SSRIs target prefrontal to raphe circuits during development modulating synaptic connectivity and emotional behavior.
Antidepressants that block the serotonin transporter, (Slc6a4/SERT), selective serotonin reuptake inhibitors (SSRIs) improve mood in adults but have paradoxical long-term effects when administered during perinatal periods, increasing the risk to develop anxiety and depression. The basis for this developmental effect is not known. Here, we show that during an early postnatal period in mice (P0-P10), Slc6a4/SERT is transiently expressed in a subset of layer 5-6 pyramidal neurons of the prefrontal cortex (PFC). PFC-SERT+ neurons establish glutamatergic synapses with subcortical targets, including the serotonin (5-HT) and GABA neurons of the dorsal raphe nucleus (DRN). PFC-to-DRN circuits develop postnatally, coinciding with the period of PFC Slc6a4/SERT expression. Complete or cortex-specific ablation of SERT increases the number of functional PFC glutamate synapses on both 5-HT and GABA neurons in the DRN. This PFC-to-DRN hyperinnervation is replicated by early-life exposure to the SSRI, fluoxetine (from P2 to P14), that also causes anxiety/depressive-like symptoms. We show that pharmacogenetic manipulation of PFC-SERT+ neuron activity bidirectionally modulates these symptoms, suggesting that PFC hypofunctionality has a causal role in these altered responses to stress. Overall, our data identify specific PFC descending circuits that are targets of antidepressant drugs during development. We demonstrate that developmental expression of SERT in this subset of PFC neurons controls synaptic maturation of PFC-to-DRN circuits, and that remodeling of these circuits in early life modulates behavioral responses to stress in adulthood.


Do patients lose weight after joint arthroplasty surgery? A systematic review.
The ability of patients with a total joint arthroplasty (TJA) to lose weight after surgery has been investigated in a few studies with inconsistent results. We asked: (1) What is the quality of evidence of current published literature on postoperative weight trends for patients who have had a TJA? (2) Do patients lose any weight after TJA? (3) Do patients lose a clinically meaningful amount of weight after TJA? We conducted a systematic review of PubMed and the Cochrane Library. Studies were summarized according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses Statement. Studies were reviewed for quality of evidence and limitations according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Twelve studies were identified, one case-cohort study and 11 case series. Most studies were from single-surgeon or single-hospital series. Five studies included THAs and TKAs, four only THAs, and three only TKAs. We determined study type, level of evidence, inclusion criteria, procedures, proportion of patients who changed weight, body composition assessment, time of composition assessment, statistical analysis performed, and subgroup analysis conducted. Owing to the observational nature of the studies and the serious limitations identified, all were considered very low quality according to GRADE criteria. Studies reported 14% to 49% of patients had some weight loss at least 1 year postoperatively. We found no conclusive evidence that weight or body composition increases, decreases, or remains the same after TJA.


Multidisciplinary management of life-threatening massive hemoptysis: a 10-year experience.
Life-threatening massive hemoptysis requires prompt action and thoracic surgical input. Although there are a number of reports regarding each therapeutic modality for medical or surgical treatment, the significance of a multidisciplinary strategy remains undetermined. From January 1995 to December 2005, 120 patients were referred to our cardiothoracic center with massive hemoptysis. We retrospectively reviewed and compared the outcomes of a recent 5-year period (2000 to 2005) with those from the previous 5 years (1995 to 1999), as we made major changes in our practice in 2000. We currently try to avoid surgery within 48 hours after onset of active hemoptysis and adopt bronchial artery embolization as a first-line therapy. Treatment decisions are made after discussions among intensive care unit physicians, thoracic surgeons, and interventional radiologists. The former group had 49 patients (57.9 +/- 14.1 years old, 41 males), and the recent group, 71 (62.2 +/- 23.5 years old, 52 males). There were no significant differences for any characteristics studied between the groups. In analyses of short-term complications after surgery, the former had a higher in-hospital mortality rate than the recent group (15% versus 0%). Furthermore, postoperative complications were seen in 8 patients (30%) in the former, whereas those occurred in 3 patients (18%) in the recent group. Bronchial artery embolization is an effective therapeutic tool and plays a pivotal role in management of life-threatening massive hemoptysis. Surgery is indicated when bronchial artery embolization is not suitable and can be safely performed in combination with a rigid bronchoscopy or bronchial artery embolization procedure. Our results indicate that a multidisciplinary approach should be adopted for management of life-threatening massive hemoptysis.


Effect of bidirectional rotation of an acupuncture needle at LI10 on acupuncture needle sensation and experimentally-induced contact heat pain in healthy human volunteers.
There is insufficient evidence of a relationship between acupuncture needle sensations (de qi) and hypoalgesia. The aim of this study was to investigate the effects of bidirectional needle rotation at LI10 on acupuncture needle sensations and heat pain thresholds. Twenty-two healthy participants received one acupuncture needle at LI10 with bidirectional rotation of the needle in one experimental session and one acupuncture needle at LI10 with mock rotation in a separate session, in a randomised order. Measurements of heat pain thresholds were taken before needle insertion, during needle retention and 15 min after needle removal. At each measurement time point, participants rated needle sensations using the Massachusetts Acupuncture Sensation Scale (MASS) and a visual analogue scale (VAS) of overall intensity of needle sensation. Bidirectional needle rotation produced significantly higher scores for VAS, MASStotal, MASSpain and MASSsensation compared with mock rotation (all p<0.001). There were significantly higher pain thresholds relative to pre-intervention baseline during (p=0.014) and after (p<0.001) bidirectional needle rotation but not during (p=0.1) or after (p=0.62) mock bidirectional needle rotation. Bidirectional needle rotation increased the pain threshold relative to baseline 15 min after the needles were removed (p=0.009). A significant but low correlation between needle sensation and change in pain threshold after needling was only found when data from mock and rotation interventions were combined. Needle rotation increases the magnitude of hypoalgesia. There is tentative evidence that needle sensation may be associated with the amount of change in pain threshold.


The protective effect of hesperetin in osteoarthritis: an in vitro and in vivo study.
Osteoarthritis (OA), a progressive joint disorder, is principally characterized by the degeneration and destruction of articular cartilage. Previous research studies demonstrated that inflammation and ECM degradation play a major role in OA development. Hesperetin, the aglycone of neohesperidin found in the peel of Citrus aurantium L. (Rutaceae), demonstrated in several studies potential anti-inflammatory activity in a variety of diseases. However, the mechanisms by which hesperetin plays a protective role in osteoarthritis (OA) are not completely understood. In this study, we found the anti-inflammatory effects of hesperetin in the progression of OA in both in vitro and in vivo experiments. In vitro, IL-1β-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), nitric oxide (NO), tumor necrosis factor alpha (TNF-α), prostaglandin E2 (PGE2), and interleukin-6 (IL-6) were inhibited by hesperetin. Moreover, hesperetin down-regulated the IL-1β-stimulated matrix metalloproteinase-13 (MMP-13) and thrombospondin motifs 5 (ADAMTS-5) while up-regulating collagen type II and aggrecan. Mechanistically, we revealed that hesperetin suppressed nuclear factor kappa B (NF-κB) signaling by activating the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in IL-1β-induced chondrocytes. Hesperetin-induced repression of OA development is shown using a DMM model. Taken together, our findings suggest that hesperetin may be a novel potential therapeutic agent for repressing the development of OA.


Lipopolysaccharide plus 12-o-tetradecanoylphorbol 13-acetate induction of migration and invasion of glioma cells in vitro and in vivo: Differential inhibitory effects of flavonoids.
In an earlier study, we reported that nitric oxide is involved in lipopolysaccharide plus 12-o-tetradecanoylphorbol 13-acetate-induced malignant transformation via increases in metalloproteinase 9 enzyme activity and inducible nitric oxide synthase gene expression in rat glioma C6 cells, however the mechanism has remained undefined. Lipopolysaccharide plus 12-o-tetradecanoylphorbol 13-acetate, but not lipopolysaccharide or 12-o-tetradecanoylphorbol 13-acetate alone, induced transformation in glioma C6 cells (but not in human glioblastoma cells GBM-8401 cells) without affecting their viability. An increase in inducible nitric oxide synthase protein expression, nitric oxide production, and metalloproteinase 9 enzyme activity is identified lipopolysaccharide/12-o-tetradecanoylphorbol 13-acetate-treated C6 cells, however lipopolysaccharide/12-o-tetradecanoylphorbol 13-acetate and 12-o-tetradecanoylphorbol 13-acetate (but not lipopolysaccharide) addition shows the similar inductive pattern on metalloproteinase 9 enzyme activity without affecting inducible nitric oxide synthase protein expression and nitric oxide production in GBM-8401 cells. Treatment of C6 cells with lipopolysaccharide/12-o-tetradecanoylphorbol 13-acetate increases the expression of phosphorylated extracellular regulated protein kinases and Jun N-terminal kinases, but not p38, proteins, and an addition of the extracellular regulated protein kinases inhibitor PD98059 or Jun N-terminal kinases inhibitors SP600125, but not the p38 inhibitor SB203580, significantly blocked lipopolysaccharide/12-o-tetradecanoylphorbol 13-acetate-induced inducible nitric oxide synthase protein expression and metalloproteinase 9 enzyme activity accompanied by blocking morphological transformation in C6 cells. Among 19 structurally related flavonoids, kaempferol and wogonin exhibit significant inhibitory effects on lipopolysaccharide/12-o-tetradecanoylphorbol 13-acetate-induced morphological transformation and colony formation, and attenuation of inducible nitric oxide synthase, phosphorylated extracellular regulated protein kinases protein expression, and metalloproteinase 9 enzyme activity was observed. 2'-OH flavone at a dose of 100 microM inhibition of lipopolysaccharide/12-o-tetradecanoylphorbol 13-acetate-induced events via apoptosis induction is identified. Furthermore, lipopolysaccharide/12-o-tetradecanoylphorbol 13-acetate, but not lipopolysaccharide or 12-o-tetradecanoylphorbol 13-acetate, induces tumoral invasion and migration in vitro and in vivo, and those are blocked by kaempferol and wogonin addition. These data suggest that combination of lipopolysaccharide and 12-o-tetradecanoylphorbol 13-acetate promotes tumoral progression via activating metalloproteinase 9 enzyme activity and inducible nitric oxide synthase gene expression, which is located downstream of mitogen-activated protein kinases activation, in rat glioma cells C6. Kaempferol and wogonin exhibit effective inhibitory effects on lipopolysaccharide/12-o-tetradecanoylphorbol 13-acetate-induced events, and thus possess the potential for further development.


