manifestations. The first status, which occurred at the age of six, was associated with transient left side thalamic involvement and the second episode with right side transient basal ganglia hyperintensity on MRI. After the second status, a persistent vegetative state with both drug-resistant epilepsia partialis continua and reticular myoclonus endured; the MRI showed progressive brain atrophy. In contrast to previous published cases, this new case of childhood-onset DNM1L encephalopathy demonstrated biphasic clinical progression. The main features of our patient were EPC, super-refractory status epilepticus, and transient and migrating subcortical thalamic hyperintensity on MRI at onset. The unusual clinical course is also noticeable, indicating possible epigenetic and/or protective factors, without underestimating the progressive and genetic basis of this encephalopathy. Precise characterization of seizures and whole-exome sequencing are crucial in order to establish early diagnosis.


Effects of 7.5% CO(2) inhalation on allocation of spatial attention to facial cues of emotional expression.
Increased vigilance to threat-related stimuli is thought to be a core cognitive feature of anxiety. We sought to investigate the cognitive impact of experimentally induced anxiety, by means of a 7.5% CO(2) challenge, which acts as an unconditioned anxiogenic stimulus, on attentional bias for positive and negative facial cues of emotional expression in the dot-probe task. In two experiments we found robust physiological and subjective effects of the CO(2) inhalation consistent with the claim that the procedure reliably induces anxiety. Data from the dot-probe task demonstrated an attentional bias to emotional facial expressions compared with neutral faces regardless of valence (happy, angry, and fearful). These attentional effects, however, were entirely inconsistent in terms of their relationship with induced anxiety. We conclude that the previously reported poor reliability of this task is the most parsimonious explanation for our conflicting findings and that future research should develop a more reliable paradigm for measuring attentional bias in this field.


Dominant mutants of the Saccharomyces cerevisiae ASF1 histone chaperone bypass the need for CAF-1 in transcriptional silencing by altering histone and Sir protein recruitment.
Transcriptional silencing involves the formation of specialized repressive chromatin structures. Previous studies have shown that the histone H3-H4 chaperone known as chromatin assembly factor 1 (CAF-1) contributes to transcriptional silencing in yeast, although the molecular basis for this was unknown. In this work we have identified mutations in the nonconserved C terminus of antisilencing function 1 (Asf1) that result in enhanced silencing of HMR and telomere-proximal reporters, overcoming the requirement for CAF-1 in transcriptional silencing. We show that CAF-1 mutants have a drastic reduction in DNA-bound histone H3 levels, resulting in reduced recruitment of Sir2 and Sir4 to the silent loci. C-terminal mutants of another histone H3-H4 chaperone Asf1 restore the H3 levels and Sir protein recruitment to the silent loci in CAF-1 mutants, probably as a consequence of the weakened interaction between these Asf1 mutants and histone H3. As such, these studies have identified the nature of the molecular defect in the silent chromatin structure that results from inactivation of the histone chaperone CAF-1.


Multiple oral Candida infections in patients with Sjogren's syndrome -- prevalence and clinical and drug susceptibility profiles.
To determine the prevalence of oral candidiasis and multiple oral Candida infections in patients with primary Sjögren's syndrome (SS), and the clinical and drug susceptibility profile. Thirty patients with primary SS were enrolled in our study. The diagnosis of oral candidiasis was based on the clinical manifestation, and confirmed by a concentrated rinse culture. Candida spp. assessment was accomplished using standard methods: Sabouraud dextrose agar with 50 mg/l chloramphenicol and CHROMagar were used for the rapid screening of clinical species, followed by the API 20C system for further species identification. In vitro antifungal drug susceptibility of Candida isolates was determined by the minimal inhibitory concentrations. In our study, 87% (26/30) of subjects had oral candidiasis, in which 42% (11/26) had multiple Candida spp. infection. Although C. albicans remains the predominant isolate, other rare species such as C. tropicalis, C. glabrata, C. parapsilosis, and C. krusei were present, alone or in combination. Chronic atrophic candidiasis is the most common clinical type of oral candidiasis in patients with SS. The susceptibilities of the 44 Candida isolates to 7 antifungal agents varied dramatically. The resistance to azoles was remarkable, and the phenomenon of cross-resistance between itraconazole and fluconazole was observed. Patients with primary SS carry a high risk of oral candidiasis and a high frequency of multiple Candida infections. The azole resistance patterns of Candida spp. support the necessity for drug susceptibility testing as a routine procedure for patients with oral Candida infections.


Value of 12-lead electrocardiogram to predict myocardial scar on FDG PET in heart failure patients.
A surface 12-lead electrocardiogram (ECG) is widely available, fast, inexpensive, and safe. However, its value to predict a true myocardial scar in patients with ischemic cardiomyopathy (ICM) has not been studied extensively yet. This study was conducted to assess whether Q waves on resting surface 12-lead ECG are predictive of non-viable myocardium in patients with ICM. We analyzed resting ECGs of 149 patients with ICM undergoing cardiac positron emission tomography (PET) with 13N-ammonia (NH3) and 18F-fluorodeoxyglucose (FDG) at our institution. Pathological Q waves and QS complexes were assigned to one of three coronary artery territories and compared to the PET findings. Myocardial scar was defined as 2 or more contiguous myocardial segments with an average (matched) reduction of NH3 and FDG uptake <50% of the maximum value. Pathological Q waves had a sensitivity and specificity of 70% and 40%, respectively, and a PPV and NPV of 37% and 73%, respectively, to detect myocardial scar on FDG PET. For QS complexes, sensitivity and specificity were 46% and 59%, respectively, and PPV and NPV were 36% and 68%, respectively. Sensitivity was lower, but specificity was significantly higher in both the LCX and RCA compared to the LAD territory (p<0.001), particularly for QS complexes. Pathological Q waves on resting 12-lead ECG have poor or at best moderate sensitivity and specificity to detect myocardial scar on FDG PET. These findings support the use of more advanced imaging techniques to assess myocardial viability in ICM.


A novel surgical technique for the large ovarian cystic mass - combined mini-laparotomy and laparoscopy.
Laparoscopic resection of ovarian cysts > ten cm in diameter can be technically challenging. Laparotomy is often the preferred surgical approach. Minimal access surgery in gynaecology has been compared to laparotomy and has been shown to result in shorter patient hospital length of stay, reduced post-operative pain, and faster return to routine activities. Minimal access surgical techniques for ovarian masses > ten cm are therefore of interest as they may offer significant benefits. To assess the feasibility of a novel surgical technique using a combination of both laparoscopy and mini-laparotomy in the surgical management of ovarian cystic masses > ten cm. Outcomes including hospital length of stay, return to usual activities, post-operative complications, and patient satisfaction were assessed. A total of 17 patients who underwent surgery by a gynaecologic oncologist at a tertiary institution in Western Australia from June 2012 to September 2013 were selected. The risk of malignancy index was used to triage patients. A mini-laparotomy incision was utilised to downsize the mass and to retrieve the specimen, while the remainder of the procedure was performed by laparoscopy. Medical records were used to collect post-operative and follow up data. Patient satisfaction at six weeks post-surgery was analysed by means of a telephone questionnaire. Patients had an average age of 52 years. They were more likely to be post-menopausal and to have a raised body mass index (BMI) (average BMI 29.6 kg/m2). All 17 patients had an ovarian mass larger than ten cm in maximal diameter. Fourteen of the 17 cases were benign. Three patients were diagnosed with early stage mucinous ovarian tumours of low malignant potential. There were no malignancies. The procedure was associated with a high level of patient satisfaction. Combined mini-laparotomy and laparoscopy to resect ovarian masses > ten cm has potential benefits for patients in terms of faster recovery, lower analgesia requirements, and improved cosmetic outcome. Larger prospective studies are required to adequately assess complication rates, quality of life, and long-term outcomes in those patients with ovarian tumours of low malignant potential.


