Cognitions in bipolar affective disorder and unipolar depression: imagining suicide.
Bipolar disorder has the highest rate of suicide of all the psychiatric disorders. In unipolar depression, individuals report vivid, affect-laden images of suicide or the aftermath of death (flashforwards to suicide) during suicidal ideation but this phenomenon has not been explored in bipolar disorder. Therefore the authors investigated and compared imagery and verbal thoughts related to past suicidality in individuals with bipolar disorder (n = 20) and unipolar depression (n = 20). The study used a quasi-experimental comparative design. The Structured Clinical Interview for DSM-IV was used to confirm diagnoses. Quantitative and qualitative data were gathered through questionnaire measures (e.g., mood and trait imagery use). Individual interviews assessed suicidal cognitions in the form of (i) mental images and (ii) verbal thoughts. All participants reported imagining flashforwards to suicide. Both groups reported greater preoccupation with these suicide-related images than with verbal thoughts about suicide. However, compared to the unipolar group, the bipolar group were significantly more preoccupied with flashforward imagery, rated this imagery as more compelling, and were more than twice as likely to report that the images made them want to take action to complete suicide. In addition, the bipolar group reported a greater trait propensity to use mental imagery in general. Suicidal ideation needs to be better characterized, and mental imagery of suicide has been a neglected but potentially critical feature of suicidal ideation, particularly in bipolar disorder. Our findings suggest that flashforward imagery warrants further investigation for formal universal clinical assessment procedures.


Antinociceptive activity of a synthetic curcuminoid analogue, 2,6-bis-(4-hydroxy-3-methoxybenzylidene)cyclohexanone, on nociception-induced models in mice.
This study investigated the potential antinociceptive efficacy of a novel synthetic curcuminoid analogue, 2,6-bis-(4-hydroxy-3-methoxybenzylidene)cyclohexanone (BHMC), using chemical- and thermal-induced nociception test models in mice. BHMC (0.03, 0.1, 0.3 and 1.0 mg/kg) administered via intraperitoneal route (i.p.) produced significant dose-related inhibition in the acetic acid-induced abdominal constriction test in mice with an ID(50) of 0.15 (0.13-0.18) mg/kg. It was also demonstrated that BHMC produced significant inhibition in both neurogenic (first phase) and inflammatory phases (second phase) of the formalin-induced paw licking test with an ID(50) of 0.35 (0.27-0.46) mg/kg and 0.07 (0.06-0.08) mg/kg, respectively. Similarly, BHMC also exerted significant increase in the response latency period in the hot-plate test. Moreover, the antinociceptive effect of the BHMC in the formalin-induced paw licking test and the hot-plate test was antagonized by pre-treatment with the non-selective opioid receptor antagonist, naloxone. Together, these results indicate that the compound acts both centrally and peripherally. In addition, administration of BHMC exhibited significant inhibition of the neurogenic nociception induced by intraplantar injections of glutamate and capsaicin with ID(50) of 0.66 (0.41-1.07) mg/kg and 0.42 (0.38-0.51) mg/kg, respectively. Finally, it was also shown that BHMC-induced antinociception was devoid of toxic effects and its antinociceptive effect was associated with neither muscle relaxant nor sedative action. In conclusion, BHMC at all doses investigated did not cause any toxic and sedative effects and produced pronounced central and peripheral antinociceptive activities. The central antinociceptive activity of BHMC was possibly mediated through activation of the opioid system as well as inhibition of the glutamatergic system and TRPV1 receptors, while the peripheral antinociceptive activity was perhaps mediated through inhibition of various inflammatory mediators.


A dark brown roast coffee blend is less effective at stimulating gastric acid secretion in healthy volunteers compared to a medium roast market blend.
Coffee consumption sometimes is associated with symptoms of stomach discomfort. This work aimed to elucidate whether two coffee beverages, containing similar amounts of caffeine, but differing in their concentrations of (β) N-alkanoyl-5-hydroxytryptamides (C5HTs), chlorogenic acids (CGAs), trigonelline, and N-methylpyridinium (N-MP) have different effects on gastric acid secretion in healthy volunteers. The intragastric pH after administration of bicarbonate with/without 200 mL of a coffee beverage prepared from a market blend or dark roast blend was analyzed in nine healthy volunteers. Coffee beverages were analyzed for their contents of C5HT, N-MP, trigonelline, CGAs, and caffeine using HPLC-DAD and HPLC-MS/MS. Chemical analysis revealed higher concentrations of N-MP for the dark brown blend (87 mg/L) compared to the market blend coffee (29 mg/L), whereas concentrations of C5HT (0.012 versus 0.343 mg/L), CGAs (323 versus 1126 mg/L), and trigonelline (119 versus 343 mg/L) were lower, and caffeine concentrations were similar (607 versus 674 mg/mL). Gastric acid secretion was less effectively stimulated after administration of the dark roast blend coffee compared to the market blend. Future studies are warranted to verify whether a high ratio of N-MP to C5HT and CGAs is beneficial for reducing coffee-associated gastric acid secretion.


Inhibition of Hypoxia-Induced Cell Motility by p16 in MDA-MB-231 Breast Cancer Cells.
Our previous studies indicated that p16 suppresses breast cancer angiogenesis and metastasis, and downregulates VEGF gene expression by neutralizing the transactivation of the VEGF transcriptional factor HIF-1α. Hypoxia stimulates tumor malignant progression and induces HIF-1α. Because p16 neutralizes effect of HIF-1α and attenuates tumor metastatic progression, we intended to investigate whether p16 directly affects one or more aspects of the malignant process such as adhesion and migration of breast cancer cells. To approach this aim, MDA-MB-231 and other breast cancer cells stably transfected with Tet-on inducible p16 were used to study the p16 effect on growth, adhesion and migration of the cancer cells. We found that p16 inhibits breast cancer cell proliferation and migration, but has no apparent effect on cell adhesion. Importantly, p16 inhibits hypoxia-induced cell migration in breast cancer in parallel with its inhibition of HIF-1α transactivation activity. This study suggests that p16's ability to suppress tumor metastasis may be partially resulted from p16's inhibition on cell migration, in addition to its known functions on inhibition of cell proliferation, angiogenesis and induction of apoptosis.


Low seroprevalence of Murray Valley encephalitis and Kunjin viruses in an opportunistic serosurvey, Victoria 2011.
To assess evidence of recent and past exposure to Murray Valley encephalitis virus (MVEV) and West Nile clade Kunjin virus (KUNV) in residents of the Murray Valley, Victoria, during a period of demonstrated activity of both viruses in early 2011. A cross-sectional serosurvey using two convenience samples: stored serum specimens from a diagnostic laboratory in Mildura and blood donors from the Murray Valley region. Specimens were collected between April and July 2011. The main outcome measure was total antibody (IgM and IgG) reactivity against MVEV and KUNV measured using an enzyme immunoassay and defined as inhibiting binding of monoclonal antibodies by >50%, when compared to negative controls. Evidence of recent exposure was measured by the presence of MVEV and KUNV IgM detected by immunofluorescence. Of 1,115 specimens, 24 (2.2%, 95% CI 1.3-3.0%) were positive for MVEV total antibody, and all were negative for MVEV IgM. Of 1,116 specimens, 34 (3.1%, 95% CI 2.0-4.0%) were positive for KUNV total antibody, and 3 (0.27%) were KUNV IgM positive. Total antibody seroprevalence for both viruses was higher in residents born before 1974. Despite widespread MVEV and KUNV activity in early 2011, this study found that seroprevalence of antibodies to both viruses was low (<5%) and little evidence of recent exposure. Our findings suggest both viruses remain epizootic in the region and local residents remain potentially susceptible to future outbreaks.


Compartmental ovarian steroidogenesis in polycystic ovary syndrome.
Compartmental ovarian steroidogenesis in vitro was investigated in polycystic ovary syndrome. Basal estrogen secretion by granulosa cells ranged from 60 to 284 pg/micrograms cell protein for 24 hours and progesterone secretion from 24 to 1646 pg/micrograms cell protein for 24 hours. In three of four specimens, the addition of either 10(-5)M testosterone or androstenedione significantly increased estrogen production, demonstrating the presence of aromatase activity. Treatment with human follicle-stimulating hormone (100 ng/mL) or human chorionic gonadotropin (100 ng/mL) significantly increased the progesterone production in three of four specimens. The thecal compartment of every patient secreted significantly more testosterone and androstenedione than the capsule and stroma and more estrogen in tissue from two of the four women. The androgen/estrogen ratio was significantly greater for the theca (16.9) than the capsule (1.1) or stroma (1.7). These data demonstrate that in polycystic ovary syndrome a portion of the follicles possess the qualitative characteristics of developing follicles, granulosa cell aromatase activity and gonadotropin responsiveness, and that the theca is likely the principal site of ovarian androgen synthesis. These findings suggest that the small follicles characteristic of polycystic ovary syndrome consist of a mixed population of developing and atretic follicles and that the peripheral androgen excess is attributable to the large mass of the thecal compartment from both follicle populations.


PvDBPII elicits multiple antibody-mediated mechanisms that reduce growth in a Plasmodium vivax challenge trial.
The receptor-binding domain, region II, of the Plasmodium vivax Duffy binding protein (PvDBPII) binds the Duffy antigen on the reticulocyte surface to mediate invasion. A heterologous vaccine challenge trial recently showed that a delayed dosing regimen with recombinant PvDBPII SalI variant formulated with adjuvant Matrix-MTM reduced the in vivo parasite multiplication rate (PMR) in immunized volunteers challenged with the Thai P. vivax isolate PvW1. Here, we describe extensive analysis of the polyfunctional antibody responses elicited by PvDBPII immunization and identify immune correlates for PMR reduction. A classification algorithm identified antibody features that significantly contribute to PMR reduction. These included antibody titre, receptor-binding inhibitory titre, dissociation constant of the PvDBPII-antibody interaction, complement C1q and Fc gamma receptor binding and specific IgG subclasses. These data suggest that multiple immune mechanisms elicited by PvDBPII immunization are likely to be associated with protection and the immune correlates identified could guide the development of an effective vaccine for P. vivax malaria. Importantly, all the polyfunctional antibody features that correlated with protection cross-reacted with both PvDBPII SalI and PvW1 variants, suggesting that immunization with PvDBPII should protect against diverse P. vivax isolates.


