The lifeline and advanced practice nursing/intervention prevention perspective.
The 988 Suicide and Crisis Lifeline (hereinafter referred to as The Lifeline) is a national effort to provide mental health crisis support for individuals or 3rd parties (requesting help for others) via a three-digit phone number. Since July 2022, the Lifeline is part of a national effort to assist individuals who are suicidal, homicidal, or distressed. Over half of suicides in the United States are completed with a gun, hence the need for an effort to focus on prevention related to a growing tragic loss of life. Psychiatric mental health nurses can be part of the prevention focus by promoting and discussing The Lifeline resource with patients, families, and colleagues. The majority of individuals requiring psychiatric-mental health services are living in the community and not institutionalized; therefore, The Lifeline is an invaluable resource to support wellness and well-being.


Serotonin Modulates Developmental Microglia via 5-HT2B Receptors: Potential Implication during Synaptic Refinement of Retinogeniculate Projections.
Maturation of functional neuronal circuits during central nervous system development relies on sophisticated mechanisms. First, axonal and dendritic growth should reach appropriate targets for correct synapse elaboration. Second, pruning and neuronal death are required to eliminate redundant or inappropriate neuronal connections. Serotonin, in addition to its role as a neurotransmitter, actively participates in postnatal establishment and refinement of brain wiring in mammals. Brain resident macrophages, that is, microglia, also play an important role in developmentally regulated neuronal death as well as in synaptic maturation and elimination. Here, we tested the hypothesis of cross-regulation between microglia and serotonin during postnatal brain development in a mouse model of synaptic refinement. We found expression of the serotonin 5-HT2B receptor on postnatal microglia, suggesting that serotonin could participate in temporal and spatial synchronization of microglial functions. Using two-photon microscopy, acute brain slices, and local delivery of serotonin, we observed that microglial processes moved rapidly toward the source of serotonin in Htr2B(+/+) mice, but not in Htr2B(-/-) mice lacking the 5-HT2B receptor. We then investigated whether some developmental steps known to be controlled by serotonin could potentially result from microglia sensitivity to serotonin. Using an in vivo model of synaptic refinement during early brain development, we investigated the maturation of the retinal projections to the thalamus and observed that Htr2B(-/-) mice present anatomical alterations of the ipsilateral projecting area of retinal axons into the thalamus. In addition, activation markers were upregulated in microglia from Htr2B(-/-) compared to control neonates, in the absence of apparent morphological modifications. These results support the hypothesis that serotonin interacts with microglial cells and these interactions participate in brain maturation.


The correction of telecanthus and epicanthal folds.
A modification of the trans-nasal wiring technique is described which provides a greater tightening of the canthal angles initially producing a greater reduction in the telecanthus and seems to eliminate late recurrence of the telecanthus. This procedure is described in conjunction with epicanthal fold repair when it occurs together with the telecanthus. The spicanthal fold repair technique involves excision of the epicanthal fold and together with abnormal subcutaneous tissue under the skin which is undermined. Meticulous skin closure of the skin edges together with compression of the skin at the base of the nose with the trans-nasal wires restores normal skin contour and canthal angle position at the base of the nose. The above technique is applied to congenital and post-traumatic deformities.


Multi-stability of circadian phase wave within early postnatal suprachiasmatic nucleus.
The suprachiasmatic nucleus (SCN) is a group of cells that functions as a biological master clock. In different SCN cells, oscillations of biochemical markers such as the expression-level of clock genes, are not synchronized but instead form slow circadian phase waves propagating over the whole cell population spatio-temporal structure is a fixed property set by the anatomy of a given SCN. Here, we show that this is not the case in early postnatal SCN. Earlier studies presumed that their Based on bioluminescence imaging experiments with Per2-Luciferase mice SCN cultures which guided computer simulations of a realistic model of the SCN, we demonstrate that the wave is not unique but can be in various modes including phase- coherent oscillation, crescent-shaped wave, and most notably, a rotating pinwheel wave that conceptually resembles a wall clock with a rotating hand. Furthermore, mode transitions can be induced by a pulse of 38.5 °C temperature perturbation. Importantly, the waves support a significantly different period, suggesting that neither a spatially-fixed phase ordering nor a specialized pacemaker having a fixed period exist in these studied SCNs. These results lead to new important questions of what the observed multi-stability means for the proper function of an SCN and its arrhythmia.


Lipid peroxidation during initiation of extracorporeal membrane oxygenation after hypoxia in endotoxemic rabbits.
Initiation of extracorporeal membrane oxygenation (ECMO) in septic children with severe respiratory failure often improves oxygenation but not pulmonary function. The factors affecting pulmonary function following onset of ECMO are not completely understood, but are thought to involve injury mediated, in part, by reactive oxygen species. We hypothesized that induction of ECMO using 100% oxygen as the sweep gas through the oxygenator would increase lipid peroxidation in endotoxin-primed animals after severe hypoxia. We further speculated that provision of oxygenated blood to the pulmonary circulation via venovenous ECMO would promote a greater degree of oxidative damage to the lung as compared to venoarterial ECMO. Eighteen New Zealand White rabbits were assigned to a control group (control) or two intervention groups subjected to 60 min of venoarterial or venovenous ECMO. ECMO was initiated following an intravenous challenge with 0.5 mg/kg of E. coli endotoxin and a period of global hypoxia leading to an arterial pH of 6.99 +/- 0.09, PaCO2 of 103 +/- 31 mmHg and PaO2 of 27 +/- 5 mmHg. Malondialdehyde (MDA), a marker of lipid peroxidation, was measured in lung tissue homogenates and in arterial plasma. Lung tissue MDA demonstrated a strong trend towards an increase in the venoarterial group (1884 +/- 945 nmol/g protein) and in the venovenous group (1905 +/- 758 nmol/g protein) in comparison to the control group (644 +/- 71 nmol/g protein) (p = 0.1; significance at 95% in Scheffe test). Lung tissue MDA in the venovenous group had a significant correlation with mean PaO2 during ECMO by regression analysis (r2 = 0.678, p = 0.044). The change in blood MDA concentration between pre-ECMO and post-ECMO values was greater in the venovenous group (pre 1.62 +/- 0.61 versus post 5.12 +/- 0.2.07 mumol/l, p = 0.043) compared with that seen in the venoarterial group (pre 1.46 +/- 0.38 versus post 3.9 +/- 0.93 mumol/l). Our data support the hypothesis that initiation of ECMO with a circuit gas oxygen concentration of 100% after global hypoxia enhances oxidative damage to lipids in endotoxin-challenged animals. During venovenous ECMO this finding is dependent on PaO2.


Analysis of chromosome III replicators reveals an unusual structure for the ARS318 silencer origin and a conserved WTW sequence within the origin recognition complex binding site.
Saccharomyces cerevisiae chromosome III encodes 11 autonomously replicating sequence (ARS) elements that function as chromosomal replicators. The essential 11-bp ARS consensus sequence (ACS) that binds the origin recognition complex (ORC) has been experimentally defined for most of these replicators but not for ARS318 (HMR-I), which is one of the HMR silencers. In this study, we performed a comprehensive linker scan analysis of ARS318. Unexpectedly, this replicator depends on a 9/11-bp match to the ACS that positions the ORC binding site only 6 bp away from an Abf1p binding site. Although a largely inactive replicator on the chromosome, ARS318 becomes active if the nearby HMR-E silencer is deleted. We also performed a multiple sequence alignment of confirmed replicators on chromosomes III, VI, and VII. This analysis revealed a highly conserved WTW motif 17 to 19 bp from the ACS that is functionally important and is apparent in the 228 phylogenetically conserved ARS elements among the six sensu stricto Saccharomyces species.


Analysis of the internal replication sequence indicates that there are three elements required for efficient replication of minute virus of mice minigenomes.
Prior analysis of minigenomes of minute virus of mice carried out by our laboratory indicated that sequences within the region of nucleotides 4489 to 4695, inboard of the 5' palindrome, are required for efficient DNA replication of the virus and are the site of specific interactions with unidentified factors present in a host cell nuclear extract (P. Tam and C. R. Astell, Virology 193:812-824, 1993; P. Tam and C. R. Astell, J. Virology 68:2840-2848, 1994). In order to examine this region in finer detail, a comprehensive library of linker-scanning mutants spanning the region was tested for the ability to support replication of minigenome constructs and for the ability to interact with host cell factors. Three short discrete sequence elements critical for replication competence were observed. Binding of host cell nuclear factors was localized to four sites, with two major complexes each appearing to have two binding sites within the region. All factor binding sites were found to be directly adjacent to or overlapping with sequence elements contributing to replication competence, and evidence suggesting a correlation between factor binding and minigenome replication is presented. A possible model is proposed for function of a viral origin within the region of the internal replication sequence which addresses the still-unresolved problem of how parvoviruses overcome the thermodynamic energy barrier involved in the rearrangement of the 5'-terminal palindrome from an extended form to a hairpin conformation.


Paired test of matrix graphs and brain connectivity analysis.
Inferring brain connectivity network and quantifying the significance of interactions between brain regions are of paramount importance in neuroscience. Although there have recently emerged some tests for graph inference based on independent samples, there is no readily available solution to test the change of brain network for paired and correlated samples. In this article, we develop a paired test of matrix graphs to infer brain connectivity network when the groups of samples are correlated. The proposed test statistic is both bias corrected and variance corrected, and achieves a small estimation error rate. The subsequent multiple testing procedure built on this test statistic is guaranteed to asymptotically control the false discovery rate at the pre-specified level. Both the methodology and theory of the new test are considerably different from the two independent samples framework, owing to the strong correlations of measurements on the same subjects before and after the stimulus activity. We illustrate the efficacy of our proposal through simulations and an analysis of an Alzheimer's Disease Neuroimaging Initiative dataset.