A retrospective 11-year analysis of obstetric patients with idiopathic thrombocytopenic purpura.
Numerous studies have examined the outcomes of infants born to mothers with idiopathic thrombocytopenic purpura (ITP). Fewer studies have discussed the morbidity of obstetric patients with ITP. We describe a retrospective study of 92 women with ITP during 119 pregnancies over an 11-year period. Most women had thrombocytopenia during pregnancy. At delivery, women in 98 pregnancies (89%) had platelet counts lower than 150 x 109/L; most had mild to moderate thrombocytopenia. For many, the pregnancy was uneventful; however, women had moderate to severe bleeding in 25 pregnancies (21.5%). Women in 37 pregnancies (31.1%) required treatment to increase platelet counts. During delivery, 44 women (37.3%) received epidural analgesia without complications, with most having a platelet count between 50 and 149 x 109/L. Most deliveries (82.4%) were vaginal. Bleeding was uncommon at delivery. Infant platelet counts at birth ranged from 12 to 436 x 109/L; 25.2% of infants had platelet counts lower than 150 x 109/L, and 9% had platelet counts lower than 50 x 109/L. Eighteen infants (14.6%) required treatment for hemostatic impairment. Two fetal deaths occurred. One was caused by hemorrhage. ITP in pregnancy carries a low risk, but mothers and infants may require therapy to raise their platelet counts.


Environment-dependent photon emission from solid state carbon dots and its mechanism.
Fluorescent carbon dots (CDs) have received great research interest in recent years, with applications in areas such as bio-imaging and chemical sensing. However, solid state photoluminescence of CDs and its related applications (e.g. optoelectronics) is a less explored territory. Here, we have systematically studied the photo emission of CDs in solid state. We found that their blue emission is highly dependent on whether the environment contains polar groups or not. Mechanism studies show that the blue emission of CDs may come from their C=O bonds conjugated with aromatic carbons, and the interaction between polar groups in environment and C=O bonds in CDs is responsible for the environment-dependent photo emission. Our conclusion here should assist the development of CDs' solid state applications.


Estimating genetic benefits of polyandry from experimental studies: a meta-analysis.
The consequences of polyandry for female fitness are controversial. Sexual conflict studies and a meta-analysis of mating rates in insects suggest that there is a longevity cost when females mate repeatedly. Even so, compensatory material benefits can elevate egg production and fertility, partly because polyandry ensures an adequate sperm supply. Polyandry can therefore confer direct benefits. The main controversy surrounds genetic benefits. The argument is analogous to that surrounding the evolution of conventional female mate choice, except that with polyandry it is post-copulatory mechanisms that might bias paternity towards males with higher breeding values for fitness. Recent meta-analyses of extra-pair copulations in birds have cast doubt on whether detectable genetic benefits exist. By contrast, another meta-analysis showed that polyandry elevates egg hatching success (possibly due to a fertilization bias towards sperm with paternal genes that elevate embryo survival) in insects. A detailed summary of whether polyandry elevates other components of offspring performance is lacking. Here we present a comprehensive meta-analysis of 232 effect sizes from 46 experimental studies. These experiments were specifically designed to try to quantify the potential genetic benefits of polyandry by controlling fully for the number of matings by females assigned to monandry and polyandry treatments. The bias-corrected 95% confidence intervals for egg hatching success (d = -0.01 to 0.61), clutch production (d = 0.07 to 0.45) and fertility (d = 0.04 to 0.40) all suggest that polyandry has a beneficial effect (although P values from parametric tests were marginally non-significant at P = 0.075, 0.052 and 0.058, respectively). Polyandry was not significantly beneficial for any single offspring performance trait (e.g. growth rate, survival, adult size), but the test power was low due to small sample sizes (suggesting that many more studies are still needed). We then calculated a composite effect size that provides an index of general offspring performance. Depending on the model assumptions, the mean effect of polyandry was either significantly positive or marginally non-significant. A possible role for publication bias is discussed. The magnitude of the reported potential genetic benefits (d = 0.07 to 0.19) are larger than those from two recent meta-analyses comparing offspring sired by social and extra-pair mates in birds (d = 0.02 to 0.04). This difference raises the intriguing possibility that cryptic, post-copulatory female choice might be more likely to generate 'good gene' or 'compatible gene' benefits than female choice of mates based on the expression of secondary sexual traits.


Arrangement of the disulphide bridges in human low-Mr kininogen.
The arrangement of the disulphide bridges in human low-Mr kininogen has been elucidated. Low-Mr kininogen contains 18 half-cystine residues forming nine disulphide bridges. The first and the last half-cystine residues of the amino acid sequence form a disulphide loop which spans the heavy- and the light-chain portion of the kininogen molecule. The other 16 half-cystine residues are linked consecutively to form eight loops of 4-20 amino acids; these loops are lined up in the heavy-chain portion of the kininogen molecule. In this way, a particular pattern of disulphide loops is formed which seems to be of critical importance for the inhibitor function of human kininogen.


[The use of the vancomycin paste for sternal hemostasis and mediastinitis prophylaxis].
Mediastinitis is one of the most feared complications for thoracic surgeons, being a significant factor in morbidity and mortality in thoracic surgery. To find a new alternative in order to prevent mediastinitis, reducing the morbidity and mortality. A retrospective study including 1020 patients operated between February 2002 and October 2005. Patients underwent bypass surgery and vancomycin paste was used rather than bone wax in all cases. Patients were followed-up for 45 months; there were only five (0.49%) cases of mediastinitis; no deaths were observed. The use of Vancomycin paste to replace bone wax proved to be a great allied to prevent mediastinitis after thoracic surgery.


Electromyography in infants and children.
Electromyography (EMG) is of proven value in the diagnosis of acute and chronic neuromuscular diseases in infants and children. When this technique is combined with nerve conduction studies, including repetitive nerve stimulation studies, it is often possible upon completion of the studies to identify the disorder as one of nerve, neuromuscular junction, or muscle. The purpose of this article is to review the principles and techniques of EMG in infants and children and to describe the EMG findings in several neuromuscular disorders.


The Effects of the Training Program and Counseling Program Given to Women Who Underwent a Mastectomy and Spouses.
Following breast cancer treatment, many families are negatively affected following the treatment for breast cancer of their women members. This study focused on assessing the effects of the training program and counseling program given to women who underwent a mastectomy and their spouses. Sixty women and 60 spouses were recruited for this study. The women in the experimental group and their spouses were provided with a four-session training program, once a week. Following this training, a 3-month follow-up and counseling were given and an assessment made. There was significant difference between average post-test scores of spouses in the experimental and control groups, in terms of problem solving (p = .003), communication (p = .033), and roles (p = .000) dimensions of family assessment device (FAD). Noting that women in the experimental and control groups demonstrated significant differences among average post-test scores in terms of role emotional (p = .045) and mental health (p = .017) dimensions of Quality of Life Scale (SF-36), a significant difference existed among average post-test scores of spouses in the experimental and control groups in terms of general health (p = .017), role physical (p = .011), role emotional (p = .003), and mental health (p = .005) dimensions of Quality of Life Scale. These results indicated that training and counseling program provided to this population produced positive effects upon family functioning and quality of life.


The dynamics of phage predation on a microcolony.
Phage predation is an important factor for controlling the bacterial biomass. At face value, dense microbial habitats are expected to be vulnerable to phage epidemics due to the abundance of fresh hosts immediately next to any infected bacteria. Despite this, the bacterial microcolony is a common habitat for bacteria in nature. Here we experimentally quantify the fate of microcolonies of Escherichia coli exposed to virulent phage T4. It has been proposed that the outer bacterial layers of the colony will shield the inner layers from the phage invasion and thereby constrain the phage to the colony's surface. We develop a dynamical model that incorporates this shielding mechanism and fits the results with experimental measurements to extract important phage-bacteria interaction parameters. The analysis suggests that, while the shielding mechanism delays phage attack, T4 phage are able to diffuse so deep into the dense bacterial environment that colony level survival of the bacterial community is challenged.