Disorders characterized by predominant or exclusive dermal inflammation.
Some cutaneous inflammatory disorders are typified by a predominant or exclusive localization in the dermis. They can be further subdivided by the principal cell types into lymphocytic, neutrophilic, and eosinophilic infiltrates, and mixtures of them are also seen in a proportion of cases. This review considers such conditions. Included among the lymphoid lesions are viral exanthems, pigmented purpuras, gyrate erythemas, polymorphous light eruption, lupus tumidus, and cutaneous lymphoid hyperplasia. Neutrophilic infiltrates are represented by infections, Sweet syndrome, pyoderma gangrenosum, and hidradenitis suppurativa, as well as a group of so-called "autoinflammatory" dermatitides comprising polymorphonuclear leukocytes. Eosinophil-dominated lesions include arthropod bite reactions, cutaneous parasitic infestations, the urticarial phase of bullous pemphigoid, Wells syndrome (eosinophilic cellulitis), hypereosinophilic syndrome, and Churg-Strauss disease. In other conditions, eosinophils are admixed with neutrophils in the corium, with or without small-vessel vasculitis. Exemplary disorders with those patterns include drug eruptions, chronic idiopathic urticaria, urticarial vasculitis, granuloma faciale, and Schnitzler syndrome (chronic urticarial with a monoclonal gammopathy).


Can a barcode scanner for blood collection improve patient identification integrity in the emergency department? A prospective before-and-after study.
To describe the effect of interventions designed to improve patient identification (PI) during pathology collection in the ED. A prospective before-and-after intervention study was conducted between June 2009 and June 2010 in a regional ED in Queensland, Australia. Interventions aimed to improve PI and specimen labelling, and consisted of: (i) education alone; and (ii) education plus an armband scanner that voice-prompted collector behaviour. Main outcomes measured included: frequency of correct key behaviours (KBs) during specimen collection, pathology integrity errors and cost of interventions. Data from 282 ED pathology collections were analysed (before: n = 115, after with education: n = 95, after with education plus armband scanner: n = 72). KBs for PI and labelling improved significantly following education plus armband scanner use. Application of armbands before sample collection increased (36% vs 90%, P < 0.001), as did asking the patient to state their name (25% vs 93%, P < 0.001) and date of birth (22% vs 93%, P < 0.001). These results were similar, albeit less pronounced, when the effect of education only was assessed. No primary patient misidentification was detected in this small study. The annual costs for a hospital to adopt the education programme with and without the armband scanner were $104,045 and $5330 respectively. ED staff had poor behaviours for identifying patients and labelling pathology specimens before intervention. These safety behaviours were considered an assumed skill. Education alone improved critical KBs markedly that was further augmented by the armband scanner. The cost to adopt education alone is relatively low compared to the addition of armband scanner technology.


A proteomics approach to investigate the process of Zn hyperaccumulation in Noccaea caerulescens (J & C. Presl) F.K. Meyer.
Zinc (Zn) is an essential trace element in all living organisms, but is toxic in excess. Several plant species are able to accumulate Zn at extraordinarily high concentrations in the leaf epidermis without showing any toxicity symptoms. However, the molecular mechanisms of this phenomenon are still poorly understood. A state-of-the-art quantitative 2D liquid chromatography/tandem mass spectrometry (2D-LC-MS/MS) proteomics approach was used to investigate the abundance of proteins involved in Zn hyperaccumulation in leaf epidermal and mesophyll tissues of Noccaea caerulescens. Furthermore, the Zn speciation in planta was analyzed by a size-exclusion chromatography/inductively coupled plasma mass spectrometer (SEC-ICP-MS) method, in order to identify the Zn-binding ligands and mechanisms responsible for Zn hyperaccumulation. Epidermal cells have an increased capability to cope with the oxidative stress that results from excess Zn, as indicated by a higher abundance of glutathione S-transferase proteins. A Zn importer of the ZIP family was more abundant in the epidermal tissue than in the mesophyll tissue, but the vacuolar Zn transporter MTP1 was equally distributed. Almost all of the Zn located in the mesophyll was stored as Zn-nicotianamine complexes. In contrast, a much lower proportion of the Zn was found as Zn-nicotianamine complexes in the epidermis. However, these cells have higher concentrations of malate and citrate, and these organic acids are probably responsible for complexation of most epidermal Zn. Here we provide evidence for a cell type-specific adaptation to excess Zn conditions and an increased ability to transport Zn into the epidermal vacuoles.


Neuroprotective effects of berberine in animal models of Alzheimer's disease: a systematic review of pre-clinical studies.
Berberine is an isoquinoline alkaloid extracted from various Berberis species which is widely used in East Asia for a wide range of symptoms. Recently, neuroprotective effects of berberine in Alzheimer's disease (AD) animal models are being extensively reported. So far, no clinical trial has been carried out on the neuroprotective effects of berberine. However, a review of the experimental data is needed before choosing berberine as a candidate drug for clinical experiments. We conducted a systematic review on AD rodent models to analyze the drug effects with minimal selection bias. Five online literature databases were searched to find publications reporting studies of the effect of berberine treatment on animal models of AD. Up to March 2018, 15 papers were identified to describe the efficacy of berberine. The included 15 articles met our inclusion criteria with different quality ranging from 3 to 5. We analyzed data extracted from full texts with regard to pharmacological effects and potential anti-Alzheimer's properties. Our analysis revealed that in multiple memory defects animal models, berberine showed significant memory-improving activities with multiple mechanisms, such as anti-inflammation, anti-oxidative stress, cholinesterase (ChE) inhibition and anti-amyloid effects. AD is likely to be a complex disease driven by multiple factors. Yet, many therapeutic strategies based on lowering β-amyloid have failed in clinical trials. This suggest that the threapy should not base on a single cause of Alzheimer's disease but rather a number of different pathways that lead to the disease. Overall we think that berberine can be a promising multipotent agent to combat Alzheimer's disease.


ISSFAL Official Statement Number 6: The importance of measuring blood omega-3 long chain polyunsaturated fatty acid levels in research.
A statement on measuring blood omega-3 long chain polyunsaturated fatty acid levels was developed and edited based on input from ISSFAL members and accepted by vote of the ISSFAL Board of Directors. Summary of Statement: Omega-3 long chain polyunsaturated fatty acid (n-3 LCPUFA) levels at baseline and post-intervention should be assessed and reported in future research to evaluate the efficacy of n-3 LCPUFA supplementation: b ecause; 1. there are numerous factors that affect n-3 LCPUFA levels in humans as described in the systematic literature review [1]; 2. assessing intake of n-3 LCPUFA from the diet and/or supplements is not sufficient to accurately determine n-3 LCPUFA levels in humans; 3. some studies do not provide sufficient doses of n-3 LCPUFA to produce a significant impact on bloodstream/organ content and there is substantial variability in the uptake of n-3 LPCUFA into tissues between individuals. In secondary analyses, clinical trials should consider the influence of fatty acid status (baseline, endpoint and change from baseline to endpoint) on the outcome variables.


Cofactor-mediated conformational control in the bifunctional kinase/RNase Ire1.
Ire1 is a signal transduction protein in the endoplasmic reticulum (ER) membrane that serves to adjust the protein-folding capacity of the ER according to the needs of the cell. Ire1 signals, in a transcriptional program, the unfolded protein response (UPR) via the coordinated action of its protein kinase and RNase domains. In this study, we investigated how the binding of cofactors to the kinase domain of Ire1 modulates its RNase activity. Our results suggest that the kinase domain of Ire1 initially binds cofactors without activation of the RNase domain. RNase is activated upon a subsequent conformational rearrangement of Ire1 governed by the chemical properties of bound cofactors. The conformational step can be selectively inhibited by chemical perturbations of cofactors. Substitution of a single oxygen atom in the terminal β-phosphate group of a potent cofactor ADP by sulfur results in ADPβS, a cofactor that binds to Ire1 as well as to ADP but does not activate RNase. RNase activity can be rescued by thiophilic metal ions such as Mn2+ and Cd2+, revealing a functional metal ion-phosphate interaction which controls the conformation and RNase activity of the Ire1 ADP complex. Mutagenesis of the kinase domain suggests that this rearrangement involves movement of the αC-helix, which is generally conserved among protein kinases. Using X-ray crystallography, we show that oligomerization of Ire1 is sufficient for placing the αC-helix in the active, cofactor-bound-like conformation, even in the absence of cofactors. Our structural and biochemical evidence converges on a model that the cofactor-induced conformational change in Ire1 is coupled to oligomerization of the receptor, which, in turn, activates RNase. The data reveal that cofactor-Ire1 interactions occur in two independent steps: binding of a cofactor to Ire1 and subsequent rearrangement of Ire1 resulting in its self-association. The pronounced allosteric effect of cofactors on protein-protein interactions involving Ire1's kinase domain suggests that protein kinases and pseudokinases encoded in metazoan genomes may use ATP pocket-binding ligands similarly to exert signaling roles other than phosphoryl transfer.


Treatment of essential trigeminal neuralgia with gamma knife surgery.
The authors present the long-term follow-up results (minimum 5 years) of patients with essential trigeminal neuralgia (TN) who were treated with gamma knife surgery (GKS). One hundred seven patients (61 females and 46 males) underwent GKS. The median follow up was time was 60 months (range 12-96 months). The target was the trigeminal root, and the maximum dose was 70 to 80 Gy. Repeated GKS was performed in 19 patients for recurrent pain, and the same dose was used. Initial successful results were achieved in 96% of patients, with complete pain relief in 80.4%. Relief was achieved after a median latency of 3 months (range 1 day-13 months). Gamma knife surgery failed in 4% of patients. Pain recurred in 25% of patients after a median latent interval of 36 months (6-94 months). The initial success rate after a second GKS was 89% and 58% of patients were pain free. Pain relapse occurred in only one patient in this group. Hypesthesia was observed in 20% of patients after the first GKS and in 32% after the second GKS. The median interval to hypaesthesia was 35 months (range 3-94 months) after one treatment and 21 months (range 1-72 months) after a second treatment. The initial success rate of pain relief was high and comparable to that reported in other studies. A higher than usual incidence of sensory impairment after GKS could be the long duration of follow-up study and due to the detailed neurological examination.