Metabotropic glutamate receptor 5 tracer [18F]-FPEB displays increased binding potential in postcentral gyrus and cerebellum of male individuals with autism: a pilot PET study.
Autism is a neurodevelopmental disorder that is first manifested during early childhood. Postmortem experiments have identified significantly elevated expression of metabotropic glutamate receptor 5 (mGluR5) in cerebellar vermis and prefrontal cortex of individuals with autism. In the current study we employed the mGluR5 tracer [18F]-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ([18F]-FPEB) to quantify mGluR5 binding in vivo in adults with autism vs. healthy controls using positron emission tomography (PET). We identified significantly higher [18F]-FPEB binding potential in the postcentral gyrus and cerebellum of individuals with autism. There was a significant negative correlation between age and [18F]-FPEB binding potential in the cerebellum but not in the postcentral gyrus. In the precuneus, [18F]-FPEB binding potential correlated positively with the lethargy subscale score for the Aberrant Behavioral Checklist (ABC). In cerebellum, there were significant negative correlations between [18F]-FPEB binding potential and ABC total score, ABC hyperactivity subscale score, and the ABC inappropriate speech subscale score. These novel findings demonstrate for the first time that mGluR5 binding is altered in critical brain areas of subjects with autism, suggesting abnormal glutamate signaling in these regions. Finally, the correlations between altered [18F]-FPEB binding potential in the cerebellum and precuneus suggest that some autistic symptoms may be influenced by abnormal glutamate signaling.


Bartonella Infection in Hematophagous, Insectivorous, and Phytophagous Bat Populations of Central Mexico and the Yucatan Peninsula.
Although emerging nonviral pathogens remain relatively understudied in bat populations, there is an increasing focus on identifying bat-associated bartonellae around the world. Many novel Bartonella strains have been described from both bats and their arthropod ectoparasites, including Bartonella mayotimonensis, a zoonotic agent of human endocarditis. This cross-sectional study was designed to describe novel Bartonella strains isolated from bats sampled in Mexico and evaluate factors potentially associated with infection. A total of 238 bats belonging to seven genera were captured in five states of Central Mexico and the Yucatan Peninsula. Animals were screened by bacterial culture from whole blood and/or polymerase chain reaction of DNA extracted from heart tissue or blood. Bartonella spp. were isolated or detected in 54 (22.7%) bats, consisting of 41 (38%) hematophagous, 10 (16.4%) insectivorous, and three (4.3%) phytophagous individuals. This study also identified Balantiopteryx plicata as another possible bat reservoir of Bartonella. Univariate and multivariate logistic regression models suggested that Bartonella infection was positively associated with blood-feeding diet and ectoparasite burden. Phylogenetic analysis identified a number of genetic variants across hematophagous, phytophagous, and insectivorous bats that are unique from described bat-borne Bartonella species. However, these strains were closely related to those bartonellae previously identified in bat species from Latin America.


Modulation of complement gene expression by glucocorticoids.
The addition of dexamethasone, prednisolone or cortisol (in order of efficacy) to human monocytes in culture produced dose-related increases in the synthesis rates of the complement components C1 inhibitor (C1-inh), factor B (B) and C2. In contrast, concentrations of C3 and lysozyme in the culture supernatants were decreased. Indomethacin stimulated synthesis of C1-inh, C2 and B, but had little effect on synthesis of C3 or lysozyme. The simultaneous addition of cycloheximide (2.5 micrograms/ml) abrogated the effects of dexamethasone on synthesis of C2, B and C1-inh, but the effect of indomethacin on the synthesis of these components was unchanged. These data suggest that protein synthesis is required for the effects of glucocorticoids on the synthesis of C2, B and C1-inh to occur. Dexamethasone and indomethacin increased the abundances of C1-inh mRNA, B mRNA and C2 mRNA in parallel with changes in the synthesis rates of these proteins. The changes in mRNA abundance were not transcriptional, but were shown to be due to increased mRNA stability. In contrast, dexamethasone decreased the expression of C3 and lysozyme by decreasing the rate of transcription of these genes. Indomethacin had no effect on transcription of the C3 and lysozyme genes. The half-lives of C3 mRNA, lysozyme mRNA and actin mRNA were not altered by dexamethasone or indomethacin. It is concluded that the effects of glucocorticoids on monocyte synthesis of C2, B and C1-inh are due to increased mRNA stability and may be related to inhibition of prostaglandin synthesis, as these effects are similar to those produced by indomethacin. The effects of dexamethasone on the synthesis of C3 and lysozyme differ from those on C2, B and C1-inh as they depend upon a decrease in gene transcription, which is not affected by indomethacin.


Variation in FGF1, FOXE1, and TIMP2 genes is associated with nonsyndromic cleft lip with or without cleft palate.
Nonsyndromic cleft lip with or without cleft palate (CL/P) is a common complex birth defect caused by the interaction between multiple genes and environmental factors. Five hundred and eighty-seven single nucleotide polymorphisms in 40 candidate genes related to orofacial clefting were tested for association with CL/P in a clefting sample composed of 300 patients and 606 controls from Estonian, Latvian, and Lithuanian populations. In case-control comparisons, the minor alleles of FGF1 rs34010 (p = 4.56 × 10(-4) ), WNT9B rs4968282 (p = 0.0013), and FOXE1 rs7860144 (p = 0.0021) were associated with a decreased risk of CL/P. Multiple haplotypes in FGF1, FOXE1, and TIMP2 and haplotypes in WNT9B, PVRL2, and LHX8 were associated with CL/P. The strongest association was found for protective haplotype rs250092/rs34010 GT in the FGF1 gene (p = 5.01 × 10(-4) ). The strongest epistatic interaction was observed between the COL2A1 and WNT3 genes. Our results provide for the first time evidence implicating FGF1 in the occurrence of CL/P, and support TIMP2 and WNT9B as novel loci predisposing to CL/P. We have also replicated recently reported significant associations between variants in or near FOXE1 and CL/P. It is likely that variation in FOXE1, TIMP2, and the FGF and Wnt signaling pathway genes confers susceptibility to nonsyndromic CL/P in Northeastern European populations.


Polypharmacy and Multimorbidity in the Urogynecology Population and Their Effect on Pelvic Floor Symptoms.
Polypharmacy and multimorbidity are common in older adults but has not been well studied in the urogynecologic patient population. The objective of this study was to determine the prevalence of polypharmacy and multimorbidity in a diverse outpatient urogynecologic population and to examine whether polypharmacy and/or multimorbidity were associated with lower urinary tract symptoms, pelvic organ prolapse, defecatory distress, and/or female sexual dysfunction. This is a secondary analysis of a dual-center cross-sectional study of new patients presenting for evaluation of pelvic floor disorders at 2 urban academic outpatient urogynecology clinics. Baseline demographics and clinical characteristics were obtained from the electronic medical record. Validated surveys were administered to determine severity of lower urinary tract symptoms (Overactive Bladder Validated 8-Question Screener, Urogenital Distress Inventory-6), pelvic floor dysfunction (Pelvic Organ Prolapse Distress Inventory-6, Colorectal-Anal Distress Inventory-8), and sexual dysfunction (6-item Female Sexual Function Index). Standard statistical techniques were used. One hundred ninety-seven women with mean age 58.8 years (SD, 13.4 years) were included, and most were of minority race/ethnicity (Black, 34.0%; Hispanic, 21.8%). The majority of participants met criteria for polypharmacy (58.4%) and multimorbidity (85.8%), with a mean prescription number of 6.5 (SD, ± 4.9) and mean number of medical comorbidities of 4.9 (SD, ± 3.3). Polypharmacy and multimorbidity were significantly associated with higher CRADI-8 scores. Specifically, polypharmacy was associated with straining with bowel movements and painful stools, whereas multimorbidity was associated with incomplete emptying and fecal urgency. There was no significant association between polypharmacy and multimorbidity with urinary symptoms, prolapse, or sexual dysfunction. Polypharmacy and multimorbidity are common in the urogynecologic population. There is a relationship between greater defecatory distress and polypharmacy and multimorbidity.


Effects of Tumor Necrosis Factor Antagonists in Patients With Primary Sclerosing Cholangitis.
Few patients with primary sclerosing cholangitis (PSC) and inflammatory bowel diseases (IBDs) are exposed to tumor necrosis factor (TNF) antagonists because of the often mild symptoms of IBD. We assessed the effects of anti-TNF agents on liver function in patients with PSC and IBD, and their efficacy in treatment of IBD. We performed a retrospective analysis of 141 patients with PSC and IBD receiving treatment with anti-TNF agents (infliximab or adalimumab) at 20 sites (mostly tertiary-care centers) in Europe and North America. We collected data on the serum level of alkaline phosphatase (ALP). IBD response was defined as either endoscopic response or, if no endoscopic data were available, clinical response, as determined by the treating clinician or measurements of fecal calprotectin. Remission was defined more stringently as endoscopic mucosal healing. We used linear regression analysis to identify factors associated significantly with level of ALP during anti-TNF therapy. Anti-TNF treatment produced a response of IBD in 48% of patients and remission of IBD in 23%. There was no difference in PSC symptom frequency before or after drug exposure. The most common reasons for anti-TNF discontinuation were primary nonresponse of IBD (17%) and side effects (18%). At 3 months, infliximab-treated patients had a median reduction in serum level of ALP of 4% (interquartile range, reduction of 25% to increase of 19%) compared with a median 15% reduction in ALP in adalimumab-treated patients (interquartile range, reduction of 29% to reduction of 4%; P = .035). Factors associated with lower ALP were normal ALP at baseline (P < .01), treatment with adalimumab (P = .090), and treatment in Europe (P = .083). In a retrospective analysis of 141 patients with PSC and IBD, anti-TNF agents were moderately effective and were not associated with exacerbation of PSC symptoms or specific side effects. Prospective studies are needed to investigate the association between use of adalimumab and reduced serum levels of ALP further.


Astragalus polysaccharides inhibit ovarian cancer cell growth via microRNA-27a/FBXW7 signaling pathway.
Astragalus polysaccharide (APS), a natural antioxidant found in Astragalus membranaceus emerging as a novel anticancer agent, exerts antiproliferative and pro-apoptotic activity in various cancer cell types, but its effect on ovarian cancer (OC) remains unknown. In the present study, we tried to elucidate the role and mechanism of APS in OC cells. Our results showed that APS treatment suppressed the proliferation and induced apoptosis in OC cells. Afterward, the microRNA (miRNA) profiles in APS-treated cells were determined by a microarray assay, and whether APS affected OV-90 cells through regulation of miRNA was determined. Among these aberrant miRNAs, miR-27a was selected for further study as its oncogenic roles in various human cancers. Moreover, we found overexpression of miR-27a reversed the antiproliferation and pro-apoptotic effects of APS on OC cells. F-box and WD-40 domain protein 7 (FBXW7), a classical tumor suppressor, was found directly targeted by miR-27a and its translation was suppressed by miR-27a in OC cells. Finally, it was also observed that knockdown of FBXW7 by si-FBXW7 reversed the tumor suppressive activity of APS in OC cells, which is similar to the effects of miR-27a overexpression. Our findings demonstrate that APS can suppress OC cell growth in vitro via miR-27a/FBXW7 axis, and this observation reveals the therapeutic potential of APS for treatment of OC.