Designer coordination polymers: dimensional crossover architectures and proton conduction.
Coordination polymers (CPs) have large degrees of freedom in framework compositions and in the structures and environment of the inner pores. This review focuses on the recent significant progress achieved by controlling these degrees of freedom. Two breakthroughs are reviewed for constructing sophisticated structures of CP frameworks, especially in dimensional crossover regions. The first is the synthesis of quasi one-dimensional halogen-bridged coordinative tubes by applying state-of-the-art techniques of coordination chemistry. The electronic state of the coordinative tube was studied by structural, spectroscopic and theoretical methods and found to be distinct from conventional one-dimensional systems. The second breakthrough is the achievement of a quasi-two-dimensional architecture by combining Langmuir-Blodgett and layer-by-layer methods. Two-dimensional LB CP films were prepared on liquid; the films were stacked layer by layer, and a crystalline quasi-two-dimensional structure was constructed. This review also covers the design of the environment of the inner pore, where hydrogen bond networks with various acidic sites were modified. By appropriate design of the hydrogen bond network, proton-conductive CPs are invented, which are summarized in this review. Types of proton donor sites are discussed and classified, and superprotonic conductive CPs were achieved in these investigations. These results will provide new strategies for constructing functional materials for smart devices.


Metformin as an adjunct therapy for the treatment of moderate to severe acne vulgaris: A randomized open-labeled study.
Insulin, insulin-like growth factor-1 (IGF-1) and essential amino acids activate the mechanistic target of rapamycin complex 1 (mTORC1), the main nutrient-sensitive kinase. Metformin, through inhibition of mTORC1 may improve acne. A 12-week, randomized, open-labeled study evaluated the efficacy and safety of metformin as an adjunct for moderate to severe facial acne. In total, 84 patients received either oral tetracycline 250 mg bd and topical benzoyl peroxide 2.5% with or without metformin 850 mg daily. Evaluations constituted lesion counts, the Cardiff Acne Disability Index (CADI), metabolic parameters and treatment success rate (Investigators Global Assessment score of 0 or 1 or improvement of two grades). Treatment success rates were higher in the metformin group (66.7% vs. 43.2%; p = .04). The mean percentage reduction from baseline in total lesion counts at Week 12 was greater in the metformin group (71.4% vs. 65.3%; p = .278). The CADI scores showed a greater mean reduction in the metformin group (4.82 vs. 4.22; p = .451). Metformin was equally efficacious in improving acne in lean and overweight subjects. Gastrointestinal symptoms were noted in 31.7% of subjects on metformin. This study presents favorable data for metformin as an adjunct for acne treatment. Further randomized placebo-controlled studies are required.


[Role of ACE2-Ang (1-7)-Mas receptor axis in heart failure with preserved ejection fraction with hypertension].
To investigate changes in the angiotensin converting enzyme 2 (ACE2) and angiotensin (1-7) [Ang (1-7)] and to explore the role of ACE2-Ang (1-7)-Mas receptor axis in hypertension with heart failure with preserved ejection fraction (HFPEF). Methods: A total of 70 patients with primary hypertension and preserved left ventricular ejection fraction (LVEF>50%) were recruited and patients were divided into a hypertension group (HBP) and a heart failure with preserved ejection fraction group (HFpEF) according to the diagnostic criteria of HFpEF. Thirty-five healthy participants were selected randomly as a control group. Enzyme linked immunosorbent assays (ELISA) method was used to detect concentration of Ang (1-7), ACE2, angiotensin II (Ang II), brain natriuretic peptide (BNP) in plasma. Male Sprague- Dawley (SD) rats was randomly divided into 2 groups: An HFpEF group (n=16) and a sham group (n=8). Rats (n=8) in the AAC group were given Ang (1-7) [0.5 mg/(kg.d), intraperitoneally] for 6 weeks, and the rest were given equal dose normal saline. Then all the rats were killed, and the hearts were taken out for hematoxylineosin (HE) staining. The protein expressions of angiotensin converting enzyme (ACE), ACE2, and Mas receptor were detected by Western blot. Results: The BNP and Ang II were significantly increased in the HBP group and the HFpEF group compared with the control group (P<0.01). There were not significantly different in levels of ACE2 and Ang (1-7) between the HBP group and control group (P>0.05), whereas those levels were significantly increased in the HFpEF group compared with the HBP group and control group (P<0.01). HE staining showed obvious hypertrophy of myocardial cell in the AAC group compared with the sham group. Hypertrophy of myocardial cell in the AAC+Ang (1-7) group was significantly higher than that in the AAC group. Expressions of ACE, ACE2, and Mas receptor proteins were significantly higher in the AAC group than those in the sham group (P<0.05), while the expressions of ACE2 and Mas receptor proteins in the AAC+Ang (1-7) group were significantly higher than those in the AAC group (P<0.05). There was no significant difference in the ACE protein expression between groups (P>0.05). Conclusion: ACE2 and Ang (1-7) are important predictive factors for the severity of heart failure and myocardial remodeling of HFpEF with hypertension; ACE2-Ang (1-7)-Mas receptor axis may play a protective role in preventing myocardial remodeling in HFpEF with hypertension.


Drusen ultrastructure imaging with spectral domain optical coherence tomography in age-related macular degeneration.
To categorize drusen ultrastructure in age-related macular degeneration (AMD) using spectral domain optical coherence tomography (SDOCT) and correlate the tomographic and photographic drusen appearances. Prospective case series. Thirty-one eyes of 31 patients with non-neovascular AMD. Subjects with drusen and a clinical diagnosis of AMD were enrolled in an SDOCT imaging study from August of 2005 to May of 2007. Foveal linear scans were acquired, and the image data were processed for analysis. Drusen were scored by 4 morphologic categories: shape, predominant internal reflectivity, homogeneity, and presence of overlying hyper-reflective foci. The prevalences of each morphologic pattern and combinations of morphologic patterns observed were calculated. The photographic appearance of each druse was compared with the tomographic classification. Interobserver and intraobserver agreement analysis was performed. Prevalence of morphologic parameters using SDOCT. Twenty-one eyes of 21 patients had SDOCT B-scans of adequate quality for analysis. On the basis of the above morphologic categories, 17 different drusen patterns were found in 120 total drusen. The most common was convex, homogeneous, with medium internal reflectivity, and without overlying hyper-reflective foci, present in 17 of 21 eyes (81%). Of the 16 eyes (76%) with nonhomogeneous drusen, 5 had a distinct hyper-reflective core. Hyper-reflective foci overlying drusen were in 7 eyes (33%). Although half of the photographically soft-indistinct drusen were convex with medium internal reflectivity and homogeneous without overlying hyper-reflective foci, the other half had significant variability in their tomographic appearance. Both interobserver and intraobserver agreement in drusen grading were high. Readers agreed the most when grading drusen shape and reflectivity, whereas the least agreement was for drusen homogeneity. Drusen ultrastructure can be imaged with SDOCT and characterized with a simple grading system. Photographic appearance may predict some but not all tomographic appearances. Trained observers have a high level of agreement with this grading system. These in vivo morphologic characteristics imaged with SDOCT may be distinct subclasses of drusen types, may relate closely to ultrastructural drusen elements identified in cadaveric eyes, and may be useful imaging biomarkers for disease severity or risk of progression. This will require validation from further studies.


Evaluating sexual health planning for the London 2012 Olympics.
The public health impact of mass gatherings should not be underestimated, requiring careful planning. This evaluation identified the successes and failures of a programme targeted to mitigate against potential increases in sexual ill health during the London 2012 Olympics. Programme planning was evaluated using documentary analysis. Stakeholders' experiences were explored using an online survey. Finally, selected stakeholders were interviewed in depth. Over 100 documents were analysed, 36 survey responses received and 12 interviews conducted. Most respondents felt aims were appropriate, potentially overambitious. 'Business as usual', with no disruption or increased demand, was reported in sexual health services. Some interviewees felt evidence for increased demand was limited, although contingency planning was needed. Signposting service users and providing 'residual risk responses' appeared successful. Planned service transformation was not fully achieved and perhaps inappropriate, although new service collaborations emerged. Over 2000 individuals participated; wider public engagement was seen as inappropriate. A 'Sex Factor 2012' competition was particularly successful. Legacy opportunities included planning work, groundwork for transformation, relationship building and continuing the resilience changes. The Games allowed sexual health services to explore new ways of working, engage with stakeholders and develop new relationships, although in reality demand for services did not increase.