Differences in risk behaviours, HIV/STI testing and HIV/STI prevalence between men who have sex with men and men who have sex with both men and women in China.
Differences in risk behaviours between men who have sex with men (MSM) and men who have sex with both men and women (MSMW) have important implications for HIV and sexually transmitted infection (STI) transmission. We examined differences in risk behaviours, HIV/STI testing, self-reported HIV/STI diagnoses, and linkage to HIV care between MSM and MSMW across China. Participants were recruited through three MSM-focused websites in China. An online survey containing items on socio-demographics, risk behaviours, testing history, self-reported HIV/STI diagnosis, and linkage to and retention in HIV care was completed from September to October 2014. Chi square tests and logistic regression analyses were conducted. MSMW were less likely to use a condom during last anal sex (p ≤ 0.01) and more likely to engage in group sex (p ≤ 0.01) and transactional sex (p ≤ 0.01) compared to MSM. Self-reported HIV/STI testing and positivity rates between MSM and MSMW were similar. Among HIV-infected MSM, there was no difference in rates of linkage to or retention in antiretroviral therapy when comparing MSM and MSMW. Chinese MSM and MSMW may benefit from different HIV and STI intervention and prevention strategies. Achieving a successful decrease in HIV/STI epidemics among Chinese MSM and MSMW will depend on the ability of targeted and culturally congruent HIV/STI control programmes to facilitate a reduction in risk behaviours.


Aquaporin3 is required for FGF-2-induced migration of human breast cancers.
The aquaporin (AQP) family consists of a number of small integral membrane proteins that transport water and glycerol. AQPs are critical for trans-epithelial fluid transport. Recent reports demonstrated that AQPs, particularly AQP1 and AQP5, are expressed in high grade tumor cells of a variety of tissue origins, and that AQPs are involved in cell migration and metastasis. Based on this background, we examined whether AQP3, another important member of the AQP family, could facilitate cell migration in human breast cancers. Potential role of AQP3 was examined using two representative breast cancer cell lines (MDA-MB-231 and Bcap-37). Briefly, AQP3 expression was inhibited with a lentivirus construct that stably expressed shRNA against the AQP3 mRNA. AQP3 expression inhibition was verified with Western blot. Cell migration was examined using a wound scratch assay in the presence of fibroblast growth factor-2 (FGF-2). In additional experiments, AQP3 was inhibited by CuSO4. Fibroblast growth factor receptor (FGFR) kinase inhibitor PD173074, PI3K inhibitor LY294002, and MEK1/2 inhibitor PD98059 were used to dissect the molecular mechanism of FGF-2 induced AQP3 expression. FGF-2 treatment increased AQP3 expression and induced cell migration in a dose dependent manner. Silencing AQP3 expression by a lentiviral shRNA inhibited FGF-2 induced cell migration. CuSO4, a water transport inhibitor selective for AQP3, also suppressed FGF-2-induced cell migration. The FGFR kinase inhibitor PD173074, significantly inhibited FGF-2-induced AQP3 expression and cell migration. The PI3K inhibitor LY294002 and MEK1/2 inhibitor PD98059 inhibited, but not fully blocked, FGF-2-induced AQP3 expression and cell migration. AQP3 is required for FGF-2-induced cell migration in cultured human breast cancer cells. Our findings also suggest the importance of FGFR-PI3K and FGFR-ERK signaling in FGF-2-induced AQP3 expression. In summary, our findings suggest a novel function of AQP3 in cell migration and metastasis of breast cancers.


Penile manipulation: The most common etiology of penile fracture at our tertiary care center.
Penile fracture is the disruption of the tunica albuginea with rupture of the corpus cavernosum secondary to blunt trauma to the erect penis. It is an unusual condition, usually underreported. According to the published literature, vigorous vaginal intercourse with women on top position is the most common etiology across the globe including India with Middle Eastern countries being the exception. A total of seven patients of penile fracture presented in emergency in the last 6 months. The etiology was penile manipulation at the time of sexual excitement in six out of seven patients of penile fracture, which was contrary to the literature published except in Middle Eastern countries. All the patients were managed by emergency exploration and repair. Thus, the incidence and etiologies of penile fracture vary according to geographic region, sexual behavior, marital status, and culture.


p107 in the public eye: an Rb understudy and more.
p107 and its related family members Rb and p130 are critical regulators of cellular proliferation and tumorigenesis. Due to the extent of functional overlap within the Rb family, it has been difficult to assess which functions are exclusive to individual members and which are shared. Like its family members, p107 can bind a variety of cellular proteins to affect the expression of many target genes during cell cycle progression. Unlike Rb and p130, p107 is most highly expressed during the G1 to S phase transition of the cell cycle in actively dividing cells and accumulating evidence suggests a role for p107 during DNA replication. The specific roles for p107 during differentiation and development are less clear, although emerging studies suggest that it can cooperate with other Rb family members to control differentiation in multiple cell lineages. As a tumor suppressor, p107 is not as potent as Rb, yet studies in knockout mice have revealed some tumor suppressor functions in mice, depending on the context. In this review, we identify the unique and overlapping functions of p107 during the cell cycle, differentiation, and tumorigenesis.


Low-dose vaporized cannabis significantly improves neuropathic pain.
We conducted a double-blind, placebo-controlled, crossover study evaluating the analgesic efficacy of vaporized cannabis in subjects, the majority of whom were experiencing neuropathic pain despite traditional treatment. Thirty-nine patients with central and peripheral neuropathic pain underwent a standardized procedure for inhaling medium-dose (3.53%), low-dose (1.29%), or placebo cannabis with the primary outcome being visual analog scale pain intensity. Psychoactive side effects and neuropsychological performance were also evaluated. Mixed-effects regression models demonstrated an analgesic response to vaporized cannabis. There was no significant difference between the 2 active dose groups' results (P > .7). The number needed to treat (NNT) to achieve 30% pain reduction was 3.2 for placebo versus low-dose, 2.9 for placebo versus medium-dose, and 25 for medium- versus low-dose. As these NNTs are comparable to those of traditional neuropathic pain medications, cannabis has analgesic efficacy with the low dose being as effective a pain reliever as the medium dose. Psychoactive effects were minimal and well tolerated, and neuropsychological effects were of limited duration and readily reversible within 1 to 2 hours. Vaporized cannabis, even at low doses, may present an effective option for patients with treatment-resistant neuropathic pain. The analgesia obtained from a low dose of delta-9-tetrahydrocannabinol (1.29%) in patients, most of whom were experiencing neuropathic pain despite conventional treatments, is a clinically significant outcome. In general, the effect sizes on cognitive testing were consistent with this minimal dose. As a result, one might not anticipate a significant impact on daily functioning.


The generation and regulation of lymphocyte populations: evidence from differentiative induction systems in vitro.
Results with a dual assay, for the induction of Thy-1+ T cells and of CR+ B cells from marker-negative precursors, confirm that thymopoietin is at present the only known selective inducer of prothymocytes. In contrast, various inducers, including ubiquitin, are active in both assays. Pharmacological evidence indicates that there are different cellular receptors for ubiquitin and thymopoietin. Prothymocytes and pro-CR+ B cells compose two distinct populations in bone marrow and spleen; their distribution in density gradients is different, and elimination of either population enriches the other proportionately. There are no noteworthy differences between induction of these two populations in regard to (a) kinetics, (b) dependence on temperature and protein synthesis, (c) activation by cAMP, and (d) inhibition by cGMP. The opposite inductive effects of cAMP and cGMP were corroborated by the use of pharmacological agents that raise or lower the levels of intracellular cyclic nucleotides. In contrast, a third induction assay, which monitors acquisition of the PC+ surface phenotype, indicates that this differentiative step, the last known for B cells, is initiated by cGMP and inhibited by cAMP. Induction of PC is also inhibited by thymopoietin, signifying that the inductive selectivity of thymopoietin is not due to restriction of its receptors to the T lineage cells. Rather it seems that receptors for thymopoietin occur also on PC-inducible and other B cells, although in this case geared biochemically to inhibition rather than expression of the succeeding gene program. This suggests a role for thymopoietin in the coordinated interregulation of lymphocyte classes, in addition to its better-known function as the thymic inducer of prothymocytes. Present data conform to a general scheme in which the cyclic nucleotides cAMP and cGMP, and agents that affect intracellular levels of these mediators, influence reciprocally the early and late (functional) phases of lymphocyte differentiation as a whole, while thymopoietin influences reciprocally the differentiation of the B and T classes of lymphocyte.


BDNF in schizophrenia, depression and corresponding animal models.
Understanding the etiology and pathogenesis schizophrenia and depression is a major challenge facing psychiatry. One hypothesis is that these disorders are secondary to a malfunction of neurotrophic factors. Inappropriate neurotrophic support during brain development could lead to structural disorganisation in which neuronal networks are established in a nonoptimal manner. Inadequate neurotrophic support in adult individuals could ultimately be an underlying mechanism leading to decreased capacity of brain to adaptive changes and increased vulnerability to neurotoxic damage. Brain-derived neurotrophic factor (BDNF) is a mediator involved in neuronal survival and plasticity of dopaminergic, cholinergic, and serotonergic neurons in the central nervous system (CNS). In this review, we summarize findings regarding altered BDNF in schizophrenia and depression and animal models, as well as the effects of antipsychotic and antidepressive treatments on the expression of BDNF.