Ultrasound diagnosis of peroneal tendon tears. A surgical correlation.
Musculoskeletal ultrasound is an established diagnostic technique for the assessment of tendon injuries. The purpose of the present study was to determine whether ultrasound is effective for evaluating peroneal tendon injuries, with surgical findings used as the standard of reference. Fifty-eight patients with a suspected peroneal tendon injury were prospectively evaluated with use of dynamic ultrasound. Twenty-five patients were found to have peroneal tendon tears and were managed operatively. Five patients with normal peroneal tendons on ultrasound examination also were managed operatively for other reasons and are included in the series as the peroneal tendons were inspected at the time of the procedure. Ultrasound and surgical criteria were used to grade the peroneal tendons on a scale from grade 0 (normal tendon) to grade III (tendon rupture). Of the sixty tendons that were evaluated operatively, twenty-five were found to be torn. The sensitivity, specificity, and accuracy of ultrasonography were 100%, 85%, and 90%, respectively. The use of dynamic ultrasound is effective for determining the presence or absence of a peroneal tendon tear and should be considered a first-line diagnostic tool.


Ocular perfusion pressure and choroidal blood flow in the rabbit.
To compare choroidal blood pressure versus flow relationships obtained by three different methods of changing the ocular perfusion pressure. Experiments were performed in pentobarbital-anesthetized rabbits with occluders on the aorta and inferior vena cava to control mean arterial pressure (MAP). The central ear artery was cannulated to measure MAP. Two 23-gauge needles were inserted through the pars plana into the vitreous: one connected to a saline-filled syringe to vary the ocular volume and the other to a pressure transducer to measure intraocular pressure (IOP). Choroidal perfusion was measured by laser-Doppler flowmetry with the probe in the vitreous over the posterior pole. In group 1 (n = 15), the MAP was varied while holding the IOP at 10, 15, 20, 25 and 30 mm Hg. In group 2 (n = 19), the IOP was increased while holding the MAP at 80, 70, 60, 50, 40, 30 and 20 mm Hg. In group 3 (n = 21), the MAP was varied without controlling the IOP. Group 1 baseline choroidal flows were similar at the five IOPs. When the flow was plotted against MAP, the curves diverged and extrapolated to intersect the pressure axis when the MAP equaled the set IOP. Group 2 baseline flows were similar at MAPs greater than 40 mm Hg. When the flow was plotted against the IOP, the curves diverged and intersected the pressure axis when the IOP equaled the MAP. In both groups, plotting the flow against the perfusion pressure (i.e., MAP minus IOP) collapsed the data points into single curves. Choroidal autoregulation occurred in all three groups; however, the low end of the autoregulatory perfusion pressure range was approximately 50 mm Hg in group 1, approximately 40 mm Hg in group 2, and approximately 30 mm Hg in group 3. The results show that the effective choroidal perfusion pressure gradient equals the MAP minus the IOP, and that choroidal autoregulation is most effective when the MAP varies and IOP is not controlled.


Survival among HIV-infected and HIV-uninfected individuals with common non-AIDS-defining cancers.
Non-AIDS-defining cancers increasingly contribute to mortality among human immunodeficiency virus (HIV)-infected individuals. However, few studies have compared cancer prognosis by HIV status with adjustment for risk factors. We conducted a cohort study of HIV-infected and HIV-uninfected adults in Kaiser Permanente California during 1996 to 2011, following subjects diagnosed with Hodgkin lymphoma or anal, prostate, colorectal, or lung cancers. We used Kaplan-Meier curves and Cox regression to assess cancer-related mortality within 5 years, comparing HIV-infected with HIV-uninfected subjects. Adjusted models included age, race/ethnicity, sex, cancer stage, cancer treatment, and smoking. Among HIV-infected and HIV-uninfected subjects, there were 68 and 51 cases of Hodgkin lymphoma, 120 and 28 of anal cancer, 150 and 2,050 of prostate cancer, 53 and 646 of colorectal cancer, and 80 and 507 of lung cancer, respectively. Five-year cancer-related survival was reduced for HIV-infected compared with HIV-uninfected subjects, reaching statistical significance for lung cancer (10% vs. 19%, P = 0.002) but not Hodgkin lymphoma (83% vs. 89%, P = 0.40) or anal (64% vs. 74%, P = 0.38), prostate (86% vs. 92%, P = 0.074), or colorectal cancers (49% vs. 58%, P = 0.55). Adjusted results were similar, with lung cancer [HR, 1.3; 95% confidence interval (CI), 1.0-1.7] and prostate cancer (HR, 2.1; 95% CI, 1.1-4.1) reaching significance. Cancer-related mortality was higher among HIV-infected compared with HIV-uninfected individuals for prostate and lung cancers, but not Hodgkin lymphoma, anal cancer, or colorectal cancer. Our findings emphasize the need for a focus on prevention, early detection, and adequate treatment of cancer among HIV-infected individuals.


Chaos-assisted tunneling in a deformed microcavity laser.
We investigate the impact of local dynamics on chaos-assisted tunneling in a highly deformed microcavity whose classical ray dynamics exhibits a small measure of trapezoidal-shaped orbit (TSO) stability islands in a main chaotic sea. These two classically completely decomposed regions in phase space can support resonance modes of their own respectively. Using numerical ray and wave analyses, we show that the emission characteristics of the TSO resonance mode are determined by local ray dynamics near TSO islands. The emission characteristics of the other high-Q resonance modes, on the other hand, are governed by usual ray-wave correspondence. We experimentally demonstrate that the TSO emission mode can be lased without selective excitations by devising a half-moon shaped highly deformed cavity. And we also show that the emission characteristics of the TSO lasing modes are well explained by numerical ray and wave analyses.


The association between dietary intake of folate and physical activity with psychological dimensions of depressive symptoms among students from Iran.
Depression in students is a major public health problem. Although several risk factors associated with depression have been identified, the cause of depression is still not clear. Several studies have demonstrated that physical activity and nutrient intake, such as increased levels of B vitamins in serum, decrease symptoms of depression. The aim of this study was to investigate the association between physical activity and dietary intake of vitamins B₆, B₉, and B₁₂ and symptoms of depression among postgraduate students. The results of this study suggest that intake of vitamin B9 may modulate the total score of Center for Epidemiological Studies Depression Scale (CES-D) and two subscales of the CES-D including depressive affect and interpersonal difficulties. This study also showed that moderate/high levels of physical activity were inversely and significantly associated with symptoms of depression (total scores) and three subscales of the CES-D including depressive affect, positive affect, and somatic complaints.


The Roles of Type 2 Cytotoxic T Cells in Inflammation, Tissue Remodeling, and Prostaglandin (PG) D2 Production Are Attenuated by PGD2 Receptor 2 Antagonism.
Human type 2 cytotoxic T (Tc2) cells are enriched in severe eosinophilic asthma and can contribute to airway eosinophilia. PGD2 and its receptor PGD2 receptor 2 (DP2) play important roles in Tc2 cell activation, including migration, cytokine production, and survival. In this study, we revealed novel, to our knowledge, functions of the PGD2/DP2 axis in Tc2 cells to induce tissue-remodeling effects and IgE-independent PGD2 autocrine production. PGD2 upregulated the expression of tissue-remodeling genes in Tc2 cells that enhanced the fibroblast proliferation and protein production required for tissue repair and myofibroblast differentiation. PGD2 stimulated Tc2 cells to produce PGD2 using the routine PGD2 synthesis pathway, which also contributed to TCR-dependent PGD2 production in Tc2 cells. Using fevipiprant, a specific DP2 antagonist, we demonstrated that competitive inhibition of DP2 not only completely blocked the cell migration, adhesion, proinflammatory cytokine production, and survival of Tc2 cells triggered by PGD2 but also attenuated the tissue-remodeling effects and autocrine/paracrine PGD2 production in Tc2 induced by PGD2 and other stimulators. These findings further confirmed the anti-inflammatory effect of fevipiprant and provided a better understanding of the role of Tc2 cells in the pathogenesis of asthma.


An update on pharmacotherapies in active development for the management of cancer regimen-associated oral mucositis.
Introduction: Oral mucositis (OM) is a common toxicity of cytotoxic cancer regimens and remains one of the most painful, injurious, and treatment-disrupting side effects of radiation and ablative therapy. Despite its frequency and impact, approved definitive preventive or therapeutic options remain limited.Areas covered: This review focuses on mechanistically active small molecules and biologicals that are under clinical development for the prevention of oral mucositis. The authors have excluded those compounds and devices for which their indication is limited to symptoms management.Expert opinion: OM remains a significant unmet clinical need. The commercial opportunities for an effective treatment have been characterized as a global market of $1 billion (US). The formulations of drugs under development vary considerably but share some several commonalities in their development scheme. All new agents are given prophylactically and are being evaluated in patients treated with concomitant chemoradiation therapy for head and neck cancer. The primary efficacy outcome for most trials is dependent on the assessment of mucositis using the scoring scale established years ago by the World Health Organization. The development activity for OM is robust with a diverse range of agents. New drug applications for effective therapeutic options for OM should be ready for review within the next few years.


Bili-Uéré: A Chimpanzee Behavioural Realm in Northern Democratic Republic of Congo.
To improve our understanding of the evolutionary origins of culture and technology in humans, it is vital that we document the full extent of behavioural diversity in our great ape relatives. About half of the world's remaining chimpanzees (Pan spp.) live in the Democratic Republic of Congo (DRC), yet until now we have known almost nothing about their behaviour. Here we describe the insect-related tool technology of Bili-Uéré chimpanzees (Pan troglodytes schweinfurthii) inhabiting an area of at least a 50,000-km2 area in northern DRC, as well as their percussive technology associated with food processing. Over a 12-year period, we documented chimpanzee tools and artefacts at 20 survey areas and gathered data on dung, feeding remains and sleeping nests. We describe a new chimpanzee tool kit: long probes used to harvest epigaeic driver ants (Dorylus spp.), short probes used to extract ponerine ants and the arboreal nests of stingless bees, wands to dip for D. kohli and stout digging sticks used to access underground meliponine bee nests. Epigaeic Dorylus tools were significantly longer than the other tool types, and D. kohli tools were significantly thinner. Tools classified as terrestrial honey-digging sticks were a significant predictor for brushed and blunted tool ends, consistent with their presumed use. We describe two potential new tool types, an "ant scoop" and a "fruit hammer." We document an extensive percussive technology used to process termite mounds of Cubitermes sp. and Thoracotermes macrothorax and hard-shelled fruits such as Strychnos, along with evidence of the pounding open of African giant snails and tortoises. We encountered some geographic variation in behaviour: we found honey-digging tools, long driver ant probes and fruit-pounding sites only to the north of the Uele River; there were more epigaeic Dorylus tools to the north and more ponerine ant tools to the south. We found no evidence of termite-fishing, despite the availability of Macrotermes muelleri mounds throughout the region. This lack of evidence is consistent with the results of dung washes, which revealed a substantial proportion of driver ants, but no evidence of Macrotermes or other termites. Our results allow us to describe a new chimpanzee behavioural complex, characterised by a general similarity of multiple behaviours across a large, ecologically diverse region but with subtle differences in prey choice and techniques. We propose that this widespread and related suite of behaviours be referred to as the Bili-Uéré Chimpanzee Behavioural Realm. Possible explanations for this pattern are a recent chimpanzee expansion across the region and the interconnectedness of this population across at least the entirety of northern DRC.