Deprescribing benzodiazepine receptor agonists taken for insomnia: a review and key messages from practice guidelines.
Long‑term benzodiazepine receptor agonist (BZRA) use for insomnia is common and highly prevalent in adults in all care settings. Evidence syntheses suggest that the therapeutic benefits of benzodiazepines for insomnia are marginal and very short term. On the harm side, BZRAs are associated with daytime sedation and confusion. Long‑term use increases the risk of falls, fractures, cognitive impairment, and motor vehicle accidents. An evidence‑based clinical practice guideline has been developed to assist with deprescribing BZRAs. This review highlights the rationale for deprescribing BZRAs used for insomnia and summarizes key messages for clinicians from the new BZRA deprescribing guideline and their supporting evidence.


Dichotomy between Attractive and Repulsive Tomonaga-Luttinger Liquids in Spin Ladders.
We present a direct NMR method to determine whether the interactions in a Tomonaga-Luttinger liquid (TLL) state of a spin-1/2 Heisenberg antiferromagnetic ladder are attractive or repulsive. For the strong-leg spin ladder compound (C_{7}H_{10}N)_{2}CuBr_{4} we find that the isothermal magnetic field dependence of the NMR relaxation rate T_{1}^{-1}(H) displays a concave curve between the two critical fields bounding the TLL regime. This is in sharp contrast to the convex curve previously reported for a strong-rung ladder, (C_{5}H_{12}N)_{2}CuBr_{4}. We show that the concavity and the convexity of T_{1}^{-1}(H), which is a fingerprint of spin fluctuations, directly reflect the attractive and repulsive fermionic interactions in the TLL, respectively. The interaction sign is alternatively determined from an indirect method combining bulk magnetization and specific heat data.


On the status of individual response specificity.
The concept of physiological individual response specificity (IRS) was critically discussed. A review of empirical studies focused on IRS magnitude, stability, and personality correlates. Using difference scores, an average of 33% of the participants showed a significant IRS. IRS stability was found in only 15% of the participants. In some studies, IRS incidence was associated with neuroticism or stress coping styles. We suggest that the IRS concept should include not only purely constitutional but also situational and psychological determinants. Predictions from this revised biopsychological model were tested with a data set comprising 48 healthy male participants who completed six tasks, which were replicated three times in 1-week intervals. At Session 1, 21% of the participants displayed a significant IRS. IRS stability was found in only 8% of the participants. Participants with a significant IRS at Session 1 reported higher levels of fear (anger and happiness as covariates) and of pounding heart. Between-session IRS (trait-IRS) but not within-session IRS (state-IRS) was associated with trait anxiety.


Detection of T-cell lymphoma-associated antigens on cord blood lymphocytes and phytohemagglutinin-stimulated blasts.
Absorption studies demonstrate that T-cell lymphoma-associated antigens detected by rabbit antisera to human T-lymphoblast cell lines are present in suspensions of cord blood lymphocytes and phytohemagglutinin-stimulated adult blood lymphocytes in amounts similar to those found in T-cell lymphoma tumor cell suspensions. Smaller amounts of antigen activity are found in suspensions of tonsil cells, thymocytes, and unstimulated adult blood lymphocytes. Little or no antigen activity is found in suspensions of lymphoblasts from patients with other types of leukemia or from B-cell lines. T-cell depletion removes antigen activity from suspensions of normal lymphocytes. These findings suggest that T-cell lymphoma-associated antigens may be fetal antigens expressed by activated T-cells.


A modular labeling strategy for in vivo PET and near-infrared fluorescence imaging of nanoparticle tumor targeting.
Advances in preclinical molecular imaging have generated new opportunities to noninvasively visualize the biodistribution and tumor targeting of nanoparticle therapeutics. Capitalizing on recent achievements in this area, we sought to develop an (89)Zr-based labeling strategy for liposomal nanoparticles that accumulate in tumors via passive targeting mechanisms. (89)Zr-labeled liposomes were prepared using 2 different approaches: click labeling and surface chelation. Pharmacokinetic and biodistribution studies, as well as PET/CT imaging of the radiolabeled nanoparticles, were performed on a mouse model of breast cancer. In addition, a dual PET/optical probe was prepared by incorporation of a near-infrared fluorophore and tested in vivo by PET and near-infrared fluorescence imaging. The surface chelation approach proved to be superior in terms of radiochemical yield and stability, as well as in vivo performance. Accumulation of these liposomes in tumor peaked at 24 h after injection and was measured to be 13.7 ± 1.8 percentage injected dose per gram. The in vivo performance of this probe was not essentially perturbed by the incorporation of a near-infrared fluorophore. We have developed a highly modular and efficient strategy for the labeling of liposomal nanoparticles with (89)Zr. In xenograft and orthotopic mouse models of breast cancer, we demonstrated that the biodistribution of these nanoparticles can be visualized by PET imaging. In combination with a near-infrared dye, these liposomal nanoparticles can serve as bimodal PET/optical imaging agents. The liposomes target malignant growth, and their bimodal features may be useful for simultaneous PET and intraoperative imaging.


The multiscale coarse-graining method. II. Numerical implementation for coarse-grained molecular models.
The multiscale coarse-graining (MS-CG) method [S. Izvekov and G. A. Voth, J. Phys. Chem. B 109, 2469 (2005); J. Chem. Phys. 123, 134105 (2005)] employs a variational principle to determine an interaction potential for a CG model from simulations of an atomically detailed model of the same system. The companion paper proved that, if no restrictions regarding the form of the CG interaction potential are introduced and if the equilibrium distribution of the atomistic model has been adequately sampled, then the MS-CG variational principle determines the exact many-body potential of mean force (PMF) governing the equilibrium distribution of CG sites generated by the atomistic model. In practice, though, CG force fields are not completely flexible, but only include particular types of interactions between CG sites, e.g., nonbonded forces between pairs of sites. If the CG force field depends linearly on the force field parameters, then the vector valued functions that relate the CG forces to these parameters determine a set of basis vectors that span a vector subspace of CG force fields. The companion paper introduced a distance metric for the vector space of CG force fields and proved that the MS-CG variational principle determines the CG force force field that is within that vector subspace and that is closest to the force field determined by the many-body PMF. The present paper applies the MS-CG variational principle for parametrizing molecular CG force fields and derives a linear least squares problem for the parameter set determining the optimal approximation to this many-body PMF. Linear systems of equations for these CG force field parameters are derived and analyzed in terms of equilibrium structural correlation functions. Numerical calculations for a one-site CG model of methanol and a molecular CG model of the EMIM(+)NO(3) (-) ionic liquid are provided to illustrate the method.


Se Status Prediction by Food Intake as Compared to Circulating Biomarkers in a West Algerian Population.
Algeria is the largest country in Africa, located close to the Mediterranean coastal area, where nutrients consumption varies widely. Local data on selenium composition of foods are not available. We postulated a close correlation between selenium status predictions from food consumption analysis with a quantitative analysis of circulating biomarkers of selenium status. Population characteristics were recorded from 158 participants and dietary selenium intake was calculated by 24-h recall. The average total plasma selenium was 92.4 ± 18.5 µg/L and the mean of selenium intake was 62.7 µg/day. The selenoprotein P concentration was 5.5 ± 2.0 mg/L and glutathione peroxidase 3 activity was 247.3 ± 41.5 U/L. A direct comparison of the dietary-derived selenium status to the circulating selenium biomarkers showed no significant interrelation. Based on absolute intakes of meat, potato and eggs, a model was deduced that outperforms the intake composition-based prediction from all food components significantly (DeLong's test, p = 0.029), yielding an area under the curve of 82%. Selenium status prediction from food intake remains a challenge. Imprecision of survey method or information on nutrient composition makes extrapolating selenium intake from food data providing incorrect insights into the nutritional status of a given population, and laboratory analyses are needed for reliable information.


Management of tuberculomas of the craniovertebral junction.
Tuberculosis of the craniovertebral junction is extremely rare. However, recent evidence suggests that the incidence of this condition may be increasing in the United Kingdom. The diagnosis is often difficult despite advances in imaging using MRI. CT guided biopsy of lesions often yields inconclusive results. The transoral approach to the anterior craniovertebral junction provides excellent access to this region with a low operative morbidity and mortality, enabling biopsy of lesions and decompression of the neuraxis. Management of secondary atlantoaxial instability, regarding both timing and method of stabilization, is controversial. We report two cases of tuberculomas of the craniovertebral junction, that illustrate the role of transoral surgery in both diagnosis and treatment of this condition. Previous management strategies are reviewed and future recommendations are presented.