Golden opportunity for intervention? Identifying vitamin D deficiency in patients with substance use disorders in hospital.
Based at a busy city hospital, the alcohol care team is a drug and alcohol specialist service, taking referrals for a wide range of patients with substance use disorders (SUD). Patients with SUD are at high risk of vitamin D deficiency; this relates to frequent fractures and proximal myopathy. The coronavirus pandemic brought vitamin D into focus. Local guidelines advise that patients at high risk of vitamin D deficiency are offered replacement. There were no local data on vitamin D deficiency prevalence or any mention of patients with SUD in local vitamin D guidelines. The main aim of this project was to offer vitamin D checks and replacement to all appropriate patients. We collected data on 207 patients, [pilot study (n=50) and two subsequent samples (n=95 and n=62)]. Our pilot study showed that no patients were offered vitamin D testing or replacement. We then offered vitamin D checks to 95 patients. Most had low vitamin D (30 patients were vitamin D deficient and 26 were vitamin D insufficient). We provided vitamin D replacement and follow-up advice. Quality improvement was demonstrated 6 months later. We collected data on a further 62 patients who were all on our current or recent caseload. Following exclusions, nearly half (48%) of patients had had a vitamin D check. Almost all of these (95%) had low vitamin D (60% being classified as deficient). Patients had not been offered vitamin D replacement despite often having multiple risk factors for vitamin D deficiency. Vitamin D checks (and subsequent replacement) rose in frequency since the outset of this project. Local guidelines should add SUD as a risk factor for vitamin D deficiency. Hospital admission provides a rich opportunity to offer this simple intervention to patients who are often poorly engaged with community services.


Primary nasopharyngeal tuberculosis mimicking exacerbation of chronic rhinosinusitis.
Nasopharyngeal tuberculosis is a rare condition, even in endemic tuberculosis areas. We report a case of primary nasopharyngeal tuberculosis from a non-endemic area, which presented with symptoms resembling exacerbation of previously diagnosed chronic rhinosinusitis. A 48-year-old man presented with extreme postnasal drip and an unpleasant nasal odour. Endoscopic examination revealed irregular thickening of the left lateral and posterior wall of the nasopharynx, partially covered with crusts and necrotic tissue. Histopathological study showed typical giant cell epithelioid granulomas with caseous necrosis. Direct examination after Ziehl-Neelsen staining was positive for tuberculosis. After six months of antituberculous triple therapy, endoscopic examination revealed a completely normal nasopharynx. To our best knowledge, this is the first published report of primary nasopharyngeal tuberculosis in a patient previously diagnosed with chronic rhinosinusitis. The difficulties in obtaining a proper diagnosis in such a case are discussed.


A breakfast with alpha-lactalbumin, gelatin, or gelatin + TRP lowers energy intake at lunch compared with a breakfast with casein, soy, whey, or whey-GMP.
Dietary protein plays a role in body weight regulation, partly due to its effects on satiety. The objective was to compare the effects of casein-, soy-, whey-, whey without glycomacropeptide (GMP)-, alpha-lactalbumin-, gelatin-, or gelatin with tryptophan (TRP)-protein breakfasts at two concentrations on subsequent satiety and energy intake (EI). Twenty-four healthy subjects (mean+/-SEM BMI: 24.8+/-0.5 kg/m(2); age: 25+/-2 years) received a breakfast; a custard with casein, soy, whey, whey-GMP, alpha-lactalbumin, gelatin, or gelatin+TRP as protein source with either 10/55/35 (normal) or 25/55/20 (high) En% protein/carbohydrate/fat in a randomized, single-blind design. At the precedingly determined time point for lunch, 180 min, subjects were offered an ad lib lunch. Appetite profile (Visual Analogue Scales, VAS) and EI were determined. Both at the level of 10 and 25 En% from protein, EI at lunch was approximately 20% lower after an alpha-lactalbumin or gelatin (+TRP) breakfast (2.5+/-0.2 MJ) compared with after a casein, soy, or whey-GMP breakfast (3.2+/-0.3 MJ, p<0.05). Appetite ratings at 180 min differed 15-25 mm (approximately 40%, p<0.05) between types of protein. Differences in EI were a function of differences in appetite ratings (R(2)=0.4, p<0.001). Different proteins (alpha-lactalbumin, gelatin, gelatin+TRP) that are approximately 40% more satiating than other proteins (casein, soy, whey, whey-GMP) induce a related approximately 20% reduction of subsequent energy intake.


Diagnostic and therapeutic challenges in the thrombotic thrombocytopenic purpura and hemolytic uremic syndromes.
Evaluation and management of patients with suspected thrombotic thrombocytopenic purpura (TTP) continue to be a critical challenge for hematologists. The diagnostic criteria are not precise, often causing uncertainty about whether it is appropriate to initiate plasma exchange (PEX), the essential treatment for TTP. Initiation of PEX remains a clinical decision; severe ADAMTS13 (< 10% activity) deficiency alone is neither sufficiently sensitive nor specific for the diagnosis of TTP. However, patients who do have severe acquired ADAMTS13 deficiency define the characteristic clinical features of TTP, the response to treatment, and the long-term outcomes. Patients with severe acquired ADAMTS13 deficiency are predominantly young women and the relative frequency of blacks is increased. Patients may present with only microangiopathic hemolytic anemia and thrombocytopenia, neurologic and renal abnormalities are often not present, fever rarely occurs; the complete "pentad" of these clinical features almost never occurs in current practice. Response to PEX is typically rapid but may not be sustained when PEX is stopped. Use of corticosteroids and rituximab has decreased the number of PEX treatments required to achieve a remission and has resulted in fewer PEX-related major complications. Relapse (in approximately 40% of patients) may be the most apparent risk after recovery, but long-term health outcomes are also very important. Minor cognitive abnormalities are common, the frequency of depression is increased, and the frequency of hypertension is increased. Careful long-term follow-up of TTP patients is essential.


Femoral cannulation for cardiopulmonary bypass with a novel bidirectional perfusion cannula.
The use of the novel bidirectional femoral cannula is described in this video tutorial. We demonstrate the percutaneous cannulation and decannulation of the femoral artery for cardiopulmonary bypass in a patient undergoing minimally invasive mitral valve surgery. The procedure itself is presented step by step for each important phase. Finally, we report the postoperative course following the successful use of a peripheral bidirectional cannula.


Youth Mental Health in North Carolina: Creative Innovations in Challenging Times.
In this issue of the North Carolina Medical Journal, youth mental health is the focus. The second half of the title of this issue brief, "creative innovations in challenging times," was designed to convey a sense of optimism and urgency for the readers. The optimism centers on the joys of birth, the wonderments of childhood and adolescence, and the discoveries and connections between families and cultures among and within North Carolina communities. The sense of urgency pertains to the current epidemiologic realities for youth between the ages of 10 and 21 and the growing economic and health care disparities impacting the vast majority of North Carolinians. The author lineup for the issue is nothing short of exceptional and includes contributions from experts in epidemiology, suicide prevention, policy and law, school mental health, telemedicine, the impact of technology and social media on youth, innovations in the dissemination of psychological science to the public, attention-deficit hyperactivity disorders, diagnostic disparities, substance misuse and abuse, K-12 education, and systems of care for families. Serving as guest editor of this issue on youth mental health for the North Carolina Medical Journal has greatly expanded the breadth and depth of my understanding of the aforementioned issues relevant for today's youth. I hope that this issue is as informative to your work, regardless of your role in serving and advocating for young people in the great state of North Carolina.


Time-resolved FTIR study of light-driven sodium pump rhodopsins.
Light-driven sodium ion pump rhodopsin (NaR) is a new functional class of microbial rhodopsin. A previous flash photolysis study of Krokinobacter eikastus rhodopsin 2 (KR2) revealed the presence of three kinetically distinct intermediates: K, L/M, and O. Previous low-temperature Fourier-transform infrared (FTIR) spectroscopy of KR2 showed that photoisomerization from the all-trans to the 13-cis form is the primary event of the Na+ pumping photocycle, but structural information on the subsequent intermediates is limited. Here, we applied step-scan time-resolved FTIR spectroscopy to KR2 and Nonlabens dokdonensis rhodopsin 2 (NdR2). Both low-temperature static and time-resolved FTIR spectra resolved a K-like intermediate, and the corresponding spectra showed few differences. Strong hydrogen-out-of-plane (HOOP) vibrations, which appeared in the K intermediate, are common among other rhodopsins. It is, however, unique for NaR that such HOOP bands are persistent in late intermediates, such as L and O intermediates. This observation strongly suggests similar chromophore structures for the K, L, and O intermediates. In fact, an isotope-labeled study that used 12,14-D2 retinal revealed that the chromophore configuration of the O intermediate in NaR is 13-cis. In contrast to the vibrations of the chromophore, those of the protein differ among intermediates, and this is related to the sodium-pumping function. The molecular mechanism of the light-driven sodium pump is discussed on the basis of the present time-resolved FTIR results.


Expression of FoxE4 and Rx visualizes the timing and dynamics of critical processes taking place during initial stages of vertebrate eye development.
Several transcription factors have a critical function during initial stages of vertebrate eye formation. In this paper, we discuss the role of the Rx subfamily of homeobox-containing genes in retinal development, and the role of the Foxe3 and FoxE4 subfamily of forkhead box-containing genes in lens development. Rx genes are expressed in the initial stages of retinal development and they play a critical role in eye formation. Elimination of Rx function in mice results in lack of eye formation. Abnormal eye development observed in the mouse mutation eyeless (ey1), the medakatemperature-sensitive mutation eyeless (el), and the zebrafish mutation chokh are caused by abnormal regulation or function of Rx genes. In humans, a mutation in Rx leads to anophthalmia. In contrast, Foxe3 and FoxE4 genes are expressed in the lens and they play an essential role in its formation. Mutations in the Foxe3 gene are the cause of the mouse mutation dysgenetic lens (dyl) and in humans, mutation in FOXE3 leads to anterior segment dysgenesis and cataracts. Since Rx and FoxE4 are expressed in the earliest stages of retina and lens development, their expression visualizes the timing and dynamics of the crucial processes that comprise eye formation. In this paper we present a model of eye development based on the expression pattern of these two genes.