[Evaluation of group and individual strategies in a diabetes education program].
To compare the effectiveness of individual and group strategies in a diabetes education program. A total of 104 type-2 diabetes outpatients enrolled in an education program of a teaching hospital in Belo Horizonte, Southeastern Brazil, were randomly selected and assigned to two different education strategies: group education (54 subjects) and individual education (50 subjects). Group education comprised three monthly sessions, which involved play and interactive dynamics. In parallel, a second group received individual education. Subjects were follow up for six months during 2006 and they were evaluated using specific questionnaires: knowledge of diabetes, psychological attitudes, change in behavior, quality of life. Clinical evaluation was performed at baseline, three and six months of intervention. Mean age was 60.6 years. The results of group and individual education were similar in the assessment tests of attitude, change of behavior and quality of life. A reduction in HbA1c levels was seen in both groups, but a statistically significant difference (p=0.012) was found only in the group education. Both strategies of diabetes education were effective, however, group education was more effective than individual education for blood glucose control.


A PC-1 amino acid variant (K121Q) is associated with faster progression of renal disease in patients with type 1 diabetes and albuminuria.
Insulin resistance characterizes type 1 diabetes in patients with albuminuria. A PC-1 glycoprotein amino acid variant, K121Q, is associated with insulin resistance. We examined the impact of the PC-1 K121Q variant on the rate of decline of the glomerular filtration rate (GFR) by creatinine clearance derived from the Cockroft-Gault formula in 77 type 1 diabetic patients with albuminuria who were followed for an average of 6.5 years (range 2.5-15). Patients carrying the Q allele (n = 22; 20 with KQ and 2 with QQ genotypes) had a faster GFR decline than those patients with the KK genotype (n = 55) (median 7.2 vs. 3.7 ml x min(-1) x year(-1); range 0.16 to 16.6 vs. -3.8 to 16.0 ml x min(-1) x year(-1); P < 0.001). Significantly more patients carrying the Q allele belonged to the highest tertile of GFR decline (odds ratio = 5.7, 95% CI 4.1-7.2, P = 0.02). Levels of blood pressure, HbA1c, and albuminuria were comparable in the two genotype groups. Albuminuria (P = 0.001), mean blood pressure (P = 0.046), and PC-1 genotype (P = 0.036) independently correlated with GFR decline. Because all patients were receiving antihypertensive treatment, the faster GFR decline in the patients carrying the Q allele could be the result of reduced sensitivity to the renoprotective effect of antihypertensive therapy. PC-1 genotyping identifies type 1 diabetic patients with a faster progression of diabetic nephropathy.


Effect of a Lens Protein in Low-Temperature Culture of Novel Immortalized Human Lens Epithelial Cells (iHLEC-NY2).
The prevalence of nuclear cataracts was observed to be significantly higher among residents of tropical and subtropical regions compared to those of temperate and subarctic regions. We hypothesized that elevated environmental temperatures may pose a risk of nuclear cataract development. The results of our in silico simulation revealed that in temperate and tropical regions, the human lens temperature ranges from 35.0 °C to 37.5 °C depending on the environmental temperature. The medium temperature changes during the replacement regularly in the cell culture experiment were carefully monitored using a sensor connected to a thermometer and showed a decrease of 1.9 °C, 3.0 °C, 1.7 °C, and 0.1 °C, after 5 min when setting the temperature of the heat plate device at 35.0 °C, 37.5 °C, 40.0 °C, and 42.5 °C, respectively. In the newly created immortalized human lens epithelial cell line clone NY2 (iHLEC-NY2), the amounts of RNA synthesis of αA crystallin, protein expression, and amyloid β (Aβ)1-40 secreted into the medium were increased at the culture temperature of 37.5 °C compared to 35.0 °C. In short-term culture experiments, the secretion of Aβ1-40 observed in cataracts was increased at 37.5 °C compared to 35.0 °C, suggesting that the long-term exposure to a high-temperature environment may increase the risk of cataracts.


Semantic computational analysis of anticoagulation use in atrial fibrillation from real world data.
Atrial fibrillation (AF) is the most common arrhythmia and significantly increases stroke risk. This risk is effectively managed by oral anticoagulation. Recent studies using national registry data indicate increased use of anticoagulation resulting from changes in guidelines and the availability of newer drugs. The aim of this study is to develop and validate an open source risk scoring pipeline for free-text electronic health record data using natural language processing. AF patients discharged from 1st January 2011 to 1st October 2017 were identified from discharge summaries (N = 10,030, 64.6% male, average age 75.3 ± 12.3 years). A natural language processing pipeline was developed to identify risk factors in clinical text and calculate risk for ischaemic stroke (CHA2DS2-VASc) and bleeding (HAS-BLED). Scores were validated vs two independent experts for 40 patients. Automatic risk scores were in strong agreement with the two independent experts for CHA2DS2-VASc (average kappa 0.78 vs experts, compared to 0.85 between experts). Agreement was lower for HAS-BLED (average kappa 0.54 vs experts, compared to 0.74 between experts). In high-risk patients (CHA2DS2-VASc ≥2) OAC use has increased significantly over the last 7 years, driven by the availability of DOACs and the transitioning of patients from AP medication alone to OAC. Factors independently associated with OAC use included components of the CHA2DS2-VASc and HAS-BLED scores as well as discharging specialty and frailty. OAC use was highest in patients discharged under cardiology (69%). Electronic health record text can be used for automatic calculation of clinical risk scores at scale. Open source tools are available today for this task but require further validation. Analysis of routinely collected EHR data can replicate findings from large-scale curated registries.


Structure of a peptide inhibitor bound to the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase.
The structure of a 20-amino acid peptide inhibitor bound to the catalytic subunit of cyclic AMP-dependent protein kinase, and its interactions with the enzyme, are described. The x-ray crystal structure of the complex is the basis of the analysis. The peptide inhibitor, derived from a naturally occurring heat-stable protein kinase inhibitor, contains an amphipathic helix that is followed by a turn and an extended conformation. The extended region occupies the cleft between the two lobes of the enzyme and contains a five-residue consensus recognition sequence common to all substrates and peptide inhibitors of the catalytic subunit. The helical portion of the peptide binds to a hydrophobic groove and conveys high affinity binding. Loops from both domains converge at the active site and contribute to a network of conserved residues at the sites of magnesium adenosine triphosphate binding and catalysis. Amino acids associated with peptide recognition, nonconserved, extend over a large surface area.


Changes in physicians' attitudes toward AIDS during residency training: a longitudinal study of medical school graduates.
Understanding the impact of training on the development of physicians' attitudes toward AIDS is important to furthering our knowledge of the mechanisms through which socialization affects professional outlook, as well as promoting an adequate supply of providers to treat people with AIDS (PWAs). This prospective panel study collected data on 383 physicians at two critical stages: as fourth-year medical students and as third-year residents. Aspects of residency training (e.g., residents' morale and positive faculty role models) were the most powerful predictors of increase in willingness to treat PWAs. Decline in willingness was primarily a product of negative social attitudes-homophobia and IVDU-phobia (aversion to intravenous drug users). Cynicism toward patient care acted as a trigger, activating the negative effects of IVDU-phobia; having an acquaintance who is HIV positive mediated the negative impact of homophobia. Notably, cynicism was associated with basic aspects of training (specific characteristics of the faculty and of the educational milieu). The findings support a view of socialization as a pervasive process implicating intrinsic aspects of training and having an impact on a broad spectrum of outlooks. Accordingly, interventions must address structural characteristics that transcend AIDS-specific concerns.


Theory and design of periodic couplers.
The theory of periodic couplers is examined from the point of view of the reciprocity theorem and a modified Born scattering approach. Design equations for several coupler configurations are presented. Efficiency and aperture size calculations are compared with previously published data for grating and Bragg couplers.


Roles of gravitational cues and efference copy signals in the rotational updating of memory saccades.
Primates are able to localize a briefly flashed target despite intervening movements of the eyes, head, or body. This ability, often referred to as updating, requires extraretinal signals related to the intervening movement. With active roll rotations of the head from an upright position it has been shown that the updating mechanism is 3-dimensional, robust, and geometrically sophisticated. Here we examine whether such a rotational updating mechanism operates during passive motion both with and without inertial cues about head/body position in space. Subjects were rotated from either an upright or supine position, about a nasal-occipital axis, briefly shown a world-fixed target, rotated back to their original position, and then asked to saccade to the remembered target location. Using this paradigm, we tested subjects' abilities to update from various tilt angles (0, +/-30, +/-45, +/-90 degrees), to 8 target directions and 2 target eccentricities. In the upright condition, subjects accurately updated the remembered locations from all tilt angles independent of target direction or eccentricity. Slopes of directional errors versus tilt angle ranged from -0.011 to 0.15, and were significantly different from a slope of 1 (no compensation for head-in-space roll) and a slope of 0.9 (no compensation for eye-in-space roll). Because the eyes, head, and body were fixed throughout these passive movements, subjects could not use efference copies or neck proprioceptive cues to assess the amount of tilt, suggesting that vestibular signals and/or body proprioceptive cues suffice for updating. In the supine condition, where gravitational signals could not contribute, slopes ranged from 0.60 to 0.82, indicating poor updating performance. Thus information specifying the body's orientation relative to gravity is critical for maintaining spatial constancy and for distinguishing body-fixed versus world-fixed reference frames.


