UK research funding bodies' views towards public participation in health-related research decisions: an exploratory study.
A challenge facing science is how to renew and improve its relationship with society. One potential solution is to ensure that the public are more involved in the scientific process from the inception of research plans to scientific dissemination strategies. However, to date, little is known about how research funding bodies view public participation in research funding decisions, and how they involve the public into their strategies and practices. This paper provides insights into how key representatives working in the UK non-commercial research funding sector perceive public participation in health-related research funding decisions and the possible implications of these. We conducted qualitative semi-structured interviews with 30 key stakeholders from 10 UK non-commercial research funding bodies that either partially or exclusively fund health-related research. The findings were written up in thematic narrative form. The different disciplines that encompass health research, and their differing frames of 'science and society', were found to influence how research funding bodies viewed and implemented public participation in research funding decisions. Relevant subsets of the public were more likely to be involved in research funding decisions than lay public, which could be linked to underlying technocratic rationales. Concerns about public participation stemmed from the highly professionalised scientific environment that the public were exposed to. Additionally, from a more positivist frame, concerns arose regarding subjective views and values held by the public that may damage the integrity of science. Underlying assumptions of technocracy largely appear to be driving PP/PE within the research grant review process, even in funding bodies that have overtly democratic ideals. Some conceptions of technocracy were more inclusive than others, welcoming different types of expertise such as patient or research-user experiences and knowledge, while others suggested taking a narrower and more positivist view of expertise as techno-scientific expertise. For research to have its maximum impact when translated into healthcare, health policies and health technologies, there needs to be sensitivity towards multiple frames of knowledge, expertise and underlying values that exist across science and society.


The history of urinary diversion.
The earliest attempt to divert urine flow from the ureters to the intestine, was performed in 1851 by John Simon. In the absence of antibiotics, ureterosigmoidostomy and its modifications during the 19th and early 20th century have been associated with high rate of surgical and metabolic complications. In 1910, Robert Coffey demonstrated a new method for ureterointestinal anastomosis, which renovated primary enthusiasm in ureterosigmoidostomy and it gained broad popularity during the next forty years. In 1950, Ferris and Odel reported 80% incidence of hyperchloremic metabolic acidosis following ureterosigmoidostomy. Based on further investigations by Lapides in 1951, Parsons, Powel and Pyrah in 1952, and Stamey in 1956, which clearly demonstrated that hyperchloremic metabolic acidosis is inevitable complication of ureterosigmoidostomy, this urinary diversion lost its popularity. In 1950's ileal conduit, popularized by Bricker, became the gold standard for the subsequent 35 years. Early attempts for continent urinary diversion occurred form 1888, by Guido Tizzoni and Alfonso Poggi, while the first reservoir-type ileal loop urinary diversion was performed by Cuneo in 1911. By better understanding of principles of detubularization, based on works of Kock and principles of clean intermittent catheterization, established by Lapides, interest in continent urinary diversion has increased. Up to date, various continent cutaneous stomal reservoirs, sigmoidorectal pouches and orthotopic bladder substitutes have been described. Regarding encouraging improvements in biocompatible materials, alloplastic bladder replacement could be the next step for the future in bladder replacement surgery.


The disc-endplate-bone-marrow complex classification: progress in our understanding of Modic vertebral endplate changes and their clinical relevance.
The disc, endplate (EP), and bone marrow region of the spine form a single anatomical and functional interdependent unit; isolated degeneration of any one structure is rare. Modic changes (MC), however, are restricted to the subchondral bone alone and based on only T1 and T2 sequences of MRI. This results in poor reliability in differentiating fat from edema and hence may give a false impression of disease inactivity. To study the changes in disc, endplate, and bone marrow as a whole in degeneration and propose a classification based on the activity status of this complex with the addition of STIR MRI sequences. Observational cohort. Patients with isolated brain, cervical, or thoracic spine injury and patients with low back pain (LBP) who underwent MRI formed the control and study groups, respectively. Demographic data, the prevalence of MC and disc-endplate-bone marrow classification (DEBC) changes, EPs undergoing reclassification based on DEBC, and comparison of the prevalence of MC, DEBC, H+modifier and DEBC with H+concordance between control and LBP group. The study determined the risk of LBP patients undergoing surgery as well as the incidence of postoperative infection based on DEBC changes. Significance was calculated by binomial test and chi-square test with the effect size of 0.3 to 0.5. Prevalence and association of outcome were calculated by Altman's odds ratio with the 95% CI and the scoring of z statistics. Logistic expression was plotted for independent variables associated with each class of both Modic and DEBC against dependent variables surgery and nonsurgery. Lumbar segments in both groups were assessed for MC types. The DEBC classification was developed with the addition of STIR images and studying the interdependent complex as a whole: type-A: acute inflammation; type-B: chronic persistence; type-C: latent and type-D: inactive. Modifier H+ was added if there was disc herniation. The classification was compared with MC and correlated to clinical outcomes. A total of 3,560 EPs of 445 controls and 8,680 EPs in 1,085 patients with LBP were assessed. Four non-MC, 560 MC-II, and 22 MC-III EPs were found to have previously undetected edema in STIR (n=542) or hyperintensity in discs (n=44) needing reclassification. The formerly undescribed type-B of DEBC, representing a chronic persistent activity state was the most common (51.8%) type. The difference between the control and LBP of H+(12% vs. 28.8%) and its co-occurrence with DEBC type 1.1% vs. 23.3%) was significant (p<.0001). The odds ratio for the need for surgery was highest (OR=5.2) when H+ and DEBC type change co-occurred. Postoperative deep infection (as determined by CDC criteria) was 0.47% in non-DEBC, compared with 2.4% in patients with DEBC (p=.002), with maximum occurrence in type-B. Classification based on the classic MC was found to need a reclassification in 586 EPs showing the shortcomings of results of previous studies. Considering the DEBC allowed better classification and better predictability for the need for surgical intervention and incidence of postoperative infection rate than MC.