Molecular mapping of a core transcriptional signature of microglia-specific genes in schizophrenia.
Besides playing a central role in neuroinflammation, microglia regulate synaptic development and is involved in plasticity. Converging lines of evidence suggest that these different processes play a critical role in schizophrenia. Furthermore, previous studies reported altered transcription of microglia genes in schizophrenia, while microglia itself seems to be involved in the etiopathology of the disease. However, the regional specificity of these brain transcriptional abnormalities remains unclear. Moreover, it is unknown whether brain and peripheral expression of microglia genes are related. Thus, we investigated the expression of a pre-registered list of 10 genes from a core signature of human microglia both at brain and peripheral levels. We included 9 independent Gene Expression Omnibus datasets (764 samples obtained from 266 individuals with schizophrenia and 237 healthy controls) from 8 different brain regions and 3 peripheral tissues. We report evidence of a widespread transcriptional alteration of microglia genes both in brain tissues (we observed a decreased expression in the cerebellum, associative striatum, hippocampus, and parietal cortex of individuals with schizophrenia compared with healthy controls) and whole blood (characterized by a mixed altered expression pattern). Our results suggest that brain underexpression of microglia genes may represent a candidate transcriptional signature for schizophrenia. Moreover, the dual brain-whole blood transcriptional alterations of microglia/macrophage genes identified support the model of schizophrenia as a whole-body disorder and lend weight to the use of blood samples as a potential source of biological peripheral biomarkers.


The volume of blood for epidural blood patch in obstetrics: a randomized, blinded clinical trial.
Our aim in this multinational, multicenter, randomized, blinded trial was to determine the optimum of 3 volumes of autologous blood for an epidural blood patch. Obstetric patients requiring epidural blood patch after unintentional dural puncture during epidural catheter insertion were allocated to receive 15, 20, or 30 mL of blood, stratified for the timing of epidural blood patch and center. Participants were followed for 5 days. The primary study end point was a composite of permanent or partial relief of headache, and secondary end points included permanent relief, partial relief, persisting headache severity, and low back pain during or after the procedure. One hundred twenty-one women completed the study. The median (interquartile range) volume administered was 15 (15-15), 20 (20-20), and 30 (22-30) mL, with 98%, 81%, and 54% of groups 15, 20, and 30 receiving the allocated volume. Among groups 15, 20, and 30, respectively, the incidence of permanent or partial relief of headache was 61%, 73%, and 67% and that of complete relief of headache was 10%, 32%, and 26%. The 0- to 48-hour area under the curve of headache score versus time was highest in group 15. The incidence of low back pain during or after the epidural blood patch was similar among groups and was of low intensity, although group 15 had the highest postprocedural back pain scores. Serious morbidity was not reported. Although the optimum volume of blood remains to be determined, we believe these findings support an attempt to administer 20 mL of autologous blood when treating postdural puncture headache in obstetric patients after unintentional dural puncture.


Effects of Ketone Bodies on Endurance Exercise.
Priorities for every athlete include improving endurance performance, optimizing training, nutrition, and recovery. Nutritional strategies are crucial to support athletes to perform at the highest level, and considering that muscular and hepatic glycogen stores are limited, alternative strategies to maximize fat metabolism have been suggested. A ketogenic diet has been proposed as a possible method of providing metabolic fuel during prolonged periods of exercise. However, clinical trials and empirical experience have produced contrasting results regarding the ergogenic value of a ketogenic diet. For this reason, using ketone esters and/or salts have been proposed to obtain nutritional ketosis without limiting carbohydrate intake. Exogenous ketones should not only represent an alternative metabolic fuel source, sparing carbohydrates, but they also may increase postexercise glycogen replenishment, decrease proteolysis, and act as metabolic modulators and signaling metabolites. While there are some encouraging results showing an increase in endurance performance, contrasting evidence regarding the efficacy of exogenous ketones for endurance performance is present and further studies should be performed to make a definitive statement.


[Role of biological membrane lipid component in hormone reception and adenylate cyclase system function].
The paper deals with a review of experimental data evidencing for an important role of phospholipids in regulation of the activity of the adenylate cyclase system sensitive to hormonal effects. These compounds play a structural role and evidently keep the receptor-enzymic complex in the state sensitive to the hormone effect. Phospholipids form a complex with the receptor subunit of adenylate cyclase or determine its microenvironment and take part in hormonal binding. Lipid components are transmitters or modulators of physico-chemical signals formed during hormone-receptor interaction. A supposition is made that phosphatidyl ethanolamine, phosphatidyl serine and probably phosphatidyl inositol interact with the catalytic subunit of adenylate cyclase and determine its activity. Supposing that several hormonal receptors are associated with adenylate cyclase only, it may be admitted that each receptor is linked with it through separate fractions of phospholipids.


Integrated photocatalytic filtration array for indoor air quality control.
Photocatalytic and filtration technologies were integrated to develop a hybrid system capable of removing and oxidizing organic pollutants from an air stream. A fluidized bed aerosol generator (FBAG) was adapted to prepare TiO(2)-loaded ventilation filters for the photodegradation of gas phase ethanol. Compared to a manually loaded filter, the ethanol photodegradation rate constant for the FBAG coated filter increased by 361%. Additionally, the presence of the photogenerated intermediate product, acetaldehyde, was reduced and the time for mineralization to CO(2) was accelerated. These improvements were attributed to the FBAG system providing a more uniform distribution of TiO(2) particles across the filter surface leading to greater accessibility by the UV light. A dual-UV-lamp system, as opposed to a single-lamp system, enhanced photocatalytic filter performance demonstrating the importance of high light irradiance and light distribution across the filter surface. Substituting the blacklight blue lamps with a UV-light-emitting-diode (UV-LED) array led to further improvement as well as suppressed the electrical energy per order (EE/O) by a factor of 6. These improvements derived from the more uniform distribution of light irradiance as well as the higher efficiency of UV-LEDs in converting electrical energy to photons.


LncRNA CRNDE Promotes ATG4B-Mediated Autophagy and Alleviates the Sensitivity of Sorafenib in Hepatocellular Carcinoma Cells.
Autophagy is closely related to the growth and drug resistance of cancer cells, and autophagy related 4B (ATG4B) performs a crucial role in the process of autophagy. The long non-coding RNA (lncRNA) colorectal neoplasia differentially expressed (CRNDE) promotes the progression of hepatocellular carcinoma (HCC), but it is unclear whether the tumor-promoting effect of CRNDE is associated with the regulation of ATG4B and autophagy. Herein, we for the first time demonstrated that CRNDE triggered autophagy via upregulating ATG4B in HCC cells. Mechanistically, CRNDE enhanced the stability of ATG4B mRNA by sequestrating miR-543, leading to the elevation of ATG4B and autophagy in HCC cells. Moreover, sorafenib induced CRNDE and ATG4B as well as autophagy in HCC cells. Knockdown of CRNDE sensitized HCC cells to sorafenib in vitro and in vivo. Collectively, these results reveal that CRNDE drives ATG4B-mediated autophagy, which attenuates the sensitivity of sorafenib in HCC cells, suggesting that the pathway CRNDE/ATG4B/autophagy may be a novel target to develop sensitizing measures of sorafenib in HCC treatment.


A quantitative study of the pathological changes in white matter in multiple system atrophy.
The density and spatial distribution of the vacuoles, glial cell nuclei and glial cytoplasmic inclusions (GCI) were studied in the white matter of various cortical and subcortical areas in 10 cases of multiple system atrophy (MSA). Vacuolation was more prevalent in subcortical than cortical areas and especially in the central tegmental tract. Glial cell nuclei widespread in all areas of the white matter studied; overall densities of glial cell nuclei being significantly greater in the central tegmental tract and frontal cortex compared with areas of the pons. The GCI were present most consistently in the external and internal capsules, the central tegmental tract and the white matter of the cerebellar cortex. The density of the vacuoles was greater in the MSA brains than in the control brains but glial cell density was similar in both groups. In the majority of areas, the pathological changes were distributed across the white matter randomly, uniformly, or in large diffuse clusters. In most areas, there were no spatial correlations between the vacuoles, glial cell nuclei and GCI. These results suggest: (i) there is significant degeneration of the white matter in MSA characterized by vacuolation and GCI; (ii) the central tegmental tract is affected significantly more than the cortical tracts; (iii) pathological changes are diffusely rather than topographically distributed across the white matter; and (iv) the development of the vacuoles and GCI appear to be unrelated phenomena.


Long-term Outcome of Pulmonary Resection for Nontuberculous Mycobacterial Pulmonary Disease.
Pulmonary resection along with multiple antimicrobial therapy has produced favorable outcomes at a few centers. However, little is known regarding the risk factors for long-term survival and microbiological recurrence after pulmonary resection for nontuberculous mycobacterial pulmonary disease (NTMPD). We evaluated the long-term outcomes of pulmonary resection, including microbiological recurrence and survival. This retrospective cohort study included 125 patients (median age, 60 years) with NTMPD treated by pulmonary resection at two referral centers between January 1994 and August 2015. Postoperative complications occurred in 27 patients (22%). The complication rate after pneumonectomy was significantly higher than those after other types of pulmonary resection (odds ratio, 4.1; 95% confidence interval [CI], 1.6-10.3; P = .005). The median follow-up period was 7.1 years. While 19 patients experienced microbiological recurrence, 26 died. Multivariate analysis revealed pneumonectomy (adjusted hazard ratio [aHR], 0.12; 95% CI, .007-.66; P = .0098) and cavitary lesions after surgery (aHR, 6.73; 95% CI, 1.68-22.7; P = .0095) to be predictors of microbiological recurrence and old age (aHR, 1.06; 95% CI, 1.01-1.13; P = .016), low body mass index (BMI; aHR for every 1-kg/m2 increase, 0.72; 95% CI, .60-.85; P < .0001), pneumonectomy (aHR, 4.38; 95% CI, 1.78-11.3; P = .014), and remnant cavitary lesions (aHR, 3.53; 95% CI, 1.35-9.57; P = .011) to be predictors of poor prognosis. Patients who could benefit from pulmonary resection should be carefully selected considering age, BMI, remnant lesions after surgery, and type of pulmonary resection.