Alterations of the [59Fe]ferric citrate biodistribution in hyperferremic mice after the administration of pyrophosphate and desferrioxamine.
One of the most efficient anions in enhancing the ability of desferrioxamine (DFO) to remove iron from transferrin in vitro has been shown to be pyrophosphate (PYP). To evaluate the in vivo effect of PYP in hyperferremic mice, the biodistribution of [59Fe]ferric citrate was studied after the i.p. administration of: 1) only saline in the control animals; 2) an aqueous solution of tetrasodium diphosphate (PYP; 40 gm/2 g of b.wt.); 3) desferral (DFO; 12 mg/20 g of b.wt.); and 4) PYP + DFO at the respective dosages shown above. The radioactivity in each organ, blood, urine and feces was measured and referred to as percentage of the injected dose. PYP administered alone acted as a weaker chelator of iron than DFO. The combined administration of DFO and PYP contributed more than DFO or PYP separately, to the increase of urinary excretion of 59Fe and to the significant decrease of the radioiron concentration in liver (.01 less than P less than .05). The above induced changes are not, however, the additive result of the separate effect of DFO and PYP. That observation would suggest that DFO + PYP combined in a unique treatment, interact with iron through a common reaction pathway and that PYP plays in vivo a synergistic role in that interaction. The kind of iron with which DFO + PYP interacts is then suggested to be the transferrin-bound iron located in extracellular spaces of tissues.


CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies.
Extending the success of chimeric antigen receptor (CAR) T cells to T-cell malignancies is problematic because most target antigens are shared between normal and malignant cells, leading to CAR T-cell fratricide. CD7 is a transmembrane protein highly expressed in acute T-cell leukemia (T-ALL) and in a subset of peripheral T-cell lymphomas. Normal expression of CD7 is largely confined to T cells and natural killer (NK) cells, reducing the risk of off-target-organ toxicity. Here, we show that the expression of a CD7-specific CAR impaired expansion of transduced T cells because of residual CD7 expression and the ensuing fratricide. We demonstrate that targeted genomic disruption of the CD7 gene prevented this fratricide and enabled expansion of CD7 CAR T cells without compromising their cytotoxic function. CD7 CAR T cells produced robust cytotoxicity against malignant T-cell lines and primary tumors and were protective in a mouse xenograft model of T-ALL. Although CD7 CAR T cells were also toxic against unedited (CD7+) T and NK lymphocytes, we show that the CD7-edited T cells themselves can respond to viral peptides and therefore could be protective against pathogens. Hence, genomic disruption of a target antigen overcomes fratricide of CAR T cells and establishes the feasibility of using CD7 CAR T cells for the targeted therapy of T-cell malignancies.


The influence of chlorhexidine on the severity of cyclosporin A-induced gingival overgrowth.
The influence of chemical plaque control, using topically applied 0.12% chlorhexidine, on the severity of cyclosporin A (CsA)-induced gingival overgrowth (GO) was evaluated. Forty Holtzman rats were divided into four groups: 1) control; 2) cyclosporin A: a 10 mg/kg/day subcutaneous dose of CsA; 3) chlorhexidine: 0.12% chlorhexidine (CHX) was applied to the buccal surface of the right mandibular molars; and 4) cyclosporin A/chlorhexidine: a combination of the treatment described for cyclosporin A and chlorhexidine groups. The animals were fed a high sucrose diet during the experiment and were sacrificed after 14 and 21 days. The histometric analysis revealed a significant increase in buccal gingival area in the cyclosporin A group compared to other groups (P < 0.01) after 21 days. The epithelium thickness of the buccal gingiva was significantly increased in the cyclosporin A group, compared to the control group (P < 0.05). The cyclosporin A/chlorhexidine group exhibited statistically significantly lower gingival overgrowth than the cyclosporin A group. These findings, if replicated in human studies, suggest that topically applied 0.12% chlorhexidine may be a valuable measure in the management of cyclosporin-induced gingival overgrowth.


A fuzzy-logic-based model to predict biogas and methane production rates in a pilot-scale mesophilic UASB reactor treating molasses wastewater.
A MIMO (multiple inputs and multiple outputs) fuzzy-logic-based model was developed to predict biogas and methane production rates in a pilot-scale 90-L mesophilic up-flow anaerobic sludge blanket (UASB) reactor treating molasses wastewater. Five input variables such as volumetric organic loading rate (OLR), volumetric total chemical oxygen demand (TCOD) removal rate (R(V)), influent alkalinity, influent pH and effluent pH were fuzzified by the use of an artificial intelligence-based approach. Trapezoidal membership functions with eight levels were conducted for the fuzzy subsets, and a Mamdani-type fuzzy inference system was used to implement a total of 134 rules in the IF-THEN format. The product (prod) and the centre of gravity (COG, centroid) methods were employed as the inference operator and defuzzification methods, respectively. Fuzzy-logic predicted results were compared with the outputs of two exponential non-linear regression models derived in this study. The UASB reactor showed a remarkable performance on the treatment of molasses wastewater, with an average TCOD removal efficiency of 93 (+/-3)% and an average volumetric TCOD removal rate of 6.87 (+/-3.93) kg TCOD(removed)/m(3)-day, respectively. Findings of this study clearly indicated that, compared to non-linear regression models, the proposed MIMO fuzzy-logic-based model produced smaller deviations and exhibited a superior predictive performance on forecasting of both biogas and methane production rates with satisfactory determination coefficients over 0.98.


TRPV2: A Key Player in Myelination Disorders of the Central Nervous System.
Transient potential receptor vanilloid 2 (TRPV2) is widely expressed through the nervous system and specifically found in neuronal subpopulations and some glial cells. TRPV2 is known to be sensitized by methionine oxidation, which results from inflammation. Here we aim to characterize the expression and regulation of TRPV2 in myelination pathologies, such as hypomyelination and demyelination. We validated the interaction between TRPV2 and its putative interactor Opalin, an oligodendrocyte marker, in mixed glial cultures under pro- and anti-inflammatory conditions. Then, we characterized TRPV2 time-course expression in experimental animal models of hypomyelination (jimpy mice) and de-/remyelination (cuprizone intoxication and experimental autoimmune encephalomyelitis (EAE)). TRPV2 showed upregulation associated with remyelination, inflammation in cuprizone and EAE models, and downregulation in hypomyelinated jimpy mice. TRPV2 expression was altered in human samples of multiple sclerosis (MS) patients. Additionally, we analyzed the expression of methionine sulfoxide reductase A (MSRA), an enzyme that reduces oxidated methionines in TRPV2, which we found increased in inflammatory conditions. These results suggest that TRPV2 may be a key player in myelination in accordance with the recapitulation hypothesis, and that it may become an interesting clinical target in the treatment of demyelination disorders.


Association between serum concentration of infliximab and efficacy in adult patients with ulcerative colitis.
We analyzed data collected during the Active Ulcerative Colitis Trials (ACT-1 and ACT-2) to assess relationships between serum concentrations of infliximab and outcomes of adults with moderate-to-severe ulcerative colitis. We compared serum concentrations of infliximab with outcomes of 728 patients with moderately-to-severely active ulcerative colitis who participated in ACT-1 or ACT-2; efficacy data were collected at weeks 8, 30, and 54 (for ACT-1 only). Relationships between serum concentration of infliximab and efficacy outcomes were assessed using trend, logistic regression, and receiver operating characteristic curve analyses. We also evaluated factors that affected the relationship between exposure and response. Median serum concentrations of infliximab at weeks 8, 30, and/or 54 were significantly higher in patients with clinical response, mucosal healing, and/or clinical remission than in patients who did not meet these response criteria. There were statistically significant relationships between quartile of infliximab serum concentration and efficacy at these time points (P < .01). Infliximab therapy was effective for a smaller proportion of patients in the lowest quartile, and these patients had lower serum levels of albumin and a higher incidence of antibodies to infliximab than patients in other quartiles. Although the relationship between exposure to infliximab and response varied among patients, approximate serum concentrations of 41 μg/mL infliximab at week 8 of induction therapy and 3.7 μg/mL at steady-state during maintenance therapy produced optimal outcomes in patients. Serum concentrations of infliximab are associated with efficacy in patients with moderate-to-severe ulcerative colitis; however, complex factors determine the relationship between exposure to this drug and response. A prospective evaluation of the value of measuring serum concentrations of infliximab should be performed before these data can be included in patient management strategies. Clinicaltrials.gov numbers: NCT00036439 and NCT00096655.