Conformational heterogeneity of the Pfr chromophore in plant and cyanobacterial phytochromes.
Phytochromes are biological photoreceptors that can be reversibly photoconverted between a dark and photoactivated state. The underlying reaction sequences are initiated by the photoisomerization of the tetrapyrrole cofactor, which in plant and cyanobacterial phytochromes are a phytochromobilin (PΦB) and a phycocyanobilin (PCB), respectively. The transition between the two states represents an on/off-switch of the output module activating or deactivating downstream physiological processes. In addition, the photoactivated state, i.e., Pfr in canonical phytochromes, can be thermally reverted to the dark state (Pr). The present study aimed to improve our understanding of the specific reactivity of various PΦB- and PCB-binding phytochromes in the Pfr state by analysing the cofactor structure by vibrational spectroscopic techniques. Resonance Raman (RR) spectroscopy revealed two Pfr conformers (Pfr-I and Pfr-II) forming a temperature-dependent conformational equilibrium. The two sub-states-found in all phytochromes studied, albeit with different relative contributions-differ in structural details of the C-D and A-B methine bridges. In the Pfr-I sub-state the torsion between the rings C and D is larger by ca. 10° compared to Pfr-II. This structural difference is presumably related to different hydrogen bonding interactions of ring D as revealed by time-resolved IR spectroscopic studies of the cyanobacterial phytochrome Cph1. The transitions between the two sub-states are evidently too fast (i.e., nanosecond time scale) to be resolved by NMR spectroscopy which could not detect a structural heterogeneity of the chromophore in Pfr. The implications of the present findings for the dark reversion of the Pfr state are discussed.


Influence of the larval phase on connectivity: strong differences in the genetic structure of brooders and broadcasters in the Ophioderma longicauda species complex.
Closely related species with divergent life history traits are excellent models to infer the role of such traits in genetic diversity and connectivity. Ophioderma longicauda is a brittle star species complex composed of different genetic clusters, including brooders and broadcasters. These species diverged very recently and some of them are sympatric and ecologically syntopic, making them particularly suitable to study the consequences of their trait differences. At the scale of the geographic distribution of the broadcasters (Mediterranean Sea and northeastern Atlantic), we sequenced the mitochondrial marker COI and genotyped an intron (i51) for 788 individuals. In addition, we sequenced 10 nuclear loci newly developed from transcriptome sequences, for six sympatric populations of brooders and broadcasters from Greece. At the large scale, we found a high genetic structure within the brooders (COI: 0.07 < F(ST) < 0.65) and no polymorphism at the nuclear locus i51. In contrast, the broadcasters displayed lower genetic structure (0 < F(ST) < 0.14) and were polymorphic at locus i51. At the regional scale, the multilocus analysis confirmed the contrasting genetic structure between species, with no structure in the broadcasters (global F(ST) < 0.001) and strong structure in the brooders (global F(ST) = 0.49), and revealed a higher genetic diversity in broadcasters. Our study showed that the lecithotrophic larval stage allows on average a 50-fold increase in migration rates, a 280-fold increase in effective size and a threefold to fourfold increase in genetic diversity. Our work, investigating complementary genetic markers on sympatric and syntopic taxa, highlights the strong impact of the larval phase on connectivity and genetic diversity.


How valence bond theory can help you understand your (bio)chemical reaction.
Almost a century has passed since valence bond (VB) theory was originally introduced to explain covalent bonding in the H2 molecule within a quantum mechanical framework. The past century has seen constant improvements in this theory, with no less than two distinct Nobel prizes based on work that is essentially developments in VB theory. Additionally, ongoing advances in both methodology and computational power have greatly expanded the scope of problems that VB theory can address. In this Tutorial Review, we aim to give the reader a solid understanding of the foundations of modern VB theory, using a didactic example of a model SN2 reaction to illustrate its immediate applications. This will be complemented by examples of challenging problems that at present can only be efficiently addressed by VB-based approaches. Finally, the ongoing importance of VB theory is demonstrated. It is concluded that VB will continue to be a major driving force for chemistry in the century to come.


Rare genomic changes as a tool for phylogenetics.
DNA sequence data have offered valuable insights into the relationships between living organisms. However, most phylogenetic analyses of DNA sequences rely primarily on single nucleotide substitutions, which might not be perfect phylogenetic markers. Rare genomic changes (RGCs), such as intron indels, retroposon integrations, signature sequences, mitochondrial and chloroplast gene order changes, gene duplications and genetic code changes, provide a suite of complementary markers with enormous potential for molecular systematics. Recent exploitation of RGCs has already started to yield exciting phylogenetic information.


Surface tuning for oxide-based nanomaterials as efficient photocatalysts.
Due to the increasingly polluted environment and the gradual depletion of fossil fuel reserves, the development of renewable technologies for environmental remediation and energy production is highly desirable. Over the past decades, oxide-based semiconductor photocatalysis has attracted much attention. On various frontiers for efficient photocatalysis, surface-tuning strategies for synthesis and modification of oxides on the nanometer scale have progressed at a fast pace. Hence, it is of significance to review recent advances in the development of surface tuning for oxide-based nanomaterials as activity-enhanced photocatalysts. In this review, special emphases, especially for recent advances in our group, are given to surface tuning of novel nanocrystallites for high thermal stability, hierarchical structure assembly, heterojunctional nanocomposites and high-energy-facet exposure, along with effective testing tools for photogenerated charge properties at the surfaces and/or interfaces. This is of great significance for fields related to energy and environment from scientific and engineering viewpoints.


Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes and Hirschsprung disease.
Distinct point mutations in the RET proto-oncogene are the cause of the inherited multiple endocrine neoplasia type 2 syndromes (MEN 2), and the congenital gut disorder Hirschsprung disease. The site and type of these mutations suggests that they have differing effects on the activity of the receptor tyrosine kinase encoded by RET. The normal function of the RET receptor tyrosine kinase has yet to be determined. However, this has been investigated by the inactivation of the RET gene in transgenic mice. The developmental abnormalities apparent in these mice, together with the observation that the major tissues affected in MEN 2 and Hirschsprung disease have a common origin in the embryonal neural crest, suggest that RET encodes a receptor for a developmental regulator involved in the genesis of a variety of neural crest derivatives, and in the organogenesis of the kidney.


Mepolizumab decreased the levels of serum galectin-10 and eosinophil cationic protein in asthma.
Mepolizumab, a humanized antibody targeting interleukin-5, decreases the number of blood eosinophils and the frequency of exacerbation of severe asthma. Galectin-10 is a protein within the cytoplasm of eosinophils and constitutes Charcot-Leyden crystals, which promotes key features of asthma. However, the relationship between time kinetics and clinical response of eosinophil-derived molecules such as galectin-10 or eosinophil cationic protein (ECP) has not been precisely investigated. This study aimed to clarify the precise time course of the levels of serum galectin-10 and ECP after mepolizumab treatment and to analyze the relationship between the levels of eosinophil-derived molecules and the clinical background or response to mepolizumab treatment. This multicenter, prospective open-label study recruited 20 patients with severe eosinophilic asthma. Mepolizumab was administered every 4 weeks for 32 weeks and the levels of various biomarkers were serially analyzed. The serum galectin-10 and ECP significantly and rapidly decreased 4 weeks after initial administration of mepolizumab. In contrast, basophil count, fractional exhaled nitric oxide, and the serum total IgE level were unchanged during treatment. Asthma Control Questionnaire-5, Asthma Health Questionnaire-33, and Lund-Mackay scores significantly improved after mepolizumab treatment. Both high ECP and eosinophil count related to better response in forced expiratory volume in 1 second (FEV1) and measurable ECP level at 4 weeks after administration of mepolizumab related to the further improvement in FEV1 toward week 32. No significant difference in improvement in FEV1 was observed in galectin-10 high group. The level of ECP at baseline was significantly related to the higher prevalence of nasal polyp and Lund-Mackay score. This study was the first to show that the levels of serum galectin-10 decreases after initial administration of mepolizumab. The significant relationship between serum ECP and better response in FEV1 suggested the potential role of serum ECP as a predictive biomarker for the efficacy of mepolizumab (UMIN000030466).


A putative transmembrane protein with histidine-rich charge clusters encoded in the H-2K/tw5 region of mice.
The H-2 complex of mice contains many genes in addition to the gene families involved in immune reactions. Some of them are believed to function in mouse development, as suggested by the findings that several embryonic lethal mutations map within or near the H-2 complex. We have analyzed the H-2K/tw5 region in an attempt to study non-H-2 genes encoded in this region. Overlapping cosmid clones spanning about 170 kilobase pairs of DNA, including the H-2K/tw5 region of the mouse, have been screened for genes expressed in embryonic carcinoma cells. A transcript of 2.8 kilobase pairs (K. Abe. J.-F. Wei, F.-S. Wei, Y.-C. Hsu, H. Uehara, K. Artzt, and D. Bennett, EMBO J. 7:3441-3449, 1988) encoded by the KE 4 gene flanking H-2K distally was identified. The transcript was abundantly expressed in embryonic carcinoma cells but was present at low levels in other tissues in adults. A cDNA for this transcript was isolated from the F9 embryonic carcinoma cell line and sequenced. It potentially encodes a protein of 436 amino acids with several interesting features. First, it contains two regions made of well-conserved repeats unusually rich in histidine residues. In the repeats, histidine alternates with other amino acids, notably glycine or serine. Second, the two histidine-rich regions are separated by three putative membrane-spanning domains. Third, the N-terminal part of the sequence shows characteristics of a signal peptide. The results indicate that the protein coded by the gene may be a transmembrane protein with histidine-rich charge clusters. A similar sequence motif found in other known genes allows speculation on the possible functional of this gene.


Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families.
Primary progressive aphasia (PPA) is a language-based dementia characterized by fluent or nonfluent language disorder as its principal feature. To describe progranulin gene mutations in 2 families with PPA. Report of affected families. Academic research. Two families, PPA1 and PPA3, were studied. Genomic DNA was isolated from 3 of 4 siblings in PPA1, from all 3 siblings in PPA3, and from more than 200 control subjects. All 12 coding exons of the progranulin gene and the 5" and 3" untranslated regions were amplified by polymerase chain reaction and were sequenced in both directions using relevant primers. Both affected members of PPA1 for whom DNA was available and both affected sisters of PPA3 had a progranulin gene mutation not found in the unaffected siblings or in the controls. The mutations likely cause a null allele and a reduction in the level of functional progranulin protein. Both affected members of PPA1 with autopsies had frontotemporal lobar degeneration with tau-negative ubiquinated inclusions. To our knowledge, these are the only known families in which affected members display phenotypical homogeneity for PPA in the initial stages of the disease. In both families, the disease segregated with progranulin gene mutations. Whether progranulin dysfunction also extends to sporadic PPA and how it affects the initial anatomical specificity of neurodegeneration remain to be determined.