Evidence and gaps in the literature on orthorexia nervosa.
To review the literature on the prevalence, risk groups and risk factors of the alleged eating disorder orthorexia nervosa. We searched Medline and Pubmed using several key terms relating to orthorexia nervosa (ON) and checked the reference list of the articles that we found. Attention was given to methodological problems in these studies, such as the use of non-validated assessment instruments, small sample size and sample characteristics, which make generalization of the results impossible. Eleven studies were found. The average prevalence rate for orthorexia was 6.9 % for the general population and 35-57.8 % for high-risk groups (healthcare professionals, artists). Dieticians and other healthcare professionals are at high risk of ON. Risk factors include obsessive-compulsive features, eating-related disturbances and higher socioeconomic status. Relevant clinical experience, published literature and research data have increased in the last few years. The definition and diagnostic criteria of ON remain unclear. Further studies are needed to clarify appropriate diagnostic methods and the place of ON among psychopathological categories.


The experience of long stay in high and medium secure psychiatric hospitals in England: qualitative study of the patient perspective.
Some forensic patients in England remain in secure care for long, possibly unnecessarily prolonged, periods, raising significant ethical and resource issues. Research focused on the patients in secure care has examined quality of life and service provision but not the perspectives of patients experiencing long stays. This study explored how long stay patients experience secure care, what factors they felt influenced long stay, and its impact upon treatment engagement and motivation to progress. Embedded within a larger epidemiological study, we conducted semi-structured interviews with a purposive sample of forty long stay patients from two high and six medium secure hospitals. Long stay was defined as a 5 years stay in medium secure care or 10 years in high secure care, or 15 years in a combination of high and medium secure. Transcripts were subject to thematic analysis, and narrative analysis at individual case level to explore the relationship between emergent themes. Four themes emerged illustrating participants' attribution, outlook, approach, and readiness for change. A typology of four long stay stances was developed (dynamic acceptance, dynamic resistance, static acceptance, static resistance). These illustrate differences in the extent to which participants believed being in secure care helped them to get better, and actively work towards progression and leaving secure care. There were considerable differences in how patients adopting these stances attributed the reasons for their long stay, they viewed their future, and their motivation to progress. Negative perceptions arose from excessive restrictions, treatment repetition and changes in therapeutic relationships, leading some patients to exhibiting tokenistic engagement and low motivation to progress. Planning care for long stay patients in secure psychiatric settings should take account of the differing stances patient's adopt towards engagement and progression. Service providers should be mindful of these stances and provide patients with individualised opportunities to progress through the secure care treatment pathway, avoiding treatment repetition and maintaining continuity in key professional relationships. Refocusing on quality of life may be appropriate for some long-term patients who are unwilling or unable to move on. For some long-term patients, purpose designed long stay setting may be appropriate.


Band 3-mediated Plasmodium vivax invasion is associated with transcriptional variation in PvTRAg genes.
The Plasmodium vivax reticulocyte invasion process is still poorly understood, with only a few receptor-ligand interactions identified to date. Individuals with the Southeast Asian ovalocytosis (SAO) phenotype have a deletion in the band 3 protein on the surface of erythrocytes, and are reported to have a lower incidence of clinical P. vivax malaria. Based on this observation, band 3 has been put forward as a receptor for P. vivax invasion, although direct proof is still lacking. In this study, we combined functional ex vivo invasion assays and transcriptome sequencing to uncover a band 3-mediated invasion pathway in P. vivax and potential band 3 ligands. Invasion by P. vivax field isolates was 67%-71% lower in SAO reticulocytes compared with non-SAO reticulocytes. Reticulocyte invasion was decreased by 40% and 27%-31% when blocking with an anti-band 3 polyclonal antibody and a PvTRAg38 peptide, respectively. To identify new band 3 receptor candidates, we mRNA-sequenced schizont-stage isolates used in the invasion assays, and observed high transcriptional variability in multigene and invasion-related families. Transcriptomes of isolates with low or high dependency on band 3 for invasion were compared by differential expression analysis, which produced a list of band 3 ligand candidates with high representation of PvTRAg genes. Our ex vivo invasion assays have demonstrated that band 3 is a P. vivax invasion receptor and confirm previous in vitro studies showing binding between PvTRAg38 and band 3, although the lower and variable inhibition levels observed suggest the involvement of other ligands. By coupling transcriptomes and invasion phenotypes from the same isolates, we identified a list of band 3 ligand candidates, of which the overrepresented PvTRAg genes are the most promising for future research.


Coronary artery aneurysm: a review and hypothesis regarding etiology.
Coronary artery aneurysm is an uncommon condition that can be a cause of death when it thromboses or ruptures. It is always associated with destruction of the tunica media, usually associated with atherosclerosis, and commonly associated with chronic inflammation. To review the pathology, epidemiologic and clinical features, and pathophysiology of coronary artery aneurysm, particularly new research results, drawing out implications for the understanding, diagnosis, and treatment of this condition. Pertinent literature and illustrative cases at our institution. Inflammation spilling over into the tunica media from the tunica intima may link atherosclerosis to aneurysm formation, but vasculitis without atherosclerosis causes coronary artery aneurysms in young children with Kawasaki disease. Increased proteolysis of extracellular matrix proteins is probably one mechanism of coronary artery aneurysm formation, either due to overactive matrix metalloproteinases or underactive inhibition of these proteinases, and an excess of transforming growth factor beta may be another mechanism in the pathogenesis. Coronary atherosclerosis is a universal disease of adults, but only 1.5% of them have coronary aneurysms; this small group may be those with a second coronary artery disease, such as vasculitis.


[Differential diagnosis of parapharyngeal mass].
Parapharyngeal lesions are rare. Tumors arising in the parapharyngeal space can be silent clinically for a long period of time. Physical findings like dislocation of the pharyngeal walls or cervical swelling are often recognized by chance. Representing three cases of parapharyngeal tumors the differential diagnosis of parapharyngeal masses and the importance of the magnetic resonance imaging will be shown. Mostly, parapharyngeal masses are represented by salivary gland tumors (40%-50%). The second most common tumors in the parapharyngeal space are neurogenic tumors (17%-25%). Paragangliomas are the third group of common parapharyngeal lesions (10%-15%). A mixed group of lesions like branchial cleft cysts, lymph nodes and hematogenic tumors represent the remaining part of the parapharyngeal masses (10%-33%). Most of the lesions (80%) are benign. Because of the magnetic response imaging a reliable preoperative diagnosis is possible in more than 80% of the tumors. The surgical management may also be influenced by the location of the tumor shown in the magnetic resonance imaging.


Multigeneic QTL: the laccase encoded within the soybean Rfs2/rhg1 locus inferred to underlie part of the dual resistance to cyst nematode and sudden death syndrome.
Multigeneic QTL present significant problems to analysis. Resistance to soybean (Glycine max (L) Merr.) sudden death syndrome (SDS) caused by Fusarium virguliforme was partly underlain by QRfs2 that was clustered with, or pleiotropic to, the multigeneic rhg1 locus providing resistance to soybean cyst nematode (SCN; Heterodera glycines). A group of five genes were found between the two markers that delimited the Rfs2/rhg1 locus. One of the five genes was predicted to encode an unusual diphenol oxidase (laccase; EC 126.96.36.199). The aim of this study was to characterize this member of the soybean laccase gene-family and explore its involvement in SDS resistance. A genomic clone and a full length cDNA was isolated from resistant cultivar 'Forrest' that were different among susceptible cultivars 'Asgrow 3244' and 'Williams 82' at four residues R/H168, I/M271, R/H330, E/K470. Additional differences were found in six of the seven introns and the promoter region. Transcript abundance (TA) among genotypes that varied for resistance to SDS or SCN did not differ significantly. Therefore the protein activity was inferred to underlie resistance. Protein expressed in yeast pYES2/NTB had weak enzyme activity with common substrates but good activity with root phenolics. The Forrest isoform may underlie both QRfs2 and rhg1.


Transcriptomic and Macroscopic Architectures of Multimodal Covariance Network Reveal Molecular-Structural-Functional Co-alterations.
Human cognition is usually underpinned by intrinsic structure and functional neural co-activation in spatially distributed brain regions. Owing to lacking an effective approach to quantifying the covarying of structure and functional responses, how the structural-functional circuits interact and how genes encode the relationships, to deepen our knowledge of human cognition and disease, are still unclear. Here, we propose a multimodal covariance network (MCN) construction approach to capture interregional covarying of the structural skeleton and transient functional activities for a single individual. We further explored the potential association between brain-wide gene expression patterns and structural-functional covarying in individuals involved in a gambling task and individuals with major depression disorder (MDD), adopting multimodal data from a publicly available human brain transcriptomic atlas and 2 independent cohorts. MCN analysis showed a replicable cortical structural-functional fine map in healthy individuals, and the expression of cognition- and disease phenotype-related genes was found to be spatially correlated with the corresponding MCN differences. Further analysis of cell type-specific signature genes suggests that the excitatory and inhibitory neuron transcriptomic changes could account for most of the observed correlation with task-evoked MCN differences. In contrast, changes in MCN of MDD patients were enriched for biological processes related to synapse function and neuroinflammation in astrocytes, microglia, and neurons, suggesting its promising application in developing targeted therapies for MDD patients. Collectively, these findings confirmed the correlations of MCN-related differences with brain-wide gene expression patterns, which captured genetically validated structural-functional differences at the cellular level in specific cognitive processes and psychiatric patients.


A sublethal ATP11A mutation associated with neurological deterioration causes aberrant phosphatidylcholine flipping in plasma membranes.
ATP11A translocates phosphatidylserine (PtdSer), but not phosphatidylcholine (PtdCho), from the outer to the inner leaflet of plasma membranes, thereby maintaining the asymmetric distribution of PtdSer. Here, we detected a de novo heterozygous point mutation of ATP11A in a patient with developmental delays and neurological deterioration. Mice carrying the corresponding mutation died perinatally of neurological disorders. This mutation caused an amino acid substitution (Q84E) in the first transmembrane segment of ATP11A, and mutant ATP11A flipped PtdCho. Molecular dynamics simulations revealed that the mutation allowed PtdCho binding at the substrate entry site. Aberrant PtdCho flipping markedly decreased the concentration of PtdCho in the outer leaflet of plasma membranes, whereas sphingomyelin (SM) concentrations in the outer leaflet increased. This change in the distribution of phospholipids altered cell characteristics, including cell growth, cholesterol homeostasis, and sensitivity to sphingomyelinase. Matrix-assisted laser desorption ionization-imaging mass spectrometry (MALDI-IMS) showed a marked increase of SM levels in the brains of Q84E-knockin mouse embryos. These results provide insights into the physiological importance of the substrate specificity of plasma membrane flippases for the proper distribution of PtdCho and SM.