Aortopulmonary fistula caused by an infected thoracic aortic false aneurysm rupturing after endovascular stent placement.
We report a case of 74-year-old man presenting with a rupture of a thoracic aortic false aneurysm after undergoing conventional total arch replacement for aortic arch aneurysm (62 mm) and endovascular stent placement for descending aortic aneurysm (70 mm). His chief complaints at the present admission were fever and sensation of dyspnea and we put him on a course of antibiotics for stent graft infection. However he died of massive hemoptysis. From a standpoint of autopsy findings, a thoracic aortic false aneurysm formed at the just proximal landing zone owing to type Ia endoleak, and simultaneously stent graft infection lead to make fistula formation between the false aneurysm and the lung. We examined ourselves that stent graft infection and aortopulmonary fistula caused by an infected thoracic aortic false aneurysm rupturing into the lung should be promptly treated such as complete removal of the stent and another revascularization in a reasonable period of time except if there are complications such as comorbid1ities or withholding of consent. We experienced and reported one rare case associated with a rupture of thoracic aortic false aneurysm caused by stent graft infection and the fistulization between the lung and the stent graft.


Patient Presentation Trends at 15 Mass-Gathering Events in South Australia.
IntroductionMass gatherings are complex events that present a unique set of challenges to attendees' health and well-being. There are numerous factors that influence the number and type of injuries and illnesses that occur at these events, including weather, event and venue type, and crowd demographics and behavior.ProblemWhile the impact of some factors, such as weather conditions and the availability of alcohol, on patient presentations at mass gatherings have been described previously, the influence of many other variables, including crowd demographics, crowd behavior, and event type, is poorly understood. Furthermore, a large number of studies reporting on the influence of these variables on patient presentations are based on anecdotal evidence at a single mass-gathering event. Data were collected by trained fieldworkers at 15 mass gatherings in South Australia and included event characteristics, crowd demographics, and weather. De-identified patient records were obtained from on-site health care providers. Data analysis included the calculation of patient proportions in each variable category, as well as the total number of patient presentations per event and the patient presentation rate (PPR). The total number of expected attendees at the 15 mass gatherings was 303,500, of which 146 presented to on-site health care services. The majority of patient presentations occurred at events with a mean temperature between 20°C and 25°C. The PPR was more than double at events with a predominantly male crowd compared to events with a more equal sex distribution. Almost 90.0% of patient presentations occurred at events where alcohol was available. The results of the study suggest that several weather, crowd, and event variables influence the type and number of patient presentations observed at mass-gathering events. Given that the study sample size did not allow for these interactions to be quantified, further research is warranted to investigate the relationships between alcohol availability, crowd demographics, crowd mobility, venue design, and injuries and illnesses.Anikeeva O, Arbon P, Zeitz K, Bottema M, Lund A, Turris S, Steenkamp M. Patient presentation trends at 15 mass-gathering events in South Australia. Prehosp Disaster Med. 2018;33(4):368-374.


Non-Parametric Blur Map Regression for Depth of Field Extension.
Real camera systems have a limited depth of field (DOF) which may cause an image to be degraded due to visible misfocus or too shallow DOF. In this paper, we present a blind deblurring pipeline able to restore such images by slightly extending their DOF and recovering sharpness in regions slightly out of focus. To address this severely ill-posed problem, our algorithm relies first on the estimation of the spatially varying defocus blur. Drawing on local frequency image features, a machine learning approach based on the recently introduced regression tree fields is used to train a model able to regress a coherent defocus blur map of the image, labeling each pixel by the scale of a defocus point spread function. A non-blind spatially varying deblurring algorithm is then used to properly extend the DOF of the image. The good performance of our algorithm is assessed both quantitatively, using realistic ground truth data obtained with a novel approach based on a plenoptic camera, and qualitatively with real images.


Klf4 is a transcription factor required for establishing the barrier function of the skin.
Located at the interface between body and environment, the epidermis must protect the body against toxic agents and dehydration, and protect itself against physical and mechanical stresses. Acquired just before birth and at the last stage of epidermal differentiation, the skin's proteinaceous/lipid barrier creates a surface seal essential for protecting animals against microbial infections and dehydration. We show here that Kruppel-like factor 4 (Klf4, encoded by the gene Klf4), highly expressed in the differentiating layers of epidermis, is both vital to and selective for barrier acquisition. Klf4-/- mice die shortly after birth due to loss of skin barrier function, as measured by penetration of external dyes and rapid loss of body fluids. The defect was not corrected by grafting of Klf4-/- skin onto nude mice. Loss of the barrier occurs without morphological and biochemical alterations to the well-known structural features of epidermis that are essential for mechanical integrity. Instead, late-stage differentiation structures are selectively perturbed, including the cornified envelope, a likely scaffold for lipid organization. Using suppressive subtractive hybridization, we identified three transcripts encoding cornified envelope proteins with altered expression in the absence of Klf4. Sprr2a is one, and is the only epidermal gene whose promoter is known to possess a functional Klf4 binding site. Our studies provide new insights into transcriptional governance of barrier function, and pave the way for unravelling the molecular events that orchestrate this essential process.


Shared decision making for prostate cancer screening: the results of a combined analysis of two practice-based randomized controlled trials.
Professional societies recommend shared decision making (SDM) for prostate cancer screening, however, most efforts have promoted informed rather than shared decision making. The objective of this study is to 1) examine the effects of a prostate cancer screening intervention to promote SDM and 2) determine whether framing prostate information in the context of other clearly beneficial men's health services affects decisions. We conducted two separate randomized controlled trials of the same prostate cancer intervention (with or without additional information on more clearly beneficial men's health services). For each trial, we enrolled a convenience sample of 2 internal medicine practices, and their interested physicians and male patients with no prior history of prostate cancer (for a total of 4 practices, 28 physicians, and 128 men across trials). Within each practice site, we randomized men to either 1) a video-based decision aid and researcher-led coaching session or 2) a highway safety video. Physicians at each site received a 1-hour educational session on prostate cancer and SDM. To assess intervention effects, we measured key components of SDM, intent to be screened, and actual screening. After finding that results did not vary by trial, we combined data across sites, adjusting for the random effects of both practice and physician. Compared to an attention control, our prostate cancer screening intervention increased men's perceptions that screening is a decision (absolute difference +41%; 95% CI 25 to 57%) and men's knowledge about prostate cancer screening (absolute difference +34%; 95% CI 19% to 50%), but had no effect on men's self-reported participation in shared decisions or their participation at their preferred level. Overall, the intervention decreased screening intent (absolute difference -34%; 95% CI -50% to -18%) and actual screening rates (absolute difference -22%; 95% CI -38 to -7%) with no difference in effect by frame. SDM interventions can increase men's knowledge, alter their perceptions of prostate cancer screening, and reduce actual screening. However, they may not guarantee an increase in shared decisions. #NCT00630188.


Prevention of central venous catheter bloodstream infections.
The majority of nosocomial bloodstream infections in critically ill patients originate from an infected central venous catheter (CVC). Catheter-related bloodstream infections (CRBSIs) cause significant morbidity and mortality and increase the cost of care. The most frequent causative organisms for CRBSI are coagulase-negative staphylococci (CoNSs), Staphylococcus aureus, enterococci, and Candida species. The path to infection frequently includes migration of skin organisms at the insertion site into the cutaneous catheter tract, resulting in microbial colonization of the catheter tip and formation of biofilm. Evidence-based strategies for the prevention of CRBSI include behavioral and educational interventions, effective skin antisepsis coupled with maximum barrier precautions, the use of antiseptic dressings, and the use of antiseptic or antibiotic impregnated catheters. Achieving and maintaining very low rates of CRBSI requires a multidisciplinary approach involving the entire health care team, the use of novel technologies in patients with the highest risk of CRBSI, and frequent reeducation of staff.


The DNA-binding polycomb group protein pleiohomeotic mediates silencing of a Drosophila homeotic gene.
Polycomb group (PcG) proteins repress homeotic genes in cells where these genes must remain inactive during development. This repression requires cis-acting silencers, also called PcG response elements. Currently, these silencers are ill-defined sequences and it is not known how PcG proteins associate with DNA. Here, we show that the Drosophila PcG protein Pleiohomeotic binds to specific sites in a silencer of the homeotic gene Ultrabithorax. In an Ultrabithorax reporter gene, point mutations in these Pleiohomeotic binding sites abolish PcG repression in vivo. Hence, DNA-bound Pleiohomeotic protein may function in the recruitment of other non-DNA-binding PcG proteins to homeotic gene silencers.


Effect of diuretics on cardiopulmonary performance in severe chronic airflow obstruction. A controlled clinical trial.
In a randomized, controlled trial, ten patients with pulmonary heart disease due to severe chronic airflow obstruction were stratified into two groups: group 1 had clinical features of congestive heart failure during respiratory failure and were regularly receiving diuretics; group 2 had no such clinical features and were not receiving diuretics. In group 1, when placebo was substituted for diuretics, pulmonary edema developed in three patients; exercise performance and ventricular function of the remaining two patients deteriorated. In group 2, there was no difference in exercise tolerance or ventricular function between placebo and diuretic therapy. The clinical deterioration in group 1 was related to abnormal left ventricular function. Thus, diuretics benefit only patients who have clinical features of congestive heart failure. In patients with isolated abnormal right ventricular function, diuretics may be harmful.


No evidence of short-term exchange of meat for sex among chimpanzees.
The meat-for-sex hypothesis posits that male chimpanzees (Pan troglodytes) trade meat with estrous females in exchange for short-term mating access. This notion is widely cited in the anthropological literature and has been used to construct scenarios about human evolution. Here we review the theoretical and empirical basis for the meat-for-sex hypothesis. We argue that chimpanzee behavioral ecology does not favor the evolution of such exchanges because 1) female chimpanzees show low mate selectivity and require little or no material incentive to mate, violating existing models of commodity exchange; and 2) meat-for-sex exchanges are unlikely to provide reproductive benefits to either partner. We also present new analyses of 28 years of data from two East African chimpanzee study sites (Gombe National Park, Tanzania; Kanyawara, Kibale National Park, Uganda) and discuss the results of previously published studies. In at least three chimpanzee communities, 1) the presence of sexually receptive females did not increase hunting probability, 2) males did not share preferentially with sexually receptive females, and 3) sharing with females did not increase a male's short-term mating success. We acknowledge that systematic meat sharing by male chimpanzees in expectation of, or in return for, immediate copulations might be discovered in future studies. However, current data indicate that such exchanges are so rare, and so different in nature from exchanges among humans, that with respect to chimpanzees, sexual bartering in humans should be regarded as a derived trait with no known antecedents in the behavior of wild chimpanzees.