[Stability of the "amok runner syndrome"].
Running amok is considered a rare but dangerous act of violence which has been investigated predominantly on a case by case basis. German-wide data on amok cases covering the decades 1980 - 1989 and 1991 - 2000 were used to perform the first epidemiological study world-wide on the stability of socio-demographic, criminological and psychiatric variables of amok behaviour. A content analysis study on nation-wide press reports of amok cases included a total of 104 subjects who were identified by combined homicidal-suicidal acts of violence and fulfilled structured criteria originally defined according to former Malayan amok events. Amok cases in both decades were comparable except for the significant increase of weapon use, especially of firearms. Total prevalence showed a tendency to decline from 1 : 5.5 million to 1 : 8.5 million men per year, females were involved in rare single cases only. The male offenders showed a bimodal age distribution with a mean of 35 years. They were professionally well qualified, but had a 5 - 7fold higher risk of unemployment than the normal population. Motives and reasons for running amok were serious but not unusual, they varied widely and addressed all areas of daily life. Most offenders were characterized by abnormal personality patterns such as passive, aggressive, impulsive and paranoid and were in possession of firearms and previously convicted. Psychiatric diseases such as psychosis, paranoia, depression or personality disorders were present in more than 50 % of cases; further 20 % were intoxicated. The presence of psychiatric disorders influenced patterns of violent behaviour in individual subjects. Victims were predominantly unknown to the offenders. Close to one third of the amok runners committed suicide or were killed by legal authorities. Amok represents a temporarily stable syndrome of extreme violent behaviour even in modern industrialized societies. Subjects exhibit a complex combination of serious causative motives, social burden and psychiatric diseases which do not explain common causes of amok rather than the origin of amok behaviour in individual cases. Amok joins the wide spectrum of human homicidal-suicidal acts which show similarities in many aspects.


Optimal Methods of Documenting Analgesic Efficacy in Neonatal Piglets Undergoing Castration.
Analgesic products for piglet castration are critically needed. This requires extensive animal experimentation such as to meet regulatory-required proof of efficacy. At present, there are no validated methods of assessing pain in neonatal piglets. This poses challenges for investigators to optimize trial design and to meet ethical obligations to minimize the number of animals needed. Pain in neonatal piglets may be subtle, transient, and/or variably expressed and, in the absence of validated methods, investigators must rely on using a range of biochemical, physiological and behavioural variables, many of which appear to have very low (or unknown) sensitivity or specificity for documenting pain, or pain-relieving effects. A previous systematic review of this subject was hampered by the high degree of variability in the literature base both in terms of methods used to assess pain and pain mitigation, as well as in outcomes reported. In this setting we provide a narrative review to assist in determining the optimal methods currently available to detect piglet pain during castration and methods to mitigate castration-induced pain. In overview, the optimal outcome variables identified are nociceptive motor and vocal response scores during castration and quantitative sensory-threshold response testing and pain-associated behaviour scores following castration.


Guidelines for optimized gene knockout using CRISPR/Cas9.
CRISPR/Cas9 technology has evolved as the most powerful approach to generate genetic models both for fundamental and preclinical research. Despite its apparent simplicity, the outcome of a genome-editing experiment can be substantially impacted by technical parameters and biological considerations. Here, we present guidelines and tools to optimize CRISPR/Cas9 genome-targeting efficiency and specificity. The nature of the target locus, the design of the single guide RNA and the choice of the delivery method should all be carefully considered prior to a genome-editing experiment. Different methods can also be used to detect off-target cleavages and decrease the risk of unwanted mutations. Together, these optimized tools and proper controls are essential to the assessment of CRISPR/Cas9 genome-editing experiments.


Age of the oldest known Homo sapiens from eastern Africa.
Efforts to date the oldest modern human fossils in eastern Africa, from Omo-Kibish1-3 and Herto4,5 in Ethiopia, have drawn on a variety of chronometric evidence, including 40Ar/39Ar ages of stratigraphically associated tuffs. The ages that are generally reported for these fossils are around 197 thousand years (kyr) for the Kibish Omo I3,6,7, and around 160-155 kyr for the Herto hominins5,8. However, the stratigraphic relationships and tephra correlations that underpin these estimates have been challenged6,8. Here we report geochemical analyses that link the Kamoya's Hominid Site (KHS) Tuff9, which