Significance of ammonia in the genesis of gastric epithelial lesions induced by Helicobacter pylori: an in vitro study with different bacterial strains and urea concentrations.
Two Helicobacter pylori products cause cell damage both in vivo and in vitro: ammonia, from bacterial urease activity, and a vacuolating toxin named VacA. In this in vitro study, the vacuolating effect of H. pylori broth culture filtrate from a VacA-positive/urease-positive strain is compared with that of a VacA-negative/urease-positive strain and a VacA-negative/urease-negative strain. The effect of VacA and ammonia was evaluated with and without addition of 10 mM urea, a physiological concentration for the human stomach, and with and without addition of 0.5 mg/ml acetohydroxamic and (AHA), an urease inhibitor. Our data show that: (1) both urease-positive H. pylori strains caused cell vacuolation in the absence of urea, the VacA-positive strain being approximatively twice as potent as the VacA-negative strain; (2) addition of urea to the culture medium caused an approximatively 3-fold increase in the vacuolating activity of both urease-positive strains; (3) a VacA-negative/urease-negative strain did not exert any vacuolating effect, either in the presence or in the absence of urea; (4) the ratio between cell vacuolation induced by VacA-positive and VacA-negative strains was enhanced by the presence of AHA: ratio was about 2 in the absence of AHA and about 6 in the presence of AHA, either with or without urea added. The increment of vacuolation is likely due to an interaction between AHA and VacA. In conclusion, a VacA-negative/urease-positive strain becomes highly cytotoxic when physiological levels of urea are present in the incubation medium. This finding suggests that all urease-positive H. pylori strains, both with and without VacA expression, should be considered as potentially cytotoxic for the human gastric mucosa, although VacA enhances the severity of cell damage.


Power in the 'Organisation': A Soft Systems Perspective.
All systems must adapt in order to survive, this is as true for a business organisation as any other system. A business exists in a turbulent environment and in order to maintain its relationship with its environment its managers have to adapt it to the circumstances. The effect of the present pandemic is an example with some staff working from home, active blended learning in the education sector and social distancing have all created an urgency to accommodate the unprecedented consequence of the situation. To effect the necessary changes that these circumstances have generated means exercising some form of power to change operating procedures. Change creates uncertainty, the threat of the reallocation of resources, delegated power, redundancies and a change in group relationships. This produces a feeling of insecurity in those within the organisation often resulting in resistance to the proposals in an attempt to maintain the status quo. They are faced with adapting or resisting to these changes. Whilst systems models of organisational behavior provide ideas about organizing and managing an enterprise these are of limited value because of the unpredictability of change. The ubiquity of communication technologies and the rise of virtual methods of working add to the pressure for change creating a climate of anxiety. Organisational power can no longer be framed by the measures once taken for granted. To this end I adopt a soft systems perspective to explore the impact of change upon an organisation and how those within react as they attempt to cope with its impact.


Prevalence of JC and BK viruses in Patients with Colorectal Cancer: A Systematic Review and Meta- Analysis.
Polyomaviruses including BK virus (BKV) and JC virus (JCV) are widespread in human and have been associated with colorectal cancer (CRC) in some studies. The aim of present systematic review and meta-analysis article is to calculate the pooled prevalence of BKV and JCV in patients with CRC and assessing their association with this malignancy. Domestic databases and Sciences Direct, PubMed, ProQuest, Web of Sciences and Scopus were searched for relevant articles up to 2nd June 2019Two independent reviewers extracted the related data from eligible articles. The pooled prevalence and pooled odds ratio (POR) and their 95% confidence interval (95% CI) were calculated using "metaprop" and "metan" commands in Stata 14. Where I2 statistics were >50%, the random effect model was used. From 1461 relevant studies, 24 articles were eligible and included in the qualitative while 19 articles included in quantitative analysis. The pooled prevalence based on diagnostic methods varies from 29% using immunohistochemistry to 52% using nested-PCR method. The likelihood of being infected with JCV was significantly higher in CRC patients compared to healthy (POR: 4.41, 95% CI: 2.13 - 9.13) controls, normal adjacent mucosa (POR: 2.79, 95% CI: 1.3-5.9) and colorectal adenoma (POR: 3.1, 95% CI: 1.5-6.5) but was not significant when non-CRC patients used as control group. The prevalence of JCV in colorectal patients was substantially variable by different methods and targets. The significant association between JCV and CRC that was observed in the present study is not indicative of causation and should be studied more in large-scale prospective designs.


Getting Personal: How Childhood Vaccination Policies Shape the Landscape of Vaccine Exemptions.
State-mandated school entry immunization requirements in the United States play an important role in achieving high vaccine coverage, but variations in vaccine exemption policies result in a patchwork of vaccine coverage across the country. In this study, we evaluate epidemiological effects and spatial variations in nonmedical exemption (NME) rates in the context of vaccine policies. We first analyze the correlation between NME rates and vaccine coverage for 3 significant childhood vaccinations. Furthermore, we assess the effects of policy changes in a subset of states, using a correlative approach at the state level and performing a clustering analysis at the county level. We find that higher rates of exemptions are associated with lower vaccination rates of school-aged children in all cases. In a subset of states where exemption policy has recently changed, we show that the effects on statewide NME rates vary widely and that decreases in NMEs can lead to an increase in other types of exemptions. Finally, our clustering analysis in California, Illinois, and Connecticut shows that policy changes affect the spatial distribution of NMEs. Our work suggests that vaccination policies have significant impacts on patterns of herd immunity. Our findings can be used to develop evidence-based vaccine legislation.


[Features of the course of temporal-lobe epilepsy in children].
Forty-nine patients (aged 7-15 years) with temporal epilepsy were examined using clinical and electrophysiological methods; 27 children were also subjected to psychological examination and 14 of them to computerized tomography of the brain. Characteristics of temporal paroxysms and correlation between the course of epilepsy and its duration and progression are described in detail. It was shown that neuroinfections, craniocerebral traumas, perinatal pathology of the nervous system and genetic predisposition play a certain role in the genesis of temporal epilepsy. Psychological examination of patients with temporal epilepsy revealed various disorders of neuropsychic processes in 27 children. In 5 cases computer-aided tomography of the brain revealed various changes including petrifacates, cysts, foci of gliosis with partial brain atrophy and deformation of the lateral ventricles.


2D-gel spot detection and segmentation based on modified image-aware grow-cut and regional intensity information.
Proteomics, the study of proteomes, has been increasingly utilized in a wide variety of biological problems. The Two-Dimensional Gel Electrophoresis (2D-PAGE) technique is a powerful proteomics technique aiming at separation of the complex protein mixtures. Spot detection and segmentation are fundamental components of 2D-gel image analysis but remain arduous and difficult tasks. Several software packages and academic approaches are available for 2D-gel image spot detection and segmentation. Each one has its respective advantages and disadvantages and achieves a different level of success in dealing with the challenges of 2D-gel image analysis. A common characteristic of the available methods is their dependency on user intervention in order to achieve optimal results, a process that can lead to subjective and non-reproducible results. In this work, the authors propose a novel spot detection and segmentation methodology for 2D-gel images. This work introduces a novel spot detection and spot segmentation methodology that is based on a multi-thresholding scheme applied on overlapping regions of the image, a custom grow-cut algorithm, a region growing scheme and morphological operators. The performance of the proposed methodology is evaluated on real as well as synthetic 2D-gel images using well established statistical measures, including precision, sensitivity, and their weighted measure, F-measure, as well as volumetric overlap, volumetric error and volumetric overlap error. Experimental results show that the proposed methodology outperforms state-of-the-art software packages and methods proposed in the literature and results in more plausible spot boundaries and more accurate segmentation. The proposed method achieved the highest F-measure (94.8%) for spot detection and the lowest volumetric overlap error (8.3%) for the segmentation process. Evaluation against state-of-the-art 2D-gel image analysis software packages and techniques proposed in the literature, including Melanie 7, Delta2D, PDQuest and Scimo, demonstrates that the proposed approach outperforms the other methods evaluated in this work and constitutes an advantageous and reliable solution for 2D-gel image analysis.


Assessing the in vivo data on low/no-calorie sweeteners and the gut microbiota.
Low/no-calorie sweeteners (LNCS) are continually under the spotlight in terms of their safety and benefits; in 2014 a study was published linking LNCS to an enhanced risk of glucose intolerance through modulation of the gut microbiota. In response, an in-depth review of the literature was undertaken to evaluate the major contributors to potential changes in the gut microbiota and their corresponding sequelae, and to determine if consuming LNCS (e.g., acesulfame K, aspartame, cyclamate, neotame, saccharin, sucralose, steviol glycosides) contributes to changes in the microbiome based on the data reported in human and animal studies. A few rodent studies with saccharin have reported changes in the gut microbiome, but primarily at high doses that bear no relevance to human consumption. This and other studies suggesting an effect of LNCS on the gut microbiota were found to show no evidence of an actual adverse effect on human health. The sum of the data provides clear evidence that changes in the diet unrelated to LNCS consumption are likely the major determinants of change in gut microbiota numbers and phyla, confirming the viewpoint supported by all the major international food safety and health regulatory authorities that LNCS are safe at currently approved levels.


University of Wisconsin experience using the Doli S lithotriptor.
To present our initial results using the Dornier Doli S lithotriptor with the 220 electromagnetic shock wave emitter to treat urinary calculi. At present, there is no published report of the efficacy of this instrument in service in the United States. We retrospectively reviewed the outcome of shock wave lithotripsy in 270 consecutive patients with solitary renal and/or ureteral stones treated from September 1998 to October 2001 with the Dornier Doli S lithotriptor. Data were collected with respect to stone size, location, and fragmentation. Of the 270 patients treated, 204 had renal stones and 66 had ureteral stones. All patients had solitary stones. The renal stones averaged 9.7 mm in size (range 4 to 26). The ureteral stones averaged 7.8 mm (range 4 to 17). Of the renal stones, 51% were located in the renal pelvis, with 18%, 5%, and 25% located in the upper, middle, and lower poles, respectively. Of the ureteral stones, 68% were located in the proximal ureter, with 14% and 18% in the mid and distal ureter, respectively. In the renal group, 176 (86%) of 204 patients achieved clinical success. Of these patients, 148 were stone free (73%) and 28 had residual fragments less than 4 mm in size (14%). In the ureteral group, 52 (79%) of 66 patients achieved clinical success. Of these patients, 50 were stone free (76%) and 2 (3%) patients had fragments less than 4 mm in size. Thirteen (6%) of 204 patients in the renal group required retreatment. Four (6%) of 62 patients in the ureteral group required retreatment. Of the patients in whom treatment failed and who had stone analysis, 16 (76%) of 21 had stones composed of predominantly calcium oxalate monohydrate. Four patients developed steinstrasse. Two were treated with retrograde stent placement, and the other two with placement of percutaneous nephrostomy. One patient developed a known perinephric hematoma but did not require a blood transfusion. Shock wave lithotripsy using the Doli S in appropriately selected patients is an effective instrument for treating urinary calculi throughout the urinary tract.