Aetiology of acute respiratory infection in preschool children requiring hospitalisation in Europe-results from the PED-MERMAIDS multicentre case-control study.
Both pathogenic bacteria and viruses are frequently detected in the nasopharynx (NP) of children in the absence of acute respiratory infection (ARI) symptoms. The aim of this study was to estimate the aetiological fractions for ARI hospitalisation in children for respiratory syncytial virus (RSV) and influenza virus and to determine whether detection of specific respiratory pathogens on NP samples was associated with ARI hospitalisation. 349 children up to 5 years of age hospitalised for ARI (following a symptom-based case definition) and 306 hospital controls were prospectively enrolled in 16 centres across seven European Union countries between 2016 and 2019. Admission day NP swabs were analysed by multiplex PCR for 25 targets. RSV was the leading single cause of ARI hospitalisations, with an overall population attributable fraction (PAF) of 33.4% and high seasonality as well as preponderance in younger children. Detection of RSV on NP swabs was strongly associated with ARI hospitalisation (OR adjusted for age and season: 20.6, 95% CI: 9.4 to 45.3). Detection of three other viral pathogens showed strong associations with ARI hospitalisation: influenza viruses had an adjusted OR of 6.1 (95% CI: 2.5 to 14.9), parainfluenza viruses (PIVs) an adjusted OR of 4.6 (95% CI: 1.8 to 11.3) and metapneumoviruses an adjusted OR of 4.5 (95% CI: 1.3 to 16.1). Influenza viruses had a PAF of 7.9%, PIVs of 6.5% and metapneumoviruses of 3.0%. In contrast, most other pathogens were found in similar proportions in cases and controls, including Streptococcus pneumoniae, which was weakly associated with case status, and endemic coronaviruses. RSV is the predominant cause of ARI hospitalisations in young children in Europe and its detection, as well as detection of influenza virus, PIV or metapneumovirus, on NP swabs can establish aetiology with high probability. PAFs for RSV and influenza virus are highly seasonal and age dependent.


Vacuole dynamics in growth cones: correlated EM and video observations.
The neuronal growth cone is a major site of surface membrane dynamics associated with uptake and release of materials, motility, and axon extension. Although intracellular membrane organelles are thought to mediate surface membrane addition and retrieval at the growth cone, membrane events are fleeting and therefore difficult to study directly. In an effort to capture transient interactions between intracellular membrane organelles and the plasmalemma at the growth cone, embryonic rat sympathetic neuron cultures were prepared for whole-mount electron microscopy (EM) by rapid freezing and freeze substitution. We identified a set of vacuole-like organelles (> or = 150 nm in diameter) that appeared to interact directly with the plasmalemma. In stereo-pair EM images the bounding membrane of some of these vacuoles had an orifice at sites where the organelle was adjoining the plasmalemma, suggesting that the organelle and surface membranes were confluent. Since this population of organelles could be labeled with cationized ferritin or HRP when added to living cultures just prior to freezing or chemical fixation, they were probably derived from the plasmalemma. Combined light microscopy and EM of individual growth cones showed that these same vacuoles had a conspicuous reverse shadowcast appearance in differential interference contrast images. Thus, we used real-time video microscopy to follow these organelles in living growth cones. Many of these vacuoles spontaneously appeared, remained visible for several minutes, and then disappeared. Reverse shadowcast vacuoles were formed at various sites throughout the growth cone, including surface membrane ruffles at the leading edge [P (peripheral)-domain] as well as quiescent and retracting regions at the growth cone base [C (central)-domain]. Vacuoles in the P-domain moved centripetally and rarely grew in size. In contrast, those in the C-domain exhibited Brownian-like movements and sometimes appeared to increase in size, raising the possibility that new membrane may be added to these organelles. Vacuoles within both the P- and C-domains shrank before rapidly disappearing, but rarely vesiculated, suggesting that they had fused with the plasmalemma. The results indicate that vacuoles are a highly dynamic population of organelles that directly communicate with the plasma membrane at the growth cone; they provide a major route of surface membrane uptake and may also play a role in membrane recycling.


[Metastatic small intestinal tumor associated with transitional cell carcinoma: a report of 2 cases and review of cases in Japan].
Transitional cell carcinoma (TCC) frequently metastasizes to lymph nodes, liver, lungs and bone. However, metastasis to the gastrointestinal tract is rare. We report two cases of bladder tumor which metastasized to the ileum. According to the literature, these are the 7th and 8th cases in Japan. Case 1: A 87-year-old man had a history of bladder tumor (TCC, grade 3, pT2bN0M0) and has transurethral resection of bladder tumor (TUR-BT) three times. Two months after the last TUR-BT, he was admitted with ileus. As computed tomography (CT) showed abdominal free air, our diagnosis was perforation of gastrointestinal tract. The patient received an operation which resected partial ileum. We found the elastic hard tumor in the ileum on the perforated lesion, which showed metastatic TCC in the ileum pathologicaly. Case 2 : A 53-year-old man visited our hospital with gross hematuria. Cystoscopy showed a non-papillary broad based tumor in the right wall of the bladder. CT showed a bladder tumor invaded into the prostate (pT4aN1M0), we performed total cyctectomy and ileal conduit after neo-adjuvant chemotherapy. During the operation, we found the tumor (2 cm in diameter) in the small intestine which was metastasized of bladder tumor.


Protein-bound polysaccharide-K (PSK) directly enhanced IgM production in the human B cell line BALL-1.
Protein-bound polysaccharide-K (PSK) prepared from the basidiomycete Coriolus versicolor has been used as a biological response modifier for the treatment of cancer patients. Many studies describing the immunomodulatory effects and direct anti-cancer effects of PSK have been reported. Most of studies describing the immunomodulatory effects focused on cellular immunity, although there were several studies which focused on humoral immunity where PSK was shown to be able to induce antibody production in vivo. However, even in these humoral immunity studies, it is thought that the enhancement of antibody production was due to the activation of cellular immunity. In this study, we investigated the direct effect of PSK on B cells and discovered that PSK was able to enhance IgM production in the human B cell line BALL-1. Furthermore, BALL-1 was shown to have the characteristic features of B-1a cells, which are independently involved in the primary immune response. These results show that there is a possibility that PSK directly acts on B cells and simultaneously enhances both humoral immunity and cellular immunity.


Cooperation between translating ribosomes and RNA polymerase in transcription elongation.
During transcription of protein-coding genes, bacterial RNA polymerase (RNAP) is closely followed by a ribosome that translates the newly synthesized transcript. Our in vivo measurements show that the overall elongation rate of transcription is tightly controlled by the rate of translation. Acceleration and deceleration of a ribosome result in corresponding changes in the speed of RNAP. Moreover, we found an inverse correlation between the number of rare codons in a gene, which delay ribosome progression, and the rate of transcription. The stimulating effect of a ribosome on RNAP is achieved by preventing its spontaneous backtracking, which enhances the pace and also facilitates readthrough of roadblocks in vivo. Such a cooperative mechanism ensures that the transcriptional yield is always adjusted to translational needs at different genes and under various growth conditions.


The use of automated prompting to facilitate handwashing in persons with dementia.
As the number of people living with dementia increases, occupational therapists are challenged with finding innovative, evidence-based ways to enable daily occupations. The use of computer technology is explored in this study as one potential intervention for this population. An automated prompting system was modified to provide both verbal and audiovisual prompts, and 8 participants with Standardized Mini-Mental State Examination (SMMSE) scores as low as 3/30 were followed over 60 trials to determine which prompting method was more effective in reducing caregiver interactions. Overall, the participants were able to complete more steps with the assistance of either automated prompt and required fewer caregiver interactions. Audiovisual prompting significantly reduced the number of caregiver interactions required. These results lend further support to the use of an automated prompting system but suggest that there are individual factors influencing the efficacy of the prompting mode, for which occupational therapists are well suited to assess and monitor.


Effects of Naltrexone on Large-Scale Network Interactions in Methamphetamine Use Disorder.
Naltrexone attenuates craving, and the subjective effects of methamphetamine and extended-release naltrexone (XR-NTX) reduces functional connectivity between regions of the striatum and limbic cortex. Naltrexone modulates neural activity at dopaminergic synapses; however, it is unclear whether naltrexone has an effect on large-scale brain networks. Functional networks interact to coordinate behavior, and as substance-use disorders are associated with an imbalance between reward and cognitive control networks, treatment approaches that target interactive brain systems underlying addiction may be a useful adjunct for behavioral therapies. The objective of this study was to examine the effect of XR-NTX on large-scale brain networks and to determine whether changes in network relationships attenuate drug use, craving, and addiction severity. Thirty-nine participants in or seeking treatment for methamphetamine-use disorder were enrolled in a clinical trial of XR-NTX between May 2013 and March 2015 (Clinicaltrials.gov NCT01822132). Functional magnetic resonance imaging (fMRI) and questionnaires were conducted before and after double-blinded randomization to a 4-week injection of XR-NTX or placebo. In the XR-NTX group, methamphetamine use was reduced along with a decrease in the coupling between executive control (ECN) and default mode (DMN) networks. As decoupling of ECN and DMN networks was associated with change in the severity of dependence, the results suggest that XR-NTX may modulate and enhance ECN attentional resources and suppress DMN self-referential and emotional processing. This study identifies the effect of naltrexone on changes in the intrinsic functional coupling of large-scale brain networks and provides a more systematic understanding of how large-scale networks interact to promote behavioral change in methamphetamine-use disorder.


Exploring the feasibility, sustainability and the benefits of the GrACE + GAIT exercise programme in the residential aged care setting.
The feasibility and benefits of a 24-week targeted progressive supervised resistance and weight-bearing exercise programme (Group Aged Care Exercise + GAIT (GrACE + GAIT)) in the residential aged care (RAC) setting was investigated as very little peer-reviewed research has been conducted in relation to exercise programmes of this duration in this cohort. A quasi-experimental study design consisting of two groups (control and exercise) explored a 24-week targeted progressive supervised resistance and weight-bearing exercise programme (GrACE + GAIT) in two RAC facilities in Northern New South Wales, Australia. A total of 42 adults consented to participate from a total of 68 eligible residents (61.7%). The primary outcome measures were feasibility and sustainability of the exercise programme via intervention uptake, session adherence, attrition, acceptability and adverse events. Secondary measures included gait speed and the spatio-temporal parameters of gait, handgrip muscle strength and sit to stand performance. Twenty-three residents participated in the exercise intervention (mean (SD) 85.4 (8.1) years, 15 females) and 19 in the control group (87.4 (6.6) years 13 females). Exercise adherence was 79.3%, with 65% of exercise participants attending ≥70% of the sessions; 100% of those originally enrolled completed the programme and strongly agreed with the programme acceptability. Zero exercise-related adverse events were reported. ANCOVA results indicated that post-intervention gait speed significantly increased (p < 0.001) with an 18.8% increase in gait speed (m/s). The GrACE + GAIT programme was shown to be feasible and significantly improve adults living in RAC facilities gait speed, handgrip strength and sit to stand performance. These results suggest that the GrACE + GAIT programme is suitable for use in the RAC sector and that it has the potential to reduce disability and improve function and quality of life of the residents.