Why do older unhealthy drinkers decide to make changes or not in their alcohol consumption? Data from the Healthy Living as You Age study.
To understand characteristics of older at-risk drinkers and reasons why they decide to change or maintain their alcohol consumption. Secondary analysis of data from a randomized controlled trial to reduce drinking in at-risk drinkers. Three primary care sites in southern California. Six hundred thirty-one adults aged 55 and older who were at-risk drinkers at baseline, 521 of whom who completed a 12-month assessment. Sociodemographic and alcohol-related characteristics of 12-month assessment completers and noncompleters and among those completing the 12-month assessment by telephone or mail were compared using descriptive statistics. Reasons why respondents maintained or changed average alcohol consumption were asked of those who completed a 12-month assessment by telephone. Factors that might motivate at-risk drinkers to reduce drinking were asked about, and frequencies were calculated for these responses. Participants were primarily male, white, highly educated, and in good health. Those who responded to the 12-month assessment by mail were more likely to be working, to be in the intervention arm, and to drink more. Most who reduced alcohol consumption and heavy drinking did so because they thought it would benefit them. Those who did not thought that drinking was not a problem for them. Both groups cited their environment and circumstances as influencing their drinking. Remaining at-risk drinkers reported that medical evidence that alcohol was harming them would motivate them to reduce drinking. Older adults report that they reduce their drinking when they recognize that their drinking habits may be causing them harm; one's environment can hinder or help one to reduce drinking.


Initial HIV-1 antigen-specific CD8+ T cells in acute HIV-1 infection inhibit transmitted/founder virus replication.
CD8-mediated virus inhibition can be detected in HIV-1-positive subjects who naturally control virus replication. Characterizing the inhibitory function of CD8(+) T cells during acute HIV-1 infection (AHI) can elucidate the nature of the CD8(+) responses that can be rapidly elicited and that contribute to virus control. We examined the timing and HIV-1 antigen specificity of antiviral CD8(+) T cells during AHI. Autologous and heterologous CD8(+) T cell antiviral functions were assessed longitudinally during AHI in five donors from the CHAVI 001 cohort using a CD8(+) T cell-mediated virus inhibition assay (CD8 VIA) and transmitted/founder (T/F) viruses. Potent CD8(+) antiviral responses against heterologous T/F viruses appeared during AHI at the first time point sampled in each of the 5 donors (Fiebig stages 1/2 to 5). Inhibition of an autologous T/F virus was durable to 48 weeks; however, inhibition of heterologous responses declined concurrent with the resolution of viremia. HIV-1 viruses from 6 months postinfection were more resistant to CD8(+)-mediated virus inhibition than cognate T/F viruses, demonstrating that the virus escapes early from CD8(+) T cell-mediated inhibition of virus replication. CD8(+) T cell antigen-specific subsets mediated inhibition of T/F virus replication via soluble components, and these soluble responses were stimulated by peptide pools that include epitopes that were shown to drive HIV-1 escape during AHI. These data provide insights into the mechanisms of CD8-mediated virus inhibition and suggest that functional analyses will be important for determining whether similar antigen-specific virus inhibition can be induced by T cell-directed vaccine strategies.


Construction of 4D infant cortical surface atlases with sharp folding patterns via spherical patch-based group-wise sparse representation.
4D (spatial + temporal) infant cortical surface atlases covering dense time points are highly needed for understanding dynamic early brain development. In this article, we construct a set of 4D infant cortical surface atlases with longitudinally consistent and sharp cortical attribute patterns at 11 time points in the first six postnatal years, that is, at 1, 3, 6, 9, 12, 18, 24, 36, 48, 60, and 72 months of age, which is targeted for better normalization of the dynamic changing early brain cortical surfaces. To ensure longitudinal consistency and unbiasedness, we adopt a two-stage group-wise surface registration. To preserve sharp cortical attribute patterns on the atlas, instead of simply averaging over the coregistered cortical surfaces, we leverage a spherical patch-based sparse representation using the augmented dictionary to overcome the potential registration errors. Our atlases provide not only geometric attributes of the cortical folding, but also cortical thickness and myelin content. Therefore, to address the consistency across different cortical attributes on the atlas, instead of sparsely representing each attribute independently, we jointly represent all cortical attributes with a group-wise sparsity constraint. In addition, to further facilitate region-based analysis using our atlases, we have also provided two widely used parcellations, that is, FreeSurfer parcellation and multimodal parcellation, on our 4D infant cortical surface atlases. Compared to cortical surface atlases constructed with other methods, our cortical surface atlases preserve sharper cortical folding attribute patterns, thus leading to better accuracy in registration of individual infant cortical surfaces to the atlas.


Selective recognition of organic pollutants in aqueous solutions with composite imprinted membranes.
In this work, thin-layer composite membranes imprinted with desmetryn or ibuprofen were prepared and studied for selective recognition of the template compounds in aqueous solutions. The imprinted membranes were developed using photoinitiated copolymerization of 2-acrylamido-2-methyl-1-propane sulphonic acid and N,N'-methylene-bis-acrylamide, in the presence of desmetryn or via copolymerization of dimethylaminoethyl methacrylate, and trimethylopropane trimethacrylate, in the presence of ibuprofen, followed by deposition of the imprinted layers on the surface of porous microfiltration supports of various chemical nature. Atomic force microscopy was used to study the surface morphological characteristics of the developed membranes. Molecularly recognition properties of imprinted membranes were evaluated by measuring their capability to bind the template molecules from polycomponent aqueous solutions. It was shown that obtained membranes may be used as selective recognising elements of portative differential capacitor sensor device for express monitoring of the target molecules in water. The sensor performance is based on registration of the alteration of dielectric permeability of composite imprinted membrane at selective binding of template molecules, when the analyzed feed solution is filtered through the membrane sample.


Host genetics predict clinical deterioration in HCV-related cirrhosis.
Single nucleotide polymorphisms (SNPs) in the epidermal growth factor (EGF, rs4444903), patatin-like phospholipase domain-containing protein 3 (PNPLA3, rs738409) genes, and near the interleukin-28B (IL28B, rs12979860) gene are linked to treatment response, fibrosis, and hepatocellular carcinoma (HCC) in chronic hepatitis C. Whether these SNPs independently or in combination predict clinical deterioration in hepatitis C virus (HCV)-related cirrhosis is unknown. We genotyped SNPs in EGF, PNPLA3, and IL28B from liver tissue from 169 patients with biopsy-proven HCV cirrhosis. We estimated risk of clinical deterioration, defined as development of ascites, encephalopathy, variceal hemorrhage, HCC, or liver-related death using Cox proportional hazards modeling. During a median follow-up of 6.6 years, 66 of 169 patients experienced clinical deterioration. EGF non-AA, PNPLA3 non-CC, and IL28B non-CC genotypes were each associated with increased risk of clinical deterioration in age, sex, and race-adjusted analysis. Only EGF non-AA genotype was independently associated with increased risk of clinical deterioration (hazard ratio [HR] 2.87; 95% confidence interval [CI] 1.31-6.25) after additionally adjusting for bilirubin, albumin, and platelets. Compared to subjects who had 0-1 unfavorable genotypes, the HR for clinical deterioration was 1.79 (95%CI 0.96-3.35) for 2 unfavorable genotypes and 4.03 (95%CI 2.13-7.62) for unfavorable genotypes for all three loci (Ptrend<0.0001). In conclusion, among HCV cirrhotics, EGF non-AA genotype is independently associated with increased risk for clinical deterioration. Specific PNPLA3 and IL28B genotypes also appear to be associated with clinical deterioration. These SNPs have potential to identify patients with HCV-related cirrhosis who require more intensive monitoring for decompensation or future therapies preventing disease progression.


Mouse and hamster mutants as models for Waardenburg syndromes in humans.
Four different Waardenburg syndromes have been defined based upon observed phenotypes. These syndromes are responsible for approximately 2% of subjects with profound congenital hearing loss. At present, Waardenburg syndromes have not been mapped to particular human chromosomes. One or more of the mouse mutant alleles, Ph (patch), s (piebald), Sp (splotch), and Mior (microphthalmia-Oak Ridge) and the hamster mutation Wh (anophthalmic white) may be homologous to mutations causing Waardenburg syndromes. In heterozygotes, phenotypic effects of these four mouse mutations and the hamster mutation are similar to the phenotypes produced by different Waardenburg syndrome mutations. The chromosomal locations and syntenic relationships associated with three of the four mouse mutant genes have been used to predict human chromosomal locations for Waardenburg syndromes: (1) on chromosome 2q near FN1 (fibronectin 1), (2) on chromosome 3p near the proto-oncogene RAF1 or 3q near RHO (rhodopsin), and (3) on chromosome 4p near the proto-oncogene KIT. Waardenburg syndromes show extensive intrafamilial phenotypic variability. Results of our studies with the hamster mutation Wh suggest that this variability may be explained in part by modifier genes segregating within families.


Evidence for Acquisition in Nature of a Chromosomal 2,4-Dichlorophenoxyacetic Acid/(alpha)-Ketoglutarate Dioxygenase Gene by Different Burkholderia spp.
We characterized the gene required to initiate the degradation of 2,4-dichlorophenoxyacetic acid (2,4-D) by the soil bacterium Burkholderia sp. strain TFD6, which hybridized to the tfdA gene of the canonical 2,4-D catabolic plasmid pJP4 under low-stringency conditions. Cleavage of the ether bond of 2,4-D by cell extracts of TFD6 proceeded by an (alpha)-ketoglutarate-dependent reaction, characteristic of TfdA (F. Fukumori and R. P. Hausinger, J. Bacteriol. 175:2083-2086, 1993). The TFD6 tfdA gene was identified in a recombinant plasmid which complemented a tfdA transposon mutant of TFD6 created by chromosomal insertion of Tn5. The plasmid also expressed TfdA activity in Escherichia coli DH5(alpha), as evidenced by enzyme assays with cell extracts. Sequence analysis of the tfdA gene and flanking regions from strain TFD6 showed 99.5% similarity to a tfdA gene cloned from the chromosome of a different Burkholderia species (strain RASC) isolated from a widely separated geographical area. This chromosomal gene has 77.2% sequence identity to tfdA from plasmid pJP4 (Y. Suwa, W. E. Holben, and L. J. Forney, abstr. Q-403, in Abstracts of the 94th General Meeting of the American Society for Microbiology 1994.). The tfdA homologs cloned from strains TFD6 and RASC are the first chromosomally encoded 2,4-D catabolic genes to be reported. The occurrence of highly similar tfdA genes in different bacterial species suggests that this chromosomal gene can be horizontally transferred.