Evaluation of diffusion parameters as early biomarkers of disease progression in glioblastoma multiforme.
The purpose of this study was to evaluate diffusion parameters at pre-, mid-, and post-radiation therapy (RT) in contrast-enhancing and nonenhancing lesions of postsurgical glioblastoma multiforme patients treated with the standard of care RT concurrently with temozolomide (TMZ) followed by adjuvant TMZ and an antiangiogenic drug. The diffusion parameters explored include baseline and short-term changes in apparent diffusion coefficient, fractional anisotropy, and eigenvalues. These diffusion parameters were examined as early markers for disease progression by relating them to clinical outcome of 6-month progression-free survival. The results indicated that changes from mid- to post-RT were significantly different between patients who progressed within 6 months vs those who were free of progression for 6 months after initiation of therapy. The study also showed that the changes in diffusion parameters from the mid- to post-RT scan may be more significant than those from pre- to mid-RT and pre- to post-RT. This is important because the mid-RT scan is currently not performed as part of the standard clinical care.


Selective modification by transglutaminase of a glutamine side chain in the hinge region of the histidine-388----glutamine mutant of yeast phosphoglycerate kinase.
The transglutaminase-catalysed incorporation of putrescine and monodansylcadaverine into yeast phosphoglycerate kinase has been studied. There is little incorporation of the amines into wild-type enzyme, but nearly stoichiometric incorporation into the histidine-388----glutamine mutant enzyme. C.d. studies show that the overall structure of the mutant enzyme is very similar to that of the wild-type enzyme. Incorporation of the amines into the mutant enzyme causes no significant change in its activity. Glutamine-388 was shown, by isolation and sequencing of the modified peptide, to be the site of incorporation of monodansylcadaverine into the mutant enzyme. The specificity of the transglutaminase reaction is discussed in the light of available data.


Plasmodium falciparum population dynamics in a cohort of pregnant women in Senegal.
Pregnant women acquire protective antibodies that cross-react with geographically diverse placental Plasmodium falciparum isolates, suggesting that surface molecules expressed on infected erythrocytes by pregnancy-associated malaria (PAM) parasites have conserved epitopes and, that designing a PAM vaccine may be envisaged. VAR2CSA is the main candidate for a pregnancy malaria vaccine, but vaccine development may be complicated by its sequence polymorphism. The dynamics of P. falciparum genotypes during pregnancy in 32 women in relation to VAR2CSA polymorphism and immunity was determined. The polymorphism of the msp2 gene and five microsatellites was analysed in consecutive parasite isolates, and the DBL5epsilon + Interdomain 5 (Id5) part of the var2csa gene of the corresponding samples was cloned and sequenced to measure variation. In primigravidae, the multiplicity of infection in the placenta was associated with occurrence of low birth weight babies. Some parasite genotypes were able to persist over several weeks and, still be present in the placenta at delivery particularly when the host anti-VAR2CSA antibody level was low. Comparison of diversity among genotyping markers confirmed that some PAM parasites may harbour more than one var2csa gene copy in their genome. Host immunity to VAR2CSA influences the parasite dynamics during pregnancy, suggesting that the acquisition of protective immunity requires pre-exposure to a limited number of parasite variants. Presence of highly conserved residues in surface-exposed areas of the VAR2CSA immunodominant DBL5epsilon domain, suggest its potential in inducing antibodies with broad reactivity.


Droplet-based microfluidic systems for high-throughput single DNA molecule isothermal amplification and analysis.
We have developed a method for high-throughput isothermal amplification of single DNA molecules in a droplet-based microfluidic system. DNA amplification in droplets was analyzed using an intercalating fluorochrome, allowing fast and accurate "digital" quantification of the template DNA based on the Poisson distribution of DNA molecules in droplets. The clonal amplified DNA in each 2 pL droplet was further analyzed by measuring the enzymatic activity of the encoded proteins after fusion with a 15 pL droplet containing an in vitro translation system.


Examining national outcomes after thyroidectomy with nerve monitoring.
Previous intraoperative nerve monitoring (IONM) studies have demonstrated modest-to-no benefit and did not include a nationwide sample of hospitals representative of broad thyroidectomy practices. This national study was designed to compare vocal cord paralysis (VCP) rates between thyroidectomy with IONM and without monitoring (conventional). We performed a retrospective analysis of 243,527 thyroidectomies during 2008 to 2011 using the Nationwide Inpatient Sample. Use of IONM increased yearly throughout the study period (2.6% [2008], 5.6% [2009], 6.1% [2010], 6.9% [2011]) and during this time, VCP rates in the IONM group initially increased year-over-year (0.9% [2008], 2.4% [2009], 2.5% [2010], 1.4% [2011]). In unadjusted analyses, IONM was associated with significantly higher VCP rates (conventional 1.4% vs IONM 1.9%, p < 0.001). After propensity score matching, IONM remained associated with higher VCP rates in partial thyroidectomy and lower VCP rates for total thyroidectomy with neck dissection. Hospital-level analysis revealed that VCP rates were not explained by differential laryngoscopy rates, decreasing the likelihood of ascertainment bias. Additionally, for hospitals in which IONM was applied to more than 50% of thyroidectomies, lower VCP rates were observed (1.1%) compared with hospitals that applied IONM to less than 50% (1.6%, p = 0.016). Higher hospital volume correlated with lower VCP rates in both groups (<75, 75 to 299, >300 thyroidectomies/year: IONM, 2.1%, 1.7%, 1.7%; conventional, 1.5%, 1.3%, 1.0%, respectively). According to this study, IONM has not been broadly adopted into practice. Overall, IONM was associated with a higher rate of VCP even after correction for numerous confounders. In particular, low institutional use of IONM and use in partial thyroidectomies are associated with higher rates of VCP. Further studies are warranted to support the broader application of IONM in patients where benefit can be reliably achieved.


External Human-Machine Interfaces Can Be Misleading: An Examination of Trust Development and Misuse in a CAVE-Based Pedestrian Simulation Environment.
To investigate pedestrians' misuse of an automated vehicle (AV) equipped with an external human-machine interface (eHMI). Misuse occurs when a pedestrian enters the road because of uncritically following the eHMI's message. Human factors research indicates that automation misuse is a concern. However, there is no consensus regarding misuse of eHMIs. Sixty participants each experienced 50 crossing trials in a Cave Automatic Virtual Environment (CAVE) simulator. The three independent variables were as follows: (1) behavior of the approaching AV (within-subject: yielding at 33 or 43 m distance, no yielding), (2) eHMI presence (within-subject: eHMI on upon yielding, off), and (3) eHMI onset timing (between-subjects: eHMI turned on 1 s before or 1 s after the vehicle started to decelerate). Two failure trials were included where the eHMI turned on, yet the AV did not yield. Dependent measures were the moment of entering the road and perceived risk, comprehension, and trust. Trust was higher with eHMI than without, and the -1 Group crossed earlier than the +1 Group. In the failure trials, perceived risk increased to high levels, whereas trust and comprehension decreased. Thirty-five percent of the participants in the -1 and +1 Groups walked onto the road when the eHMI failed for the first time, but there were no significant differences between the two groups. eHMIs that provide anticipatory information stimulate early crossing. eHMIs may cause people to over-rely on the eHMI and under-rely on the vehicle-intrinsic cues. eHMI have adverse consequences, and education of eHMI capability is required.