Design of cytocompatible bacteria-repellent bio-based polyester films via an aqueous photoactivated process.
Nosocomial infections are often induced by the presence of pathogenic organisms on the surface of medical devices or hospital equipment. Chemical or topographical modifications of the surface are recognized as efficient strategies to prevent bacteria adhesion but they may have negative impact on the material interaction with living tissues. Here we have developed a photoactivated method for the modification of a biocompatible polymer, poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBHV) under aqueous conditions. A photoinduced free-radical technique employing a grafting-from process in water media has been successfully performed to covalently anchored fluorine or PEG groups onto PHBHV surfaces. PEGylated hydrophilic surfaces showed higher bacteria-repellency performances than fluorinated hydrophobic films, achieving a >98% anti-adhesion efficiency against Escherichia coli and Staphylococcus aureus. In addition, these surfaces allowed for the adhesion and proliferation of human dermal fibroblasts without the evidence of cytotoxicity.


Implicit play or explicit cognitive behaviour therapy: The impact of intervention approaches to facilitate social skills development in adolescents.
Early adolescence is a time of increased social interaction with peers. Social competence is related to pretend play ability in younger children, but a lack of pretend play ability in childhood may also be associated with social challenges in early adolescence. Adolescents who find social situations challenging experience alienation from peers resulting in lowered self-regard. This paper presents an exploratory study comparing an Implicit group intervention (age-appropriate play based group (PB)) to an Explicit group intervention Cognitive Behavioural Therapy (CBT) to increase social ability in adolescents. Six adolescents, three female and three male, were in the Implicit group (PB; mean age 12.3 years, SD = 1.21). Six male adolescents were in the Explicit group (CBT; mean age 13.3 years, SD = 1.03). All participants were assessed pre- and post the 8-week intervention for social competence, cognitive flexibility and narrative ability. The Implicit group (PB) was assessed through an age appropriate play assessment. Seven participants had a formal diagnosis, including autism spectrum disorder, and all were in mainstream high schools. The Explicit group (CBT) showed a medium effect for social engagement, total social skills, emotional engagement and a large effect for a decrease in flexible thinking. The Implicit group (PB) showed a large impact for narrative ability with increases in ability to sequence events, initiation and creation of plot, understanding character roles and total movie score, with medium effects for generation of problems, precise vocabulary and use of symbols. The Implicit group (PB) maintained cognitive flexibility, and decreased in social self-scoring which showed medium effects for externalising and internalising. This paper contributes to evidence that the choice of social skills intervention impacts different skill sets. For neuro-diverse adolescents, the cognitive intervention impacted social and emotional engagement and the play-based intervention impacted a wider range of abilities related to narrative social interaction.


Evaluation of 'TRY': an algorithm for neonatal continuous positive airways pressure in low-income settings.
Non-invasive respiratory support using bubble continuous positive airway pressure (bCPAP) is useful in treating babies with respiratory distress syndrome. Despite its proven clinical and cost-effectiveness, implementation is hampered by the inappropriate administration of bCPAP in low-resource settings. A clinical algorithm-'TRY' (based on Tone: good; Respiratory distress; Yes, heart rate above 100 beats/min)-has been developed to correctly identify which newborns would benefit most from bCPAP in a teaching hospital in Malawi. To evaluate the reliability, sensitivity and specificity of TRY when employed by nurses in a Malawian district hospital. Nursing staff in a Malawian district hospital baby unit were asked, over a 2-month period, to complete TRY assessments for every newly admitted baby with the following inclusion criteria: clinical evidence of respiratory distress and/or birth weight less than 1.3 kg. A visiting paediatrician, blinded to nurses' assessments, concurrently assessed each baby, providing both a TRY assessment and a clinical decision regarding the need for CPAP administration. Inter-rater reliability was calculated comparing nursing and paediatrician TRY assessment outcomes. Sensitivity and specificity were estimated comparing nurse TRY assessments against the paediatrician's clinical decision. Two hundred and eighty-seven infants were admitted during the study period; 145 (51%) of these met the inclusion criteria, and of these 57 (39%) received joint assessments. The inter-rater reliability was high (kappa 0.822). Sensitivity and specificity were 92% and 96%, respectively. District hospital nurses, using the TRY-CPAP algorithm, reliably identified babies that might benefit from bCPAP and thus improved its effective implementation.


Community-based health efforts for the prevention of falls in the elderly.
Falls are a major public health problem in the elderly population. The associated health care cost is great. It has therefore become an important public health matter to evaluate those interventions that might be effective in reducing the risk of falls. Risk factors that predict an increased risk of falling are described. We discuss interventions that can be employed in the community to reduce the risk of falls and associated injuries by discipline, including physiotherapy, occupational therapy, and physician-led interventions. We also discuss the cost-effectiveness of such interventions.


Within-Subject Performance on a Real-Life, Complex Task and Traditional Lab Experiments: Measures of Word Learning, Raven Matrices, Tapping, and CPR.
In this data report, we describe a three-session experiment spanning six months. Several well-controlled laboratory tasks (Word Learning, Raven Matrices, and Tapping) and Cardiopulmonary Resuscitation (CPR), a complex but well-defined real-world task, were administered. Data are reported from 50 participants for the first session, 40 for the second, and 34 for the third. CPR is a useful domain for studying real-world performance inside the laboratory because clear performance standards can be applied to quantifying learners' proficiency covering both the first steps that need to be taken prior to the initiation of CPR (declarative knowledge) as well as the compressions and ventilations themselves (procedural skill). This research resulted in a rich dataset with a range of different measures for all participants. For all tasks, the complete set of raw data are made available along with relevant aggregate performance scores (see https://osf.io/m8bxe/). The raw data in particular will enable other researchers to explore potential analyses and modeling beyond the scope of our own. The details of the data collection protocol and available data are documented here to facilitate this process.


Genetics of psychic ability - A pilot case-control exome sequencing study.
It is commonly believed that psychic ability, like many mental and physical traits, runs in families. This suggests the presence of a genetic component. If such a component were found, it would constitute a biological marker of psychic ability and inform environmental or pharmacologic means of enhancing or suppressing this ability. A case-control study design was used to evaluate differences between psychic cases and non-psychic controls. Over 3,000 candidates globally were screened through two online surveys to locate people who claimed they and other family members were psychic. Measures of relevance to the claimed abilities (e.g., absorption, empathy, schizotypy) were collected and based on those responses, individuals with indications of psychotic or delusional tendencies were excluded from further consideration. Eligible candidates were then interviewed and completed additional screening tests. Thirteen individuals were selected as the final "psychic cases," and ten age-, sex-, and ethnicity-matched individuals with no claims of psychic ability were selected as controls. DNA from the saliva of these 23 participants was subjected to whole-exome sequencing. Two independent bioinformatics analyses were blindly applied to the sequenced data, one focusing exclusively on protein-coding sequences and another that also included some adjacent noncoding sequences. Sequencing data were obtained for all samples, except for one in the control group that did not pass the quality controls and was not included in further analyses. After unblinding the datasets, none of the protein-coding sequences (i.e., exons) showed any variation that discriminated between cases and controls. However, a difference was observed in the intron (i.e., non-protein-coding region) adjacent to an exon in the TNRC18 gene (Trinucleotide Repeat-Containing Gene 18 Protein) on chromosome 7. This variation, an alteration of GG to GA, was found in 7 of 9 controls and was absent from all psychic cases. The most conservative interpretation of these results is that they result from random population sampling. However, when the results are considered in relation to other lines of evidence, the results are more provocative. Further research is justified to replicate and extend these findings.


Bronchial embolisation for infected pulmonary artery pseudoaneurysms causing haemoptysis.
To report the authors' experience of bronchial artery embolisation (BAE) in a series of patients to control haemoptysis associated with infected pulmonary artery pseudoaneurysms (PAPs). All patients who underwent BAE based on computed tomography angiography (CTA) findings indicative of haemoptysis between February 2019 and September 2022 at Xiangyang Central Hospital were identified. Charts of patients with haemoptysis and infectious PAPs were reviewed retrospectively. Data were collected data on age, sex, underlying pathology, source pulmonary artery of the PAP, association with cavitary lesions or consolidation, systemic angiography findings, technical and clinical success, and follow-up. Seventeen PAPs were treated in 16 patients, with a mean age of 60.3 years (range: 37-82 years). The most common underlying cause was tuberculosis (15/16, 93.8%). Imaging by CTA did not identify the source pulmonary artery for 15 (88.2%) PAPs; all were associated with cavitary lesions or consolidation. All PAPs were visualised on systemic angiography. The technical and clinical success rates were both 87.5%. Two patients who experienced a recurrence of haemoptysis during follow-up underwent repeat CTA, which confirmed the elimination of the previous PAP. BAE may be a valuable technique to control haemoptysis associated with infectious PAPs that are visualised on systemic angiography. A possible contributing factor is PAPs arising from very small pulmonary arteries.