Psychological interventions for people with psychotic experiences: A systematic review and meta-analysis of controlled and uncontrolled effectiveness and economic studies.
Many people with psychotic experiences do not develop psychotic disorders, yet those who seek help demonstrate high clinical complexity and poor outcomes. In this systematic review and meta-analysis, we evaluated the effectiveness and cost-effectiveness of psychological interventions for people with psychotic experiences. We searched 13 databases for studies of psychological interventions for adults with psychotic experiences, but not psychotic disorders. Our outcomes were the proportion of participants remitting from psychotic experiences (primary); changes in positive and negative psychotic symptoms, depression, anxiety, functioning, distress, and quality of life; and economic outcomes (secondary). We analysed results using multilevel random-effects meta-analysis and narrative synthesis. A total of 27 reports met inclusion criteria. In general, there was no strong evidence for the superiority of any one intervention. Five studies reported on our primary outcome, though only two reports provided randomised controlled trial evidence that psychological intervention (specifically, cognitive behavioural therapy) promoted remission from psychotic experiences. For secondary outcomes, we could only meta-analyse trials of cognitive behavioural therapy. We found that cognitive behavioural therapy was more effective than treatment as usual for reducing distress (pooled standardised mean difference: -0.24; 95% confidence interval = [-0.37, -0.10]), but no more effective than the control treatment for improving any other outcome. Individual reports indicated that cognitive behavioural therapy, mindfulness-based cognitive therapy, sleep cognitive behavioural therapy, systemic therapy, cognitive remediation therapy, and supportive treatments improved at least one clinical or functional outcome. Four reports included economic evaluations, which suggested cognitive behavioural therapy may be cost-effective compared with treatment as usual. Our meta-analytic findings were primarily null, with the exception that cognitive behavioural therapy may reduce the distress associated with psychotic experiences. Our analyses were limited by scarcity of studies, small samples and variable study quality. Several intervention frameworks showed preliminary evidence of positive outcomes; however, the paucity of consistent evidence for clinical and functional improvement highlights a need for further research into psychological treatments for psychotic experiences. CRD42016033869.


Generation of an adenoviral vaccine vector based on simian adenovirus 21.
Adenoviral vectors can be used to generate potent humoral and cellular immune responses to transgene products. Use of adenoviral vectors based on non-human isolates may allow for their utilization in populations harbouring neutralizing antibodies to common human serotypes. A vector chimera was constructed using simian adenovirus 22 (a serotype belonging to the species Human adenovirus E) and simian adenovirus 21 (a serotype belonging to the species Human adenovirus B) expressing the Ebola (Zaire) virus glycoprotein (Ad C5/C1-ZGP). This chimeric adenovirus vector was used as a model to test its efficacy as a genetic vaccine and comparisons were made to a vector based on the commonly used human adenovirus C serotype 5 (Adhu5-ZGP). Ebola glycoprotein-specific T- and B-cell responses were measured in B10BR mice vaccinated with either Adhu5-ZGP or Ad C5/C1-ZGP vectors. Both vectors resulted in Ebola glycoprotein-specific gamma interferon-expressing T cells, although the Ad C5/C1-ZGP vector appeared to induce lower frequencies with kinetics slower than those elicited by the Adhu5-ZGP vector. The total immunoglobulin G response to Ebola glycoprotein was similar in sera from mice vaccinated with either vector. Two rhesus macaques vaccinated with the Ad C5/C1-ZGP vector were found to mount T-cell and antibody responses to the Ebola glycoprotein. It was found that a single administration of the chimeric Ad C5/C1-ZGP vector protected mice against a lethal challenge with a mouse-adapted strain of the Ebola (Zaire) virus.


We can work it out: Group decision-making builds social identity and enhances the cognitive performance of care residents.
Group-based interventions have been argued to slow the cognitive decline of older people residing in care by building social identification and thereby increasing motivation and engagement. The present study explored the identity-cognition association further by investigating the impact of a group decision-making intervention on cognition. Thirty-six care home residents were assigned to one of three conditions: an Intervention in which they made decisions about lounge refurbishment as a group, a Comparison condition in which staff made these decisions, or a no-treatment Control. Cognitive function, social identification, home satisfaction, and lounge use were measured before and after the intervention. Participants in the Intervention condition showed significant increases on all measures, and greater improvement than participants in both Comparison and Control conditions. Consistent with social identity theorizing, these findings point to the role of group activity and social identification in promoting cognitive integrity and well-being among care residents.


An Extensive Case of Merkel Cell Carcinoma due to Fright of COVID-19.
Merkel cell carcinoma (MCC) is a subtype of nonmelanoma skin cancer (NMSC) with increasing incidence. Clinically, MCC resembles other far less-aggressive NMSCs, and the pathogenesis is still not understood completely. Rapid diagnosis and treatment are essential to improve overall survival. We present a case report of a 74-year-old female, who had noticed a rapidly growing, oozing tumor on her right flank. She was hesitant to contact the dermatology ward where she had regular checkups as she was afraid of contracting COVID-19. This was in the beginning of the COVID-19 pandemic. At presentation, she had a large exophytic MCC on her right flank and multiple metastases. The disease was at a late stage, and palliative care was the only treatment option left. With this case, we wish to report a rather uncharacteristic location and size of an MCC tumor and suggest that fear of the pandemic and the COVID-19 lockdown has impacted dramatically on attendance of symptomatic patients.


Cytoskeletal tension actively sustains the migratory T-cell synaptic contact.
When migratory T cells encounter antigen-presenting cells (APCs), they arrest and form radially symmetric, stable intercellular junctions termed immunological synapses which facilitate exchange of crucial biochemical information and are critical for T-cell immunity. While the cellular processes underlying synapse formation have been well characterized, those that maintain the symmetry, and thereby the stability of the synapse, remain unknown. Here we identify an antigen-triggered mechanism that actively promotes T-cell synapse symmetry by generating cytoskeletal tension in the plane of the synapse through focal nucleation of actin via Wiskott-Aldrich syndrome protein (WASP), and contraction of the resultant actin filaments by myosin II. Following T-cell activation, WASP is degraded, leading to cytoskeletal unraveling and tension decay, which result in synapse breaking. Thus, our study identifies and characterizes a mechanical program within otherwise highly motile T cells that sustains the symmetry and stability of the T cell-APC synaptic contact.


Masking and color inheritance along the apparent motion path.
Long-range apparent motion is the illusory motion that can be perceived when two static and distant stimuli are presented in succession. Within some spatiotemporal range not only is motion sensed, but it appears as if one stimulus is displaced from one place to another (termed beta or optimal motion). Several groups have found that this illusory percept can interact with perception of a physically present stimulus, but some disagree on the origin of these interactions. We know little about how suppressive effects depend on feature-similarity between a target and the stimuli in apparent motion (inducers)-which would indicate an early perceptual locus-or even about the minimal conditions under which to obtain this effect. Unlike early studies that used a two-stroke apparent motion paradigm, we were able to demonstrate that motion can mask stimuli presented at interpolated locations along the apparent motion path, as shown by the elevation of contrast thresholds compared to a control condition. Apparent motion masking depended on color similarity between target and inducers. Further, we found evidence that the color of inducers alters the apparent color of intervening gray probes, indicating some inheritance or chromatic averaging across distant locations, but no clear evidence of predictive updating. Finally, the analysis of the presentation times delivering maximal masking effects suggests a predictive interpolation process is responsible for interference by apparent motion filling-in. We discuss alternative mechanisms, in particular the possible role of apparent-motion-induced metacontrast masking in generating this pattern of results.


Evolution and genetics of bighead and silver carps: Native population conservation versus invasive species control.
Bighead carp (Hypophthalmichthys nobilis) and silver carp (H. molitrix), collectively called bigheaded carps, are cyprinids native mainly to China and have been introduced to over 70 countries. Paleontological and molecular phylogenetic analyses demonstrate bighead and silver carps originated from the Yangtze-Huanghe River basins and modern populations may have derived from the secondary contact of geographically isolated fish during the last glacial events. Significant genetic differences are found among populations of native rivers (Yangtze, Pearl, and Amur) as well as introduced/invasive environments (Mississippi R., USA and Danube R., Hungary), suggesting genetic backgrounds and ecological selection may play a role in population differentiation. Population divergence of bighead carp or silver carp has occurred within their native rivers, whereas, within the Mississippi River Basin (MRB)-an introduced region, such genetic differentiation is likely taking place at least in silver carp. Interspecific hybridization between silver and bighead carps is rare within their native regions; however, extensive hybridization is observed in the MRB, which could be contributed by a shift to a more homogenous environment that lacks reproductive isolation barriers for the restriction of gene flow between species. The wild populations of native bighead and silver carps have experienced dramatic declines; in contrast, the introduced bigheaded carps overpopulate the MRB and are considered two invasive species, which strongly suggests fishing capacity (overfishing and underfishing) be a decisive factor for fishery resource exploitation and management. This review provides not only a global perspective of evolutionary history and population divergence of bigheaded carps but also a forum that calls for international research collaborations to deal with critical issues related to native population conservation and invasive species control.


"Consulted to death": Personal stress as a major barrier to environmental co-management.
Co-management is widely seen as a way of improving environmental governance and empowering communities. When successful, co-management enhances the validity and legitimacy of decision-making, while providing stakeholders with influence over processes and outcomes that directly impact them. However, our research with participants in co-management across several cases leads us to argue that many of the individuals who contribute to co-management are subject to significant personal stress arising from both the logistical and social/emotional demands of participation in these processes. We argue that the literature on co-management has touched on this only indirectly, and that personal stress is a major challenge for participants that ought to be integrated into research agendas and addressed by policy-makers. In this article, we review the contours of the personal stress issue as it has appeared in our observations of co-management events and interviews with participants. While these findings are partial and preliminary, we argue that personal stress has theoretical and practical significance to the broader literature and process design. We conclude the article with recommendations for participants, researchers and policy-makers about how to consider and respond to problems of personal stress.