Prophylactic efficacy of melatonin on cyclophosphamide-induced liver toxicity in mice.
The current study aimed to evaluate the protective effects of melatonin, a pineal secretory product, against hepatotoxicity induced by cyclophosphamide (CP) in mice. Mice were pretreated with melatonin intraperitoneally for 7 consecutive days before the administration of a single intraperitoneal dose of 200 mg/kg CP. 24 hr after CP administration, the mice were anesthetized, blood was then removed, and serum toxicity enzymes activities were evaluated. After the blood sampling, all animals were killed, livers were then removed, and histological studies were conducted. Serum toxicity marker enzymes were significantly increased after CP treatment but restored in melatonin pretreated groups. In addition, administration of CP induced necrotic hepatocyte with small crushed nuclei, portal space with severe inflammation, and hepatocytes surrounded by lymphocytic infiltration in hepatic tissues. However, melatonin effectively protected against CP-induced histopathological abnormalities in the liver tissues. Our results reveal that melatonin produces a potent hepatoprotective mechanism against CP. Therefore, melatonin could be a potent candidate to use concomitantly as a supplement agent against hepatotoxicity of CP for the patients undergoing chemotherapy.


Inequality in cataract blindness and services: moving beyond unidimensional analyses of social position.
Inequalities in cataract blindness are well known, but data are rarely disaggregated to explore the combined effects of a range of axes describing social disadvantage. We examined inequalities in cataract blindness and services at the intersection of three social axes. Three dichotomous social variables (sex (male/female); place of residence (urban/rural); literacy (literate/illiterate)) from cross-sectional national blindness surveys in Pakistan (2001-2004; n=16 507) and Nigeria (2005-2007; n=13 591) were used to construct eight subgroups, with disadvantaged subgroups selected a priori (ie, women, rural dwellers, illiterate). In each data set, the social distribution of cataract blindness, cataract surgical coverage (CSC) and effective cataract surgical coverage (eCSC) were examined. Inequalities were assessed comparing the best-off and worst-off subgroups using rate differences and rate ratios (RRs). Logistic regression was used to assess cumulative effects of multiple disadvantage. Disadvantaged subgroups experienced higher prevalence of cataract blindness, lower CSC and lower eCSC in both countries. A social gradient was present for CSC and eCSC, with coverage increasing as social position improved. Relative inequality in eCSC was approximately twice as high as CSC (Pakistan: eCSC RR 2.7 vs CSC RR 1.3; Nigeria: eCSC RR 8.7 vs CSC RR 4.1). Cumulative disadvantage was observed for all outcomes, deteriorating further with each additional axis along which disadvantage was experienced. Each outcome tended to be worse with the addition of each layer of social disadvantage. Illiterate, rural women fared worst in both settings. Moving beyond unidimensional analyses of social position identified subgroups in most need; this permits a more nuanced response to addressing the inequitable distribution of cataract blindness.


Environmental interactions with the toxicity of plant essential oils to the poultry red mite Dermanyssus gallinae.
The toxicity of a range of plant essential oils to the poultry red mite, Dermanyssus gallinae (De Geer) (Acari: Dermanyssidae), a serious ectoparasitic pest of laying hens throughout Europe and elsewhere, was assessed in the laboratory. Dermanyssus gallinae may cause losses in egg production, anaemia and, in extreme cases, death of hens. With changes in legislation and consumer demand, alternatives to synthetic acaricides are needed to manage this pest. Fifty plant essential oils were selected for their toxicity to arthropods reported in the literature. Twenty-four of these essential oils were found to kill > 75% of adult D. gallinae in contact toxicity tests over a 24-h period at a rate of 0.21 mg/cm(2). Subsequent testing at lower rates showed that the essential oils of cade, manuka and thyme were especially toxic to adult D. gallinae. The toxicity of the seven most acaricidal essential oils was found to be stable at different temperatures likely to be encountered in commercial poultry housing (15 degrees C, 22 degrees C and 29 degrees C), although results suggest that humidity and dust might influence the toxicity of some of the oils tested. The toxicity of clove bud essential oil to D. gallinae, for example, was increased at high humidity and dust levels compared with ambient levels. The results suggest that certain essential oils may make effective botanical pesticides for use against D. gallinae, although it is likely that issues relating to the consistency of the toxic effect of some oils will determine which oils will be most effective in practice.


Visible light mediated homo- and heterocoupling of benzyl alcohols and benzyl amines on polycrystalline cadmium sulfide.
The oxidative coupling of sp(3) hybridized carbon atoms by photocatalysis is a valuable synthetic method as stoichiometric oxidation reagents can be avoided and dihydrogen is the only byproduct of the reaction. Cadmium sulfide, a readily available semiconductor, was used as a visible light heterogeneous photocatalyst for the oxidative coupling of benzyl alcohols and benzyl amines by irradiation with blue light. Depending on the structure of the starting material, good to excellent yields of homocoupling products were obtained as mixtures of diastereomers. Cross-coupling between benzyl alcohols and benzyl amines gave product mixtures, but was selective for the coupling of tetrahydroisoquinolines to nitromethane. The results demonstrate that CdS is a suitable visible light photocatalyst for oxidative bond formation under anaerobic conditions.


Latent Classes of Symptoms related to Clinically Depressed Mood in Adolescents.
The diagnosis of major depressive disorder (MDD), according to the Diagnostic and Statistical Manual of Mental Disorders, is based only on adult symptomatology of depression and not adapted for age and gender. This may contribute to the low diagnostic specificity and validity of adolescent MDD. In this study, we investigated whether latent classes based on symptoms associated with depressed mood could be identified in a sample of adolescents seeking psychiatric care, regardless of traditionally defined diagnostic categories. Self-reports of the Strengths and Difficulties Questionnaire and the Development and Well-Being Assessment were collected consecutively from all new patients between the ages of 13 and 17 years at two psychiatric outpatient clinics in Stockholm, Sweden. Those who reported depressed mood at intake yielded a sample of 21 boys and 156 girls. Latent class analyses were performed for all screening items and for the depression-specific items of the Development and Well-Being Assessment. The symptoms that were reported in association with depressed mood differentiated the adolescents into two classes. One class had moderate emotional severity scores on the Strengths and Difficulties Questionnaire and mainly symptoms that were congruent with the Diagnostic and Statistical Manual of Mental Disorders criteria for MDD. The other class had higher emotional severity scores and similar symptoms to those reported in the first class. However, in addition, this group demonstrated more diverse symptomatology, including vegetative symptoms, suicidal ideation, anxiety, conduct problems, body dysmorphic symptoms, and deliberate vomiting. The classes predicted functional impairment in that the members of the second class showed more functional impairment. The relatively small sample size limited the generalizability of the results of this study, and the amount of items included in the analysis was restricted by the rules of latent class analysis. No conclusions about gender differences between the classes could be could be drawn as a result of the low number of boys included in the study. Two distinct classes were identified among adolescents with depressed mood. The class with highest emotional symptom severity score and the most functional impairment had a more diverse symptomatology that included symptoms that were not congruent with the traditional diagnostic criteria of MDD. However, this additional symptomatology is clinically important to consider. As a result, the clinical usefulness of the Diagnostic and Statistical Manual of Mental Disorders during the diagnostic process of adolescent depression is questioned.


Ossified Posterior Longitudinal Ligament Existing at an Intervertebral Level Limits Compensatory Mechanism of Cervical Lordosis after Muscle-Preserving Selective Laminectomy.
As C7 slope increases, lordotic change of C2-C7 angle compensates for adjustments in cervical sagittal balance. However, ossification of the posterior longitudinal ligament (OPLL) may affect the compensatory mechanism of the cervical spine. This study aims to evaluate the impact of OPLL on cervical lordotic compensation after muscle-preserving selective laminectomy (SL). This study involved 235 patients with cervical spondylotic myelopathy (CSM) and OPLL who underwent ≥ 3 consecutive levels of SL. OPLL was classified into continuous, segmental, mixed, or localized type on the basis of the criteria previously reported. In this study, based on the motion preservation at the intervertebral level, patients were divided into CSM (n = 114), OPLL segmental type (OPLL-S; n = 44), and other types of OPLL (OPLL-O; i.e., continuous, mixed, and localized; n = 77). The cervical sagittal alignment, degree of spinal cord decompression, and surgical outcomes were compared among the three groups. The OPLL-O group had a larger postoperative C7 slope (p = 0.020), larger pre- (p = 0.021) and postoperative (p = 0.001) C2-C7 sagittal vertical axis, and greater pre- (p = 0.034) and postoperative (p = 0.002) C7 slope minus C2-C7 angle. Narrower postoperative spinal cord clearance (PSCC) from OPLL (p < 0.001) and more residual spinal cord compression (p < 0.001) were observed in the OPLL-O group. Correlation between postoperative C7 slope minus C2-C7 angle and PSCC was detected (r = -0.238, p < 0.001). The recovery rate of the Japanese Orthopedic Association score was slightly lower in the OPLL-O group (p < 0.001), and it was correlated with postoperative residual spinal cord compression (r = -0.305, p < 0.001). OPLL-O limits cervical lordotic compensation, resulting in cervical sagittal balance mismatch. It affects the degree of spinal cord decompression, which might be related to surgical outcome.


Occurrence of Neospora caninum antibodies in capybaras (Hydrochaeris hydrochaeris) from São Paulo State, Brazil.
Capybara (Hydrochaeris hydrochaeris) is a large rodent distributed throughout tropical America. Antibodies to Neospora caninum in 213 feral capybaras from 11 counties of the State of São Paulo, Brazil, were assessed using the indirect immunofluorescent antibody test (titer >or=1:25) and found in 20 (9.4%), with titers of 1:25 in 4, 1:50 in 7, and 1:100 in 9 animals. This is the first report of occurrence of N. caninum antibodies in capybaras.