Central nervous system metastases and oligoprogression during treatment with tyrosine kinase inhibitors in oncogene-addicted non-small cell lung cancer: how to treat and when?
Up to 70% of non-small cell lung cancer (NSCLC) patients develop central nervous system (CNS) metastases during the course of their disease, especially those with oncogenic drivers treated with a first-generation tyrosine kinase inhibitor (TKI), because of the relatively poor CNS penetration. CNS metastases are associated with a negative impact on quality of life and survival. As, with the introduction of newer generation TKIs, the survival rates are increasing in this particular population, treatment and/or prevention of CNS metastases becomes even more relevant and the TKI with the best CNS efficacy should be selected. Unfortunately, CNS efficacy data in clinical trials are not fully comparable. Furthermore, oligoprogression to the brain without extracranial progression regularly occurs in the oncogenic driver population and both local therapy and switch of systemic therapy are possible treatment options. However, the best order of systemic and local therapy is still not precisely known. In this narrative review, we will summarize incidence and treatment of CNS metastases in oncogene driven NSCLC, including the optimal treatment of CNS oligometastatic disease (synchronous as well as oligoprogressive).


Characterization of SARS-CoV-2 Aerosols Dispersed During Noninvasive Respiratory Support of Patients With COVID-19.
In the midst of the COVID-19 pandemic, noninvasive respiratory support (NRS) therapies such as high-flow nasal cannula (HFNC) and noninvasive ventilation (NIV) were central to respiratory care. The extent to which these treatments increase the generation and dispersion of infectious respiratory aerosols is not fully understood. The objective of this study was to characterize SARS-CoV-2 aerosol dispersion from subjects with COVID-19 undergoing NRS therapy. Several different aerosol sampling devices were used to collect air samples in the vicinity of 31 subjects with COVID-19, most of whom were receiving NRS therapy, primarily HFNC. Aerosols were collected onto filters and analyzed for the presence of SARS-CoV-2 RNA. Additional measurements were collected in an aerosol chamber with healthy adult subjects using respiratory therapy devices under controlled and reproducible conditions. Fifty aerosol samples were collected from subjects receiving HFNC or NIV therapy, whereas 6 samples were collected from subjects not receiving NRS. Only 4 of the 56 aerosol samples were positive for SARS-CoV-2 RNA, and all positive samples were collected using a high air flow scavenger mask collection device placed in close proximity to the subject. The chamber measurements with healthy subjects did not show any significant increase in aerosol dispersion caused by the respiratory therapy devices compared to baseline. Our findings demonstrate very limited detection of SARS-CoV-2-containing aerosols in the vicinity of subjects with COVID-19 receiving NRS therapies in the clinical setting. These results, combined with controlled chamber measurements showing that HFNC and NIV device usage was not associated with increased aerosol dispersion, suggest that NRS therapies do not result in increased dispersal of aerosols in the clinical setting.


Post-Ischemic Bowel Stricture: CT Features in Eight Cases.
To investigate the characteristic radiologic features of post-ischemic stricture, which can then be implemented to differentiate that specific disease from other similar bowel diseases, with an emphasis on computed tomography (CT) features. Eight patients with a diagnosis of ischemic bowel disease, who were also diagnosed with post-ischemic stricture on the basis of clinical or pathologic findings, were included. Detailed clinical data was collected from the available electronic medical records. Two radiologists retrospectively reviewed all CT images. Pathologic findings were also analyzed. The mean interval between the diagnosis of ischemic bowel disease and stricture formation was 57 days. The severity of ischemic bowel disease was variable. Most post-ischemic strictures developed in the ileum (n = 5), followed by the colon (n = 2) and then the jejunum (n = 1). All colonic strictures developed in the "watershed zone." The pathologic features of post-ischemic stricture were deep ulceration, submucosal/subserosal fibrosis and chronic transmural inflammation. The mean length of the post-ischemic stricture was 7.4 cm. All patients in this study possessed one single stricture. On contrast-enhanced CT, most strictures possessed concentric wall thickening (87.5%), with moderate enhancement (87.5%), mucosal enhancement (50%), or higher enhancement in portal phase than arterial phase (66.7%). Post-ischemic strictures develop in the ileum, jejunum and colon after an interval of several weeks. In the colonic segment, strictures mainly occur in the "watershed zone." Typical CT findings include a single area of concentric wall thickening of medium length (mean, 7.4 cm), with moderate and higher enhancement in portal phase and vasa recta prominence.


Sketching of Mirror-Symmetric Shapes.
This paper presents a system to create mirror-symmetric surfaces from free-form sketches. The system takes as input a hand-drawn sketch and generates a surface whose silhouette approximately matches the input sketch. The input sketch typically consists of a set of curves connected at their endpoints, forming T-junctions and cusps. Our system is able to identify the skewed-mirror and translational symmetry between the hand-drawn curves and uses this information to reconstruct the occluded parts of the surface and its 3D shape.


Views on researcher-community engagement in autism research in the United Kingdom: a mixed-methods study.
There has been a substantial increase in research activity on autism during the past decade. Research into effective ways of responding to the immediate needs of autistic people is, however, less advanced, as are efforts at translating basic science research into service provision. Involving community members in research is one potential way of reducing this gap. This study therefore investigated the views of community involvement in autism research both from the perspectives of autism researchers and of community members, including autistic adults, family members and practitioners. Results from a large-scale questionnaire study (n = 1,516) showed that researchers perceive themselves to be engaged with the autism community but that community members, most notably autistic people and their families, did not share this view. Focus groups/interviews with 72 participants further identified the potential benefits and remaining challenges to involvement in research, especially regarding the distinct perspectives of different stakeholders. Researchers were skeptical about the possibilities of dramatically increasing community engagement, while community members themselves spoke about the challenges to fully understanding and influencing the research process. We suggest that the lack of a shared approach to community engagement in UK autism research represents a key roadblock to translational endeavors.


Backward Walking Styles and Impact on Spatiotemporal Gait Characteristics.
Forward walking (FW) is a common balance assessment tool. However, its sensitivity is limited by the ceiling effect. Reverse gait, such as backward walking (BW), has been reported to have more advantages than FW for balance assessment. Three factors related to postural instability (i.e., increased speeds, restricted arm swing, and reduced visual feedback) during BW were investigated to determine BW conditions that have the potential to predict falls. Three-dimensional analyses were used to analyze seven walking conditions. FW and BW at self-selected and fast speeds were analyzed to identify the effects of speed. Walking with normal arm swings, crossed arms, and abducted arms during BW was tested to determine the effects of arm position. BW with closed and open eyes was compared to investigate the effects of visual feedback. BW had a significantly shorter step length than FW at high speeds. When the arms were abducted, the stance phase (%) was significantly lower compared to when arms were crossed during BW. Moreover, BW with closed eyes revealed significantly higher mediolateral center of mass (COM) displacements than with open eyes. We observed that BW with fast speeds, a crossed arm position, and closed eyes has the potential to help assess fall risk because it requires higher balance ability through spatiotemporal and COM adjustment.


Reducing patient-staff contact in fast-track total hip arthroplasty has no effect on patient-reported outcomes, but decreases satisfaction amongst patients with self-perceived complications: analysis of 211 patients.
Several studies have compared fast-track with conventional pathways for total hip arthroplasty (THA) patients, but none have compared different fast-track pathways. Due to COVID-19 restrictions, our department had to minimize patient-staff contact in the THA pathway. First, telephone consultations were implemented instead of an outpatient clinic visit and subsequently preoperative patient education was discontinued. This enabled us to compare patient-reported outcomes and satisfaction among 3 fast-track pathways. We collected data from patients treated for hip osteoarthritis with THA at Gødstrup Hospital between 2018 and 2021. The patients had experienced 1 of 3 pathways and were interviewed via telephone between 2 and 6 months after discharge. We analyzed the influence of patient pathway on patient-reported pain and mobility level, self-perceived complications, and compliance using logistic regression. We then compared the pathway's effect on patient satisfaction both for the total sample and for the patients who experienced complications. The amount of patient-staff contact in the patient pathway did not have any influence on patientreported outcomes or the probability of self-perceived complications. For the full sample, patient-staff contact had no statistically significant influence on patient satisfaction either, but for the subgroup of patients experiencing complications, the pathways with less patient-staff contact reduced satisfaction. Patient satisfaction was primarily related to pain and mobility outcomes. Our results indicate that reducing patient-staff contact in fast-track THA can be done without influencing mobility and pain outcomes, but the overall satisfaction among patients with self-perceived complications will be negatively affected.