Autopsy rates in the Netherlands: 35 years of decline.
Although the autopsy still is a valuable tool in health statistics, health care quality control, medical education, and biomedical research, autopsy rates have been declining worldwide. The aim of this study was to examine trends of overall, clinical and forensic autopsy rates among adults in the Netherlands over the last four decades, and trends per sex, age (groups), and hospital type. We performed a retrospective study covering 35 years of Dutch national death counts (1977-2011), the number of in-hospital deceased patients, the number of deaths due to external causes, and the proportion of autopsies performed in these populations. The effects of sex, age and hospital category were analysed by linear and logistic regression and differences were evaluated by chi-square tests. Overall autopsy rates declined by 0.3% per calendar year, clinical autopsy rates by 0.7% per calendar year (from 31.4% to 7.7%), and forensic autopsy rates did not decline. Per calendar year the fraction of in-hospital deceased patients decreased by 0.2%. Autopsy rates were highest among men and younger patients; clinical autopsy rates were highest for patients dying in academic hospitals. In the Netherlands clinical autopsy rates have rapidly declined while at the same time the fraction of in-hospital deaths decreased, both contributing to the overall reduced absolute number of autopsies performed. It is important to improve awareness among both clinicians and general practitioners of the significance of the clinical autopsy.


ACOG Committee opinion no. 554: reproductive and sexual coercion.
Reproductive and sexual coercion involves behavior intended to maintain power and control in a relationship related to reproductive health by someone who is, was, or wishes to be involved in an intimate or dating relationship with an adult or adolescent. This behavior includes explicit attempts to impregnate a partner against her will, control outcomes of a pregnancy, coerce a partner to have unprotected sex, and interfere with contraceptive methods. Obstetrician-gynecologists are in a unique position to address reproductive and sexual coercion and provide screening and clinical interventions to improve health outcomes. Because of the known link between reproductive health and violence, health care providers should screen women and adolescent girls for intimate partner violence and reproductive and sexual coercion at periodic intervals such as annual examinations, new patient visits, and during obstetric care (at the first prenatal visit, at least once per trimester, and at the postpartum checkup). Interventions include education on the effect of reproductive and sexual coercion and intimate partner violence on patients' health and choices, counseling on harm-reduction strategies, and prevention of unintended pregnancies by offering long-acting methods of contraception that are less detectable to partners.


Measurement of lepton differential distributions and the top quark mass in t t ¯ production in pp collisions at s = 8 TeV with the ATLAS detector.
This paper presents single lepton and dilepton kinematic distributions measured in dileptonic t t ¯ events produced in 20.2 fb - 1 of s = 8 TeV pp collisions recorded by the ATLAS experiment at the LHC. Both absolute and normalised differential cross-sections are measured, using events with an opposite-charge e μ pair and one or two b-tagged jets. The cross-sections are measured in a fiducial region corresponding to the detector acceptance for leptons, and are compared to the predictions from a variety of Monte Carlo event generators, as well as fixed-order QCD calculations, exploring the sensitivity of the cross-sections to the gluon parton distribution function. Some of the distributions are also sensitive to the top quark pole mass; a combined fit of NLO fixed-order predictions to all the measured distributions yields a top quark mass value of m t pole = 173.2 ± 0.9 ± 0.8 ± 1.2 GeV, where the three uncertainties arise from data statistics, experimental systematics, and theoretical sources.


Effect of the Mahatma Gandhi National Rural Employment Guarantee Act (MGNREGA) on malnutrition of infants in Rajasthan, India: a mixed methods study.
Analyse the effect of the Mahatma Gandhi National Rural Employment Guarantee Act (MGNREGA), a wage-for-employment policy of the Indian Government, on infant malnutrition and delineate the pathways through which MGNREGA affects infant malnutrition. MGNREGA could reduce infant malnutrition through positive effects on household food security and infant feeding. Mixed methods using cross-sectional study and focus group discussions conducted in Dungarpur district, Rajasthan, India. Infants aged 1 to <12 months and their mothers/caregivers. Final sample 528 households with 1056 participants, response rate 89.6%. Selected households were divided into MGNREGA-households and non-MGNREGA-households based on participation in MGNREGA between August-2010 and September-2011. Infant malnutrition measured using anthropometric indicators - underweight, stunting, and wasting (WHO criteria). We included 528 households with 1,056 participants. Out of 528, 281 households took part in MGNREGA between August'10, and September'11. Prevalence of wasting was 39%, stunting 24%, and underweight 50%. Households participating in MGNREGA were less likely to have wasted infants (OR 0·57, 95% CI 0·37-0·89, p = 0·014) and less likely to have underweight infants (OR 0·48, 95% CI 0·30-0·76, p = 0·002) than non-participating households. Stunting did not differ significantly between groups. We did 11 focus group discussions with 62 mothers. Although MGNREGA reduced starvation, it did not provide the desired benefits because of lower than standard wages and delayed payments. Results from path analysis did not support existence of an effect through household food security and infant feeding, but suggested a pathway of effect through low birth-weight. Participation in MGNREGA was associated with reduced infant malnutrition possibly mediated indirectly via improved birth-weight rather than by improved infant feeding. Addressing factors such as lack of mothers' knowledge and inappropriate feeding practices, over and above the social and economic policies, is key in efforts to reduce infant malnutrition.


Is walking to school associated with improved metabolic health?
Active commuting to/from school is an important source of physical activity that has been declining over the past years. Although it is an affordable and simple way of increasing physical activity levels it is still unclear whether it has enough potential to improve health. Therefore, the aim of this cross sectional study was to examine the relationship between active commuting to/from school and metabolic risk factors in 10 to 12 year old children. Participants were 229 adolescents, selected through consecutive sampling, (121 girls) with mean age of 11.65 (±0.73) years old from Porto, Portugal. Means of transport to/from school was accessed by asking: "How do you usually travel to school?" and "How do you usually travel from school?". Active commuting was considered if children reported at least one of the trips (to or from school) by active means. Total physical activity was obtained with Actigraph accelerometer for 7 consecutive days. Lipid profile measurements were conducted with Cholestech LDX® analyser. Waist circumference and blood pressure were measured by standard methods. The criteria for metabolic syndrome defined by International Diabetes Federation for children and adolescents were used. Adjusted binary logistic regression analysis suggested that walkers have higher odds to have a better waist circumference (OR = 2.64, 95% CI = 1.63-6.01) and better high density lipoprotein cholesterol (OR = 2.14, 95% CI = 1.01-4.52) profiles than non-active commuters, independent of moderate-to-vigorous physical activity. No associations were found for other metabolic risk factors. Exertions to increase and maintain walking to school may be particularly relevant as it is likely to have a positive impact on children's health and eventually decrease metabolic and cardiovascular diseases.


Measuring thermal rupture force distributions from an ensemble of trajectories.
Rupture, bond breaking, or extraction from a deep and narrow potential well requires considerable force while producing minimal displacement. In thermally fluctuating systems, there is not a single force required to achieve rupture, but a spectrum, as thermal forces can both augment and inhibit the bond breaking. We demonstrate measurement and interpretation of the distribution of rupture forces between pairs of colloidal particles bonded via the van der Waals attraction. The otherwise irreversible bond is broken by pulling the particles apart with optical tweezers. We show that an ensemble of the particle trajectories before, during and after the rupture event may be used to produce a high fidelity description of the distribution of rupture forces. This analysis is equally suitable for describing rupture forces in molecular and biomolecular contexts with a number of measurement techniques.


Runx1-mediated hematopoietic stem-cell emergence is controlled by a Gata/Ets/SCL-regulated enhancer.
The transcription factor Runx1/AML1 is an important regulator of hematopoiesis and is critically required for the generation of the first definitive hematopoietic stem cells (HSCs) in the major vasculature of the mouse embryo. As a pivotal factor in HSC ontogeny, its transcriptional regulation is of high interest but is largely undefined. In this study, we used a combination of comparative genomics and chromatin analysis to identify a highly conserved 531-bp enhancer located at position + 23.5 in the first intron of the 224-kb mouse Runx1 gene. We show that this enhancer contributes to the early hematopoietic expression of Runx1. Transcription factor binding in vivo and analysis of the mutated enhancer in transient transgenic mouse embryos implicate Gata2 and Ets proteins as critical factors for its function. We also show that the SCL/Lmo2/Ldb-1 complex is recruited to the enhancer in vivo. Importantly, transplantation experiments demonstrate that the intronic Runx1 enhancer targets all definitive HSCs in the mouse embryo, suggesting that it functions as a crucial cis-regulatory element that integrates the Gata, Ets, and SCL transcriptional networks to initiate HSC generation.


Cloning and expression of afpA, a gene encoding an antifreeze protein from the arctic plant growth-promoting rhizobacterium Pseudomonas putida GR12-2.
The Arctic plant growth-promoting rhizobacterium Pseudomonas putida GR12-2 secretes an antifreeze protein (AFP) that promotes survival at subzero temperatures. The AFP is unusual in that it also exhibits a low level of ice nucleation activity. A DNA fragment with an open reading frame encoding 473 amino acids was cloned by PCR and inverse PCR using primers designed from partial amino acid sequences of the isolated AFP. The predicted gene product, AfpA, had a molecular mass of 47.3 kDa, a pI of 3.51, and no previously known function. Although AfpA is a secreted protein, it lacked an N-terminal signal peptide and was shown by sequence analysis to have two possible secretion systems: a hemolysin-like, calcium-binding secretion domain and a type V autotransporter domain found in gram-negative bacteria. Expression of afpA in Escherichia coli yielded an intracellular 72-kDa protein modified with both sugars and lipids that exhibited lower levels of antifreeze and ice nucleation activities than the native protein. The 164-kDa AFP previously purified from P. putida GR12-2 was a lipoglycoprotein, and the carbohydrate was required for ice nucleation activity. Therefore, the recombinant protein may not have been properly posttranslationally modified. The AfpA sequence was most similar to cell wall-associated proteins and less similar to ice nucleation proteins (INPs). Hydropathy plots revealed that the amino acid sequence of AfpA was more hydrophobic than those of the INPs in the domain that forms the ice template, thus suggesting that AFPs and INPs interact differently with ice. To our knowledge, this is the first gene encoding a protein with both antifreeze and ice nucleation activities to be isolated and characterized.