Intranasal delivery of influenza subunit vaccine formulated with GEM particles as an adjuvant.
Nasal administration of influenza vaccine has the potential to facilitate influenza control and prevention. However, when administered intranasally (i.n.), commercially available inactivated vaccines only generate systemic and mucosal immune responses if strong adjuvants are used, which are often associated with safety problems. We describe the successful use of a safe adjuvant Gram-positive enhancer matrix (GEM) particles derived from the food-grade bacterium Lactococcus lactis for i.n. vaccination with subunit influenza vaccine in mice. It is shown that simple admixing of the vaccine with the GEM particles results in a strongly enhanced immune response. Already after one booster, the i.n. delivered GEM subunit vaccine resulted in hemagglutination inhibition titers in serum at a level equal to the conventional intramuscular (i.m.) route. Moreover, i.n. immunization with GEM subunit vaccine elicited superior mucosal and Th1 skewed immune responses compared to those induced by i.m. and i.n. administered subunit vaccine alone. In conclusion, GEM particles act as a potent adjuvant for i.n. influenza immunization.


Delayed vaginal SHIV infection in VRC01 and anti-α4β7 treated rhesus macaques.
VRC01 protects macaques from vaginal SHIV infection after a single high-dose challenge. Infusion of a simianized anti-α4β7 mAb (Rh-α4β7) just prior to, and during repeated vaginal exposures to SIVmac251 partially protected macaques from vaginal SIV infection and rescued CD4+ T cells. To investigate the impact of combining VRC01 and Rh-α4β7 on SHIV infection, 3 groups of macaques were treated with a suboptimal dosing of VRC01 alone or in combination with Rh-α4β7 or with control antibodies prior to the initiation of weekly vaginal exposures to a high dose (1000 TCID50) of SHIVAD8-EO. The combination Rh-α4β7-VRC01 significantly delayed SHIVAD8-EO vaginal infection. Following infection, VRC01-Rh-α4β7-treated macaques maintained higher CD4+ T cell counts and exhibited lower rectal SIV-DNA loads compared to controls. Interestingly, VRC01-Rh-α4β7-treated macaques had fewer IL-17-producing cells in the blood and the gut during the acute phase of infection. Moreover, higher T cell responses to the V2-loop of the SHIVAD8-EO envelope in the VRC01-Rh-α4β7 group inversely correlated with set point viremia. The combination of suboptimal amounts of VRC01 and Rh-α4β7 delayed infection, altered antiviral immune responses and minimized CD4+ T cell loss. Further exploration of the effect of combining bNAbs with Rh-α4β7 on SIV/HIV infection and antiviral immune responses is warranted and may lead to novel preventive and therapeutic strategies.


Influence of crosslinking on the mechanical behavior of 3D printed alginate scaffolds: Experimental and numerical approaches.
Tissue scaffolds fabricated by three-dimensional (3D) bioprinting are attracting considerable attention for tissue engineering applications. Because the mechanical properties of hydrogel scaffolds should match the damaged tissue, changing various parameters during 3D bioprinting has been studied to manipulate the mechanical behavior of the resulting scaffolds. Crosslinking scaffolds using a cation solution (such as CaCl2) is also important for regulating the mechanical properties, but has not been well documented in the literature. Here, the effect of varied crosslinking agent volume and crosslinking time on the mechanical behavior of 3D bioplotted alginate scaffolds was evaluated using both experimental and numerical methods. Compression tests were used to measure the elastic modulus of each scaffold, then a finite element model was developed and a power model used to predict scaffold mechanical behavior. Results showed that crosslinking time and volume of crosslinker both play a decisive role in modulating the mechanical properties of 3D bioplotted scaffolds. Because mechanical properties of scaffolds can affect cell response, the findings of this study can be implemented to modulate the elastic modulus of scaffolds according to the intended application.


Efficacy of on-demand treatment in reducing morbidity in patients with hereditary angioedema due to C1 inhibitor deficiency.
Angioedema due to hereditary deficiency of C1 inhibitor causes temporarily disability. Guidelines recommend early on-demand treatment of attacks to reduce morbidity. In this prospective observational study, we evaluated the efficacy of on-demand approach. From January 2009 to August 2014, data on attacks and treatments were collected from 227 patients from our centre in Milan. A total of 4244 attacks were reported; 50% were treated with approved therapies (pdC1-INH or icatibant), 15% were with tranexamic acid, and 35% were not treated. Attack locations were peripheral cutaneous (46%), abdominal (34%), multiple (12%), facial (5%) and laryngeal (3%). Attack severities were moderate (48%), mild (28%) and severe (24%). Median attack duration (data available for 2393 attacks) with approved therapies was 10 h, significantly shorter than without treatment (45 h) or with tranexamic acid (38 h). Most of the treatments were self-administered: 93% with icatibant and 59% with pd-C1-INH. Median attack duration with icatibant was 8 and 11.5 h with pd-C1 INH. Median time from onset of symptoms to drug administration was 1 h with icatibant and 2 h with pd-C1INH and median time from drug administration to complete resolution was 5.5 and 8 h, respectively. Second treatment was required in 12.7% of icatibant-treated attacks and in 1.9% of pdC1-INH-treated attacks. This study provides evidence that on-demand treatment is effective in reducing disease-related morbidity. The use of on-demand treatment in Italy has increased up to 50% of attacks in the last years, reflecting a better adherence to international guidelines.


Triatomines as experimental vectors of trypanosomes of Asian monkeys.
Systematic surveys of the wild macaques of South Asia by blood culture resulted in the discovery that trypanosomiasis is enzootic in the simians of Indonesia, Malaysia, India, and Thailand. The isolates obtained differ in morphology, metabolism, and ability to multiply in arthropods. Following this discovery, interest focused on possible transmissions of these trypanosomiases. Laboratory-reared and wild-caught insects were studied to determine which are satisfactory intermediate hosts and potential natural vectors. Successful results were obtained with insectary-reared reduviids and Indonesian isolates. In Rhodnius prolixus and Triatoma rubrofasciata the Indonesian trypanosomes multiply for periods which can exceed 40 days. The flagellate infections are in the digestive tract, whereas trypanosomes have never been seen in the salivary glands or in the hemolymph. The feces of trypanosome-carrying reduviids are infective, suggesting a stercoreal method of infection of mammals, and infection was produced in experiments in which feeding by the insects was not possible. The relevance of these findings to natural transmission in Indonesia is not known. Experiments with insects and all other trypanosomal isolates have been negative. The natural transmission mechanism(s) of the simian trypanosomiases in South Asia remains an unsolved problem.


Contextual effects of noise on vocalization encoding in primary auditory cortex.
Robust auditory perception plays a pivotal function for processing behaviorally relevant sounds, particularly with distractions from the environment. The neuronal coding enabling this ability, however, is still not well understood. In this study, we recorded single-unit activity from the primary auditory cortex (A1) of awake marmoset monkeys (Callithrix jacchus) while delivering conspecific vocalizations degraded by two different background noises: broadband white noise and vocalization babble. Noise effects on neural representation of target vocalizations were quantified by measuring the responses' similarity to those elicited by natural vocalizations as a function of signal-to-noise ratio. A clustering approach was used to describe the range of response profiles by reducing the population responses to a summary of four response classes (robust, balanced, insensitive, and brittle) under both noise conditions. This clustering approach revealed that, on average, approximately two-thirds of the neurons change their response class when encountering different noises. Therefore, the distortion induced by one particular masking background in single-unit responses is not necessarily predictable from that induced by another, suggesting the low likelihood of a unique group of noise-invariant neurons across different background conditions in A1. Regarding noise influence on neural activities, the brittle response group showed addition of spiking activity both within and between phrases of vocalizations relative to clean vocalizations, whereas the other groups generally showed spiking activity suppression within phrases, and the alteration between phrases was noise dependent. Overall, the variable single-unit responses, yet consistent response types, imply that primate A1 performs scene analysis through the collective activity of multiple neurons. The understanding of where and how auditory scene analysis is accomplished is of broad interest to neuroscientists. In this paper, we systematically investigated neuronal coding of multiple vocalizations degraded by two distinct noises at various signal-to-noise ratios in nonhuman primates. In the process, we uncovered heterogeneity of single-unit representations for different auditory scenes yet homogeneity of responses across the population.


SreA-mediated iron regulation in Aspergillus fumigatus.
Aspergillus fumigatus, the most common airborne fungal pathogen of humans, employs two high-affinity iron uptake systems: iron uptake mediated by the extracellular siderophore triacetylfusarinine C and reductive iron assimilation. Furthermore, A. fumigatus utilizes two intracellular siderophores, ferricrocin and hydroxyferricrocin, to store iron. Siderophore biosynthesis, which is essential for virulence, is repressed by iron. Here we show that this control is mediated by the GATA factor SreA. During iron-replete conditions, SreA deficiency partially derepressed synthesis of triacetylfusarinine C and uptake of iron resulting in increased cellular accumulation of both iron and ferricrocin. Genome-wide DNA microarray analysis identified 49 genes that are repressed by iron in an SreA-dependent manner. This gene set, termed SreA regulon, includes all known genes involved in iron acquisition, putative novel siderophore biosynthetic genes, and also genes not directly linked to iron metabolism. SreA deficiency also caused upregulation of iron-dependent and antioxidative pathways, probably due to the increased iron content and iron-mediated oxidative stress. Consistently, the sreA disruption mutant displayed increased sensitivity to iron, menadion and phleomycin but retained wild-type virulence in a mouse model. As all detrimental effects of sreA disruption are restricted to iron-replete conditions these data underscore that A. fumigatus faces iron-depleted conditions during infection.


Next generation biofilm inhibitors for Pseudomonas aeruginosa: Synthesis and rational design approaches.
The bacterial biofilms and the emergence of multiple drug resistance have become a major threat for current medical treatment of nosocomial infections. It has been estimated that about 65-80% of microbial infections in the developed countries are associated with biofilms. Given the prominence of biofilms in infectious diseases, increasing efforts toward the development of small molecules that will modulate bacterial biofilm development and maintenance is on the rise. Till date, marine natural products have shown a tremendous potential as pharma leads and also given new skeletons which would be used as biofilm/QS inhibitors. Medically relevant biofilm forming bacteria such as Pseudomonas aeruginosa which is most frequently isolated bacteria in nosocomial infection is believed to be a model organism for biofilm studies. Hence, in this review, we have highlighted the development of small molecules that inhibit and/or disperse bacterial biofilms of P. aeruginosa in particular. Additionally, the rational design approaches as well as synthetic methodologies along with biological studies has been accounted in this article.