17β-Estradiol, a potential ally to alleviate SARS-CoV-2 infection.
Considering that female sexual hormones may modulate the inflammatory response and also exhibit direct effects on the cells of the immune system, herein, we intend to discuss the sex differences and the role of estradiol in modulating the lung and systemic inflammatory response, focusing on its possible application as a treatment modality for SARS-CoV-2 patients. COVID-19 patients develop severe hypoxemia early in the course of the disease, which is silent most of the time. Small fibrinous thrombi in pulmonary arterioles and a tumefaction of endothelial were observed in the autopsies of fatal COVID-19 cases. Studies showed that the viral infection induces a vascular process in the lung, which included vasodilation and endothelial dysfunction. Further, the proportions of CD4+ T and CD8+ T lymphocytes were strongly reduced in patients with severe SARS-CoV-2 infection. Estradiol is connected with CD4+ T cell numbers and increases T-reg cell populations, affecting immune responses to infection. It is known that estradiol exerts a protective effect on endothelial function, activating the generation of nitric oxide (NO) via endothelial nitric oxide synthase. Estrogen attenuates the vasoconstrictor response to various stimuli and induces vasodilation in the pulmonary vasculature during stress situations like hypoxia. It exerts a variety of rapid actions, which are initiated after its coupling with membrane receptors, which in turn, may positively modulate vascular responses in pulmonary disease and help to maintain microvascular flow. Direct and indirect mechanisms underlying the effects of estradiol were investigated, and the results point to a possible protective effect of estradiol against COVID-19, indicating that it may be considered as an adjuvant therapeutic element for the treatment of patients affected by the novel coronavirus.


Simple, speedy, sensitive, and specific serodiagnosis of pertussis by using a particle agglutination test.
We developed a particle agglutination test (KPA) with poly(gamma-methyl L-glutamate) as the solid particle for measurement of pertussis toxin (PT) antibody. In this study, KPA was assessed as a means of serodiagnosing pertussis, and the results were compared with those of indirect enzyme-linked immunosorbent assay (indirect ELISA) and the microagglutination test. First, four serum samples were collected from each of 21 healthy children: before and 4 weeks after receiving three primary doses of acellular pertussis vaccines and before and 4 weeks after receiving a booster dose. In all 21 vaccinees, a significant rise in PT antibody titers was observed by KPA after each vaccination, and among all 84 serum samples collected, an excellent correlation was demonstrated between the values obtained by indirect ELISA and those obtained by KPA (r = 0.92). Second, paired serum samples were collected at intervals of approximately 2 weeks from 51 patients with culture-confirmed pertussis. A significant increase in titer (fourfold or more) was observed in 39 (76%) patients by KPA, 34 (67%) patients by indirect ELISA, and 23 (45%) patients by the microagglutination test. In acute- and convalescent-phase sera collected from 20 nonpertussis patients, there were no changes in titers by KPA. The KPA procedure was as simple as that of the microagglutination test, and the reaction time was only 2 h (or overnight). In this study, KPA was demonstrated to be a simple, speedy, sensitive, and specific serodiagnostic method for pertussis.


Constitutive activity of the metabotropic glutamate receptor 2 explored with a whole-cell label-free biosensor.
Label-free cellular assays using a biosensor provide new opportunities for studying G protein-coupled receptor (GPCR) signaling. As opposed to conventional in vitro assays, integrated receptor-mediated cellular responses are determined in real-time rather than a single downstream signaling pathway. In this study, we examined the potential of a label-free whole cell impedance-based biosensor system (i.e. xCELLigence) to study the pharmacology of one GPCR in particular, the mGlu2 receptor. This receptor is a target for the treatment of several psychiatric diseases such as schizophrenia and depression. After optimization of assay conditions to prevent interference of endogenous glutamate in the culture medium, detailed pharmacological assessments were performed. Concentration-response curves showed a concentration-dependent increase in impedance for agonists and positive allosteric modulators, whereas receptor inhibition by an antagonist or negative allosteric modulator resulted in a concentration-dependent decrease in cellular impedance. Interestingly, constitutive receptor activity was observed that was decreased by LY341495, which therefore behaved as an inverse agonist here, a property that was heretofore unappreciated. This was confirmed by concentration-dependent modulation of LY341495 potency and efficacy by a allosteric modulators. In summary, the use of the xCELLigence system to study mGlu2 receptor pharmacology was validated. This is the first class C GPCR to be characterized extensively by such method, opening new avenues to study receptor pharmacology including inverse agonism and demonstrating its value for future drug discovery efforts of mGlu receptors as well as other GPCRs.


A preliminary in vitro study of the incidence and position of the root canal isthmus in maxillary and mandibular first molars.
To investigate in vitro the incidence and position of the root canal isthmus in extracted mesiobuccal roots of maxillary and mesial roots of mandibular first molars. Fifty maxillary and 50 mandibular molars were included in the study. The mesiobuccal roots of maxillary molars and the mesial roots of mandibular molars were sectioned from their crowns in the furcation region and embedded in clear resin. Transverse serial 1-mm-thick sections from the apical 6 mm were prepared. The apical side of each section was stained with India ink and observed through a light microscope. The sample images were saved to disk using a digital camera and the root canals in terms of the number present and the incidence and classification of isthmuses. In the mesiobuccal root of the maxillary first molars, 70% had one canal, whereas 29.5% had two canals. In the mesial root of mandibular molars, 41% had one canal, whereas 59% had two canals. In some sections, more than two canals were found close to the apical foramen. The isthmus incidence was greatest 3-5 mm from the apex. In teeth having two canals, a complete or partial isthmus was frequently observed in the sections between 3 and 4 mm from the apex. Of the isthmuses present, 22% were complete and 37% partial in mandibular molars and 17.3% were complete and 11.7% partial in maxillary molars. The incidence of isthmus in the mesiobuccal root of the maxillary first molars and in the mesial root of the mandibular first molars was high, particularly in sections 3-5 mm from the apex. Cleaning the isthmus is a major challenge during root canal treatment.


Environmental characteristics of early childhood education and care centres and young children's weight status: A systematic review.
The aim of this systematic review was to summarize ECEC environmental correlates of weight status in children under the age of 6years. Six databases (PubMed, PsycINFO, CINAHL, SPORTDiscus, Scopus, and Web of Science) were searched until March 2017. Observational studies examining the relationship between ECEC environmental characteristics and weight status in children aged 0-6years were included. Data was extracted using a predesigned form. Eight studies, representing 4862 children, met the inclusion criteria. Twenty-two environmental characteristics were identified and classified into four domains (physical, political, economic, and sociocultural); of these, six correlates were found. 'Active environment' 'sedentary opportunities', 'active play time', 'high sugar and high fat served', 'educators' weight' and 'educators' habitual physical activity level' were associated with weight status in young children. However, for most environmental characteristics examined, strong evidence is not available yet, due to variations across studies on the measures of environmental characteristics and analytical methodologies. Stronger empirical evidence in greater quantity is needed. Future studies in this area are recommended to investigate the environmental influence using an ecological approach and to examine the potential mediators, with a focus on the settings of family-based centres and samples representing toddlers and/or infants.


The biomechanics of race walking: literature overview and new insights.
This review aims to provide both researchers and coaches with a comprehensive overview of race walking biomechanics and to point out new viable route for future analyses. The examined literature has been divided into three categories according to the method of analysis: kinematics, ground reaction forces and joint power/efficiency. From an overall view, race walking athletes seem to adhere to the 'straightened knee' rule, but at race speed they do not observe the 'no-flight time' rule. The coach-oriented analysis highlights that stride length (SL) is more important than stride frequency (SF) for increasing speed and it is mainly obtained by ankle and hip joint power. Moreover, kinematic differences (SF, SL and flight time) between male and female athletes were shown. Also, we found that the maximal speed prediction according to dynamic similarity theory with walking (Froude number) is not applicable as the 3D trajectory of the body centre of mass does not follow an arc of circumference as in walking. The analysed literature shows some shortcomings: (1) the data collection is often unreliable because of the mixture of gender and performance level and (2) the analysis has sometimes been performed on a limited number of strides and speeds. These limitations lead to a scattered and incomplete gait description and a biased application of the results. The research strategy adopted so far is promising but further rigorous analyses need to be approached to obtain a fully comprehensive picture of race walking and to provide coaches with consistent results and reference values.