Mammalian cell entry genes in Streptomyces may provide clues to the evolution of bacterial virulence.
Understanding the evolution of virulence is key to appreciating the role specific loci play in pathogenicity. Streptomyces species are generally non-pathogenic soil saprophytes, yet within their genome we can find homologues of virulence loci. One example of this is the mammalian cell entry (mce) locus, which has been characterised in Mycobacterium tuberculosis. To investigate the role in Streptomyces we deleted the mce locus and studied its impact on cell survival, morphology and interaction with other soil organisms. Disruption of the mce cluster resulted in virulence towards amoebae (Acanthamoeba polyphaga) and reduced colonization of plant (Arabidopsis) models, indicating these genes may play an important role in Streptomyces survival in the environment. Our data suggest that loss of mce in Streptomyces spp. may have profound effects on survival in a competitive soil environment, and provides insight in to the evolution and selection of these genes as virulence factors in related pathogenic organisms.


Reticular erythematous mucinosis: histopathological and immunohistochemical features of 25 patients compared with 25 cases of lupus erythematosus tumidus.
Reticular erythematous mucinosis (REM) and lupus erythematosus tumidus (LET) share similarities. However, to our knowledge no study extensively compared the histological features of these two conditions. The aim of this study is to compare the histological and immunohistochemical features of REM and LET. We evaluated epidermal thickness, hyperkeratosis, dermo-epidermal junction changes, interstitial mucin deposition, vessel dilatation and pattern, type and density of the inflammatory infiltrate in 25 cases of REM and LET. Anti-CD3, anti-CD20, anti-CD68, anti-CD4, anti-CD8, anti-CD123, anti-CD2AP, anti-IgG and anti-C3 antibodies were tested in a subset of patients. Both diseases are characterized by perivascular dermal infiltrates of lymphocytes mainly CD4+ positive and increased dermal mucin. However, REM tended to show more scattered and more superficial lymphocytes with more superficial mucin and to have less frequent immunoglobulin and complement depositions along the dermo-epidermal junction. Plasmacytoid dendritic cells (PDCs) were less represented in REM, and were mainly found as single cells differently from LET. REM and LET present some differences in the infiltrate, including PDCs, the mucin deposition and the immunoreactant deposition at the dermo-epidermal junction that justify the distinction of the two diseases and suggest different pathogenetic mechanisms.


Amphibian decline and extinction: what we know and what we need to learn.
For over 350 million yr, thousands of amphibian species have lived on Earth. Since the 1980s, amphibians have been disappearing at an alarming rate, in many cases quite suddenly. What is causing these declines and extinctions? In the modern era (post 1500) there are 6 leading causes of biodiversity loss in general, and all of these acting alone or together are responsible for modern amphibian declines: commercial use; introduced/exotic species that compete with, prey on, and parasitize native frogs and salamanders; land use change; contaminants; climate change; and infectious disease. The first 3 causes are historical in the sense that they have been operating for hundreds of years, although the rate of change due to each accelerated greatly after about the mid-20th century. Contaminants, climate change, and emerging infectious diseases are modern causes suspected of being responsible for the so-called 'enigmatic decline' of amphibians in protected areas. Introduced/exotic pathogens, land use change, and infectious disease are the 3 causes with a clear role in amphibian decline as well as extinction; thus far, the other 3 causes are only implicated in decline and not extinction. The present work is a review of the 6 causes with a focus on pathogens and suggested areas where new research is needed. Batrachochytrium dendrobatidis (Bd) is a chytrid fungus that is an emerging infectious disease causing amphibian population decline and species extinction. Historically, pathogens have not been seen as a major cause of extinction, but Bd is an exception, which is why it is such an interesting, important pathogen to understand. The late 20th and early 21st century global biodiversity loss is characterized as a sixth extinction event. Amphibians are a striking example of these losses as they disappear at a rate that greatly exceeds historical levels. Consequently, modern amphibian decline and extinction is a lens through which we can view the larger story of biodiversity loss and its consequences.


Long term effects of a first pregnancy on serum concentrations of dehydroepiandrosterone sulfate and dehydroepiandrosterone.
A previous paper in this journal reported that first pregnancy was followed by a marked decrease in dehydro-epiandrosterone sulfate (DHAS) and dehydroepiandrosterone (DHA) levels. We report here confirmatory observations from cross-sectional measurements in 460 women. In premenopausal subjects (n = 306), the mean DHAS level was 21% lower (P = 0.005) and the mean DHA level was 32% lower (P less than 0.001) in parous than in nulliparous women. Neither DHAS nor DHA was related to parity in postmenopausal women (n = 154).


The Analgesic Effect of Transcranial Direct Current Stimulation (tDCS) combined with Physical Therapy on Common Musculoskeletal Conditions: A Systematic Review and Meta-Analysis.
The analgesic effects of transcranial Direct Current Stimulation (tDCS) combined with physical therapy remain unclear. To systematically review available evidence comparing tDCS with any physical therapy modality (PTM) to PTM alone or PTM with sham tDCS on pain relief on common musculoskeletal (MSK) conditions, namely knee osteoarthritis (KOA), chronic low back pain (CLBP), myofascial pain syndrome (MPS) and fibromyalgia. EMBASE and MEDLINE were searched from inception to April 2019 for randomized controlled trials. Reviewers independently assessed the studies quality and extracted data according to the PRISMA protocol. The GRADE approach was used to asses quality of evidence and a "Summary of Findings" table was created. The analyses used random-effects model. The primary outcome was pain reduction after treatment. Eight articles were included. Only one study had low risk of bias. Quality of evidence was considered low or very low. Significant reduction in pain scores were found for fibromyalgia and KOA (Standardized mean difference (SMD) = -1.94 [95% CI: -3.37 to -0.49; I 2=76.4%] and SMD = -2.35 [95% CI: -3.63 to -1.06; I 2=69.7%] respectively). Subgroup analysis considering the type of PTM despite MSK condition revealed significant reduction in pain scores for exercise, SMD = -1.20 [95% CI: -1.683 to -0.717; I 2=10.8%]. Large heterogeneity and low quality of evidence and limited number of studies were found. Results suggest a potential analgesic effect of tDCS in combination with a PTM for fibromyalgia and KOA. Subgroup analysis suggests a stronger effect of tDCS when combined with an exercise based PTM.


Using an intravenous catheter system to prevent needlestick injury.
To identify the effect of a sharps awareness campaign and the introduction of a safety catheter device on the annual incidence of needlestick injuries between 2003 and 2007. In 2003, a sharps awareness campaign began in San Martino Hospital in Genoa, Italy. In 2005, a safety catheter was introduced and healthcare workers were trained in its use. Data for all occupational accidents from 2003 to 2007 were collected and analysed. After introduction of the sharps awareness campaign and use of safety catheters, reported incidents of sharps injuries involving catheters fell from 19 in 2004 to two in 2007 and in neither of those two cases were needlestick prevention devices used. Overall, the rate of needlestick injuries was 24.1 per 100,000 cases when conventional catheters were used and 0.4 per 100,000 cases with safety catheters. The sharps awareness campaign and newly adopted needlestick prevention device may have contributed to the prevention of percutaneous injuries caused by catheters. Until the onset of the campaign, the reported annual incidence of needlestick injuries was six. This increased to a peak of 19 reported injuries in 2004, which could be attributed to improved reporting effected by the campaign.


Management of failed hypospadias: choosing the right method and achieving optimal results.
Because of the complexity of the abnormalities and limited options for reconstruction of failed hypospadias, creating a neourethra presents a challenge to surgeons. We reviewed our experiences with staged urethroplasty strategies to repair the penis of failed hypospadias. We retrospectively reviewed 56 consecutives patients following multiple unsuccessful hypospadias repairs from 2010 to 2016. Patients were divided into the following two groups based on their penile conditions and urethroplasty procedures: staged buccal mucosa graft Bracka urethroplasty (group1) and two-stage urethroplasty with additional buccal mucosa graft augmentation of the dorsal urethral plate (group2). Median follow-ups were 26.5 months (12-59 months) and 28.6 months (14-59 months) in the group 1 and group 2. After the second stage, three patients (11.1%) in group 1 and two patients (6.89%) in group 2 did not have a meatal opening at the top of the glans. Three patients (11.1%) in group 1 and 4 patients (13.79%) in group 2 had urethrocutaneous fistulas. One patient (3.70%) in group 1 and no patients in group 2 had meatal stenosis. Two patients (6.89%) in group 2 and no patients in group 1 had urethral strictures; all patients with strictures were cured using dilations, so follow-up surgeries were not required. No patients in either group had signs of diverticulum or residual chordee. Three patients (11.1%) in group 1 and 4 patients (13.79%) in group 2 needed reoperations. Failed hypospadias repairs were often due to the underestimation of the penile conditions at the prior surgery. The results indicated that two-staged strategies were preferred for treating complex situations during the intermediate period of our study. Staged buccal mucosa graft Bracka urethroplasty and two-stage urethroplasty with additional buccal mucosa graft augmentation of the dorsal urethral plate severed as reliable approaches in complex hypospadias cases and could improve the overall success rate.


RcsB and RcsC: a two-component regulator of capsule synthesis in Escherichia coli.
Colanic acid capsule synthesis in Escherichia coli K-12 is regulated by RcsB and RcsC. The amino acid sequences of these two proteins, deduced from the nucleotide sequence reported here, demonstrate their homology to environmentally responsive two-component regulators that have been reported in both gram-positive and gram-negative bacteria. In our model, RcsC acts as the sensor and RcsB acts as the receiver or effector to stimulate capsule synthesis from cps genes. In addition, RcsC shows limited homology to the other effectors in its C terminus. Fusions of rcsC to phoA that resulted in PhoA+ strains demonstrated that RcsC is a transmembrane protein with a periplasmic N-terminal domain and cytoplasmic C-terminal domain. Additional control of this regulatory network is provided by the dependence on the alternate sigma factor, RpoN, for the synthesis of RcsB. The rcsB and rcsC genes, which are oriented convergently with their stop codons 196 base pairs apart, are separated by a long direct repeat including two repetitive extragenic palindromic sequences.