Potential of FX06 to prevent disease progression in hospitalized non-intubated COVID-19 patients - the randomized, EU-wide, placebo-controlled, phase II study design of IXION.
More than 2.7 million hospitalizations of COVID-19-infected patients have occurred in Europe alone since the outbreak of the coronavirus in 2020. Interventions against SARS-CoV-2 are still in high need to prevent admissions to ICUs worldwide. FX06, a naturally occurring peptide in humans and other mammals, has the potential to reduce capillary leak by improving endothelial dysfunction and thus preventing the deterioration of patients. With IXION, we want to investigate the potential of FX06 to prevent disease progression in hospitalized, non-intubated COVID-19 patients. IXION is an EU-wide, multicentre, placebo-controlled, double-blinded, parallel, randomized (2:1) phase II clinical study. Patient recruitment will start in September 2022 (to Q2/2023) in Germany, Italy, Lithuania, Spain, Romania, Portugal, and France. A total of 306 hospitalized patients (≥ 18 years and < 75 years) with a positive SARS-CoV-2 PCR test and a COVID-19 severity of 4-6 according to the WHO scale will be enrolled. After randomization to FX06 or placebo, patients will be assessed until day 28 (and followed up until day 60). FX06 (2 × 200 mg per day) or placebo will be administered intravenously for 5 consecutive days. The primary endpoint is to demonstrate a difference in the proportion of patients with progressed/worsened disease state in patients receiving FX06 compared to patients receiving placebo. Secondary endpoints are lung function, oxygen saturation and breathing rate, systemic inflammation, survival, capillary refill time, duration of hospital stay, and drug accountability. With IXION, the multidisciplinary consortium aims to deliver a new therapy in addition to standard care against SARS-CoV-2 for the clinical management of COVID-19 during mild and moderate stages. Potential limitations might refer to a lack of recruiting and drop-out due to various possible protocol violations. While we controlled for drop-outs in the same size estimation, recruitment problems may be subject to external problems difficult to control for. EudraCT 2021-005059-35 . Registered on 12 December 2021. Study Code TMP-2204-2021-47.


Environmental Enrichment Ameliorates Behavioral Impairments Modeling Schizophrenia in Mice Lacking Metabotropic Glutamate Receptor 5.
Schizophrenia arises from a complex interplay between genetic and environmental factors. Abnormalities in glutamatergic signaling have been proposed to underlie the emergence of symptoms, in light of various lines of evidence, including the psychotomimetic effects of NMDA receptor antagonists. Metabotropic glutamate receptor 5 (mGlu5) has also been implicated in the disorder, and has been shown to physically interact with NMDA receptors. To clarify the role of mGlu5-dependent behavioral expression by environmental factors, we assessed mGlu5 knockout (KO) mice after exposure to environmental enrichment (EE) or reared under standard conditions. The mGlu5 KO mice showed reduced prepulse inhibition (PPI), long-term memory deficits, and spontaneous locomotor hyperactivity, which were all attenuated by EE. Examining the cellular impact of genetic and environmental manipulation, we show that EE significantly increased pyramidal cell dendritic branching and BDNF protein levels in the hippocampus of wild-type mice; however, mGlu5 KO mice were resistant to these alterations, suggesting that mGlu5 is critical to these responses. A selective effect of EE on the behavioral response to the NMDA receptor antagonist MK-801 in mGlu5 KO mice was seen. MK-801-induced hyperlocomotion was further potentiated in enriched mGlu5 KO mice and treatment with MK-801 reinstated PPI disruption in EE mGlu5 KO mice only, a response that is absent under standard housing conditions. Together, these results demonstrate an important role for mGlu5 in environmental modulation of schizophrenia-related behavioral impairments. Furthermore, this role of the mGlu5 receptor is mediated by interaction with NMDA receptor function, which may inform development of novel therapeutics.


Component Analysis of the Illegal Handmade Pills and Capsules for Self-Medicating Substance Dependence in Tehran, Iran.
To self-medicate substance dependence, many substance users consume herbal medicines delivered in herbal medicine shops which are prepared through non-standard methods using a variety of different materials. Hence, the present study was carried out aiming to investigate and analyze the content of such herbal medicines. Four herbal medicine shops were selected from each of the 22 zones of Tehran City, Iran, and a total of 95 samples were purchased. A package containing 6 types of medication that was advertised by a satellite TV channel, was also purchased. Using high-performance liquid chromatography (HPLC) method, the samples were analyzed in the laboratory to detect different types of materials. Among the samples, 23 and 72 samples were uncovered compressed pills (Dragon pills) and capsules filled with colored powders (handmade self-medicating substance dependence capsules), respectively. The package advertised in the satellite TV was prepared in 6 various forms. The most common substances present in all the samples were as follows: diphenoxylate, tramadol, opioids, acetaminophen, and codeine with values of 90%, 86%, 78%, 69%, and 68%, respectively. On average, 5 of the above mentioned substances were present in each sample; moreover, 63% of the samples contained 5 or more substances. In addition, 42 (41%) of the samples contained all the 5 main substances including opioids, codeine, tramadol, diphenoxylate, and acetaminophen. The findings of this study showed that handmade capsules and pills used for self-medicating substance dependence and also medicines advertised in the satellite TV channels contain different amounts of opioids, amphetamine, benzodiazepines, tramadol, codeine, and other substances that cause problems for substance users who are going to abandon substance abuse.


Behavioral effects of modafinil in marmoset monkeys.
Modafinil is increasingly used in sleep disturbances in general and in neurodegenerative diseases and is recently being used in healthy people for attention control. However, the application of modafinil is possibly not only restricted to alertness enhancing effects. More insight in this compound may lead to new applications. Not all behavioral aspects have been studied sufficiently; therefore, more detailed investigations on modafinil's positive and aversive behavioral effects are addressed in this paper. Determination of effects of modafinil in marmoset monkeys with observational methods and with behavioral tests measuring locomotor activity, hand-eye coordination, response to a threat situation and startle response. Two hours after oral administration of modafinil in doses of 50, 100, 150, and 225 mg/kg, animals were observed and tested in the behavioral test systems. Locomotor activity was increased after 100 mg/kg modafinil in the Bungalow test and after 100, 150, and 225 mg/kg, as found in the movement parameters of the human threat test. Moreover, modafinil showed anxiolytic-like effects in the human threat test. No other side effects were observed, nor were the hand-eye coordination and startle response affected. Besides psychostimulation, modafinil has no aversive effects in the doses used in the domains measured. The potential anxiolytic-like effects of modafinil may create new possibilities for the therapeutic use of modafinil.


Measurement of muscle protein degradation in live mice by accumulation of bestatin-induced peptides.
Bestatin, an aminopeptidase inhibitor, permits the degradation of cellular proteins to di- and tripeptides but interferes with the further breakdown of these peptides to amino acids. We propose to measure instant rates of protein degradation in skeletal muscles of intact mice by the accumulation of bestatin-induced intermediates. Muscle protein was labeled by injection of L-[guanidino-14C]arginine; 3 days later, maximum accumulation of intermediates was measured in abdominal wall muscles 10 min after the intravenous injection of 5 mg of bestatin. The peptides were partially purified and hydrolyzed in 6 N HCl, and the radioactivity in peptide-derived arginine was determined, after conversion to 14CO2 by treatment with arginase and urease. The measurement of bestatin-induced intermediates provides a unique tool for studying acute changes in muscle protein turnover in live mice. We observed a 62% increase in muscle protein breakdown after a 16-h fast, which was reversed by refeeding for 3.5 h, and a 38% increase after 3 days of protein depletion.


Imaging of the hepatic arterial infusion pump: Primer for radiologists.
Hepatic arterial infusion (HAI) pumps are used to deliver liver-directed therapy by allowing the administration of selective chemotherapy to the liver via a catheter implanted most commonly into the gastroduodenal artery connected to a subcutaneous pump. This selective administration helps maximize the chemotherapeutic effect within the hepatic tumors while minimizing systemic toxicity. While HAI therapy has primarily been used to treat liver-only metastatic colorectal cancer, the indications have expanded to other malignancies, including intrahepatic cholangiocarcinoma. Radiologists play an important role in pre-operative planning, assessment of treatment response, and evaluation for potential complications using various imaging studies, including computed tomography angiography, magnetic resonance imaging, and perfusion scintigraphy. This article describes the radiologist's role as part of a multi-disciplinary oncology team to help maximize the success of HAI therapy and also helps radiologists familiarize themselves with various aspects of HAI pumps.


Molecular characterization of pncA gene mutations in Mycobacterium tuberculosis clinical isolates from China.
A sample of 35 pyrazinamide (PZA)-resistant and 30 PZA-susceptible clinical isolates recovered from Beijing and Taiyuan City, China were characterized by SSCP and sequence analysis for mutations in the pncA gene that encodes the Mycobacterium tuberculosis PZase. The purpose of this study was to understand the molecular basis and the characteristics of pncA gene mutations and its relation to PZA resistance in M. tuberculosis strains from China. Several mutations with base changes leading to amino acid substitutions were found in the PZA-resistant isolates. No mutations were seen in the 243 PZA-susceptible isolates. Among the 35 PZA-resistant isolates, 32 isolates (91.4%) had nucleotide substitutions, insertions and deletions that resulted in amino-acid substitution; or frameshifts in some strains. Other previously uncharacterized mutations were found as follows: Asn118->Thr, CG insertion at position 501; CC insertion at nucleotide position 403; a 8 base-pair deletion at start codon; Pro54->Thr; AG insertion at 368; Tyr41->His, Ser88->stop, and A insertion at nucleotide position 301. IS6110 subtyping revealed that each strain was unique; indicative of the epidemiologic independence of the isolates.


Cholera outbreaks in South and Southeast Asia: descriptive analysis, 2003-2012.
We conducted descriptive analysis of available information regarding the epidemiology of cholera outbreaks in South and Southeast Asia during 2003-2012. Information from 58 articles, 8 reports, and World Health Organization databases were analyzed. Overall, 113 cholera outbreaks were studied in South and Southeast Asia during the past 10 years. The majority of the outbreaks (69%) occurred in Southeast Asia, including India (52%). The highest number of outbreaks was observed in 2004 (25.7%). The most commonly identified source was contaminated water: however, in some countries, the spread of cholera was facilitated via contaminated seafood (e.g., Myanmar, Thailand, and Singapore). Several genotypes and phenotypes of Vibrio cholerae, the causative agent of cholera, were identified in the outbreaks, including V. cholerae O1 El Tor (Ogawa and Inaba) and V. cholerae O139. The emergence of multidrug-resistant V. cholerae strains was a major concern. Cholera-related mortality was found to be low across the outbreaks, except in Orissa, India (currently Odisha) during 2007, where the case fatality rate was 8.6%. Potential limitations included underreporting, discrepancies, possible exclusion of nonindexed reports, and incomprehensive search terms. The provision of safe water and proper sanitation appear to be critical for the control of further spread of cholera in South Asian and Southeast Asian regions.