Mind-body interventions during pregnancy for preventing or treating women's anxiety.
Anxiety during pregnancy is a common problem. Anxiety and stress could have consequences on the course of the pregnancy and the later development of the child. Anxiety responds well to treatments such as cognitive behavioral therapy and/or medication. Non-pharmacological interventions such as mind-body interventions, known to decrease anxiety in several clinical situations, might be offered for treating and preventing anxiety during pregnancy. To assess the benefits of mind-body interventions during pregnancy in preventing or treating women's anxiety and in influencing perinatal outcomes. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 November 2010), MEDLINE (1950 to 30 November 2010), EMBASE (1974 to 30 November 2010), the National Center for Complementary and Alternative Medicine (NCCAM) (1 December 2010), ClinicalTrials.gov (December 2010) and Current Controlled Trials (1 December 2010), searched the reference lists of selected studies and contacted professionals and authors in the field. Randomized controlled trials, involving pregnant women of any age at any time from conception to one month after birth, comparing mind-body interventions with a control group. Mind-body interventions include: autogenic training, biofeedback, hypnotherapy, imagery, meditation, prayer, auto-suggestion, tai-chi and yoga. Control group includes: standard care, other pharmacological or non-pharmacological interventions, other types of mind-body interventions or no treatment at all. Three review authors independently assessed trials for inclusion all assessed risk of bias for each included study. We extracted data independently using an agreed form and checked it for accuracy. We included eight trials (556 participants), evaluating hypnotherapy (one trial), imagery (five trials), autogenic training (one trial) and yoga (one trial). Due to the small number of studies per intervention and to the diversity of outcome measurements, we performed no meta-analysis, and have reported results individually for each study. Compared with usual care, in one study (133 women), imagery may have a positive effect on anxiety during labor decreasing anxiety at the early and middle stages of labor (MD -1.46; 95% CI -2.43 to -0.49; one study, 133 women) and (MD -1.24; 95% CI -2.18 to -0.30). Another study showed that imagery had a positive effect on anxiety and depression in the immediate postpartum period. Autogenic training might be effective for decreasing women's anxiety before delivering. Mind-body interventions might benefit women's anxiety during pregnancy. Based on individual studies, there is some but no strong evidence for the effectiveness of mind-body interventions for the management of anxiety during pregnancy. The main limitations of the studies were the lack of blinding and insufficient details on the methods used for randomization.


Expression of phosphorylcholine-specific B cells during murine development.
The TEPC 15 (T15) clonotype, a putatively germline antibody specificity, does not appear in the neonatal B-cell repertoire until approximately 1 wk of age. This report extends this observation by the demonstration that (a) the T15 clonotype follows similar kinetics of appearance in germfree as well as conventionally-reared mice; (b) maternal influences and genetic background play a minor role in the development of the T15 clonotype since CBFI neonates raised by C57BL/6 or BALB/c mothers acquire the T15 clonotype at the same time in ontogeny as BALB/c neonates; (c) the lack of phosphorylcholine (PC)-specific B cells shortly after birth is reflected in a dearth of PC-binding cells in the neonate as well; and (d) no PC-specifc B cells are found in 19-day fetal liver or in bone marrow until 7 days of life, coincident with their appearance in the spleen. These findings, along with a previous report that PC-specific splenic B cells are tolerizable as late as day 10 after birth, confirm the invariant, late occurrence of the T15 clonotype and support a highly- ordered, rigorously predetermined mechanism for the acquisition of the B- cell repertoire. The results are discussed in light of other studies on the ontogeny of B-cell specificity, and in terms of the implications on the mechanism by which antibody diversity is generated.


Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy.
Adrenergic beta-blocking agents were given to 7 patients with advanced congestive cardiomyopathy who had tachycardia at rest (98 plus or minus 13 beats/min). The patients were on beta-adrenergic receptor blockade for 2 to 12 months (average 5-4 months). One patient was given alprenolol 50 mg twice daily and the other patients were given practolol 50 to 400 mg twice daily. Virus infection had occurred in 6 of the patients before the onset of symptoms of cardiac disease. All patients were in a steady state or were progressively deteriorating at the start of beta-adrenergic receptor blockade. Conventional treatment with digitalis and diuretics was unaltered or reduced during treatment with beta-blocking agents. An improvement was seen in their clinical condition shortly after administration of the drugs. Continued treatment resulted in an increase in physical working capacity and a reduction of heart size. Noninvasive investigations including phonocardiogram, carotid pulse curve, apex cardiogram, and echocardiogram showed improved ventricular function in all cases. The present study indicates that adrenergic beta-blocking agents can improve heart function in at lease some patients with congestive cardiomyopathy. Furthermore, it is suggested that increased catecholamine activity may be an important factor for the development of this disease, as has been shown in animal experiments.


Complementary and alternative medical therapies for chronic low back pain: What treatments are patients willing to try?
Although back pain is the most common reason patients use complementary and alternative medical (CAM) therapies, little is known about the willingness of primary care back pain patients to try these therapies. As part of an effort to refine recruitment strategies for clinical trials, we sought to determine if back pain patients are willing to try acupuncture, chiropractic, massage, meditation, and t'ai chi and to learn about their knowledge of, experience with, and perceptions about each of these therapies. We identified English-speaking patients with diagnoses consistent with chronic low back pain using automated visit data from one health care organization in Boston and another in Seattle. We were able to confirm the eligibility status (i.e., current low back pain that had lasted at least 3 months) of 70% of the patients with such diagnoses and all eligible respondents were interviewed. Except for chiropractic, knowledge about these therapies was low. Chiropractic and massage had been used by the largest fractions of respondents (54% and 38%, respectively), mostly for back pain (45% and 24%, respectively). Among prior users of specific CAM therapies for back pain, massage was rated most helpful. Users of chiropractic reported treatment-related "significant discomfort, pain or harm" more often (23%) than users of other therapies (5-16%). Respondents expected massage would be most helpful (median of 7 on a 0 to 10 scale) and meditation least helpful (median of 3) in relieving their current pain. Most respondents indicated they would be "very likely" to try acupuncture, massage, or chiropractic for their back pain if they did not have to pay out of pocket and their physician thought it was a reasonable treatment option. Most patients with chronic back pain in our sample were interested in trying therapeutic options that lie outside the conventional medical spectrum. This highlights the need for additional studies evaluating their effectiveness and suggests that researchers conducting clinical trials of these therapies may not have difficulties recruiting patients.


Tel-eVax: a genetic vaccine targeting telomerase for treatment of canine lymphoma.
we have recently shown that Tel-eVax, a genetic vaccine targeting dog telomerase (dTERT) and based on Adenovirus (Ad)/DNA Electro-Gene-Transfer (DNA-EGT) technology can induce strong immune response and increase overall survival (OS) of dogs affected by multicentric Diffuse Large B cell Lymphoma (DLBCL) when combined to COP therapy in a double-arm study. Here, we have utilized a clinically validated device for veterinary electroporation called Vet-ePorator™, based on Cliniporator™ technology currently utilized and approved in Europe for electrochemotherapy applications and adapted to electrogenetransfer (EGT). 17 dogs affected by DLBCL were vaccinated using two Ad vector injections (Prime phase) followed by DNA-EGT (Boost phase) by means of a Vet-ePorator™ device and treated in the same time with a 27-week Madison Wisconsin CHOP protocol. The immune response was measured by ELISA assays using pool of peptides. No significant adverse effects were observed. The OS of vaccine/CHOP animals was 64.5 weeks, in line with the previous study. Dogs developed antibodies against the immunizing antigen. Tel-eVax in combination with CHOP is safe and immunogenic in lymphoma canine patients. These data confirm the therapeutic efficacy of dTERT vaccine and hold promise for the treatment of dogs affected by other cancer types. More importantly, our findings may translate to human clinical trials and represent new strategies for cancer treatment.


Extensive microbial diversity within the chicken gut microbiome revealed by metagenomics and culture.
The chicken is the most abundant food animal in the world. However, despite its importance, the chicken gut microbiome remains largely undefined. Here, we exploit culture-independent and culture-dependent approaches to reveal extensive taxonomic diversity within this complex microbial community. We performed metagenomic sequencing of fifty chicken faecal samples from two breeds and analysed these, alongside all (n = 582) relevant publicly available chicken metagenomes, to cluster over 20 million non-redundant genes and to construct over 5,500 metagenome-assembled bacterial genomes. In addition, we recovered nearly 600 bacteriophage genomes. This represents the most comprehensive view of taxonomic diversity within the chicken gut microbiome to date, encompassing hundreds of novel candidate bacterial genera and species. To provide a stable, clear and memorable nomenclature for novel species, we devised a scalable combinatorial system for the creation of hundreds of well-formed Latin binomials. We cultured and genome-sequenced bacterial isolates from chicken faeces, documenting over forty novel species, together with three species from the genus Escherichia, including the newly named species Escherichia whittamii. Our metagenomic and culture-based analyses provide new insights into the bacterial, archaeal and bacteriophage components of the chicken gut microbiome. The resulting datasets expand the known diversity of the chicken gut microbiome and provide a key resource for future high-resolution taxonomic and functional studies on the chicken gut microbiome.


Preexisting human antibodies neutralize recently emerged H7N9 influenza strains.
The emergence and seasonal persistence of pathogenic H7N9 influenza viruses in China have raised concerns about the pandemic potential of this strain, which, if realized, would have a substantial effect on global health and economies. H7N9 viruses are able to bind to human sialic acid receptors and are also able to develop resistance to neuraminidase inhibitors without a loss in fitness. It is not clear whether prior exposure to circulating human influenza viruses or influenza vaccination confers immunity to H7N9 strains. Here, we demonstrate that 3 of 83 H3 HA-reactive monoclonal antibodies generated by individuals that had previously undergone influenza A virus vaccination were able to neutralize H7N9 viruses and protect mice against homologous challenge. The H7N9-neutralizing antibodies bound to the HA stalk domain but exhibited a difference in their breadth of reactivity to different H7 influenza subtypes. Mapping viral escape mutations suggested that these antibodies bind at least two different epitopes on the stalk region. Together, these results indicate that these broadly neutralizing antibodies may contribute to the development of therapies against H7N9 strains and may also be effective against pathogenic H7 strains that emerge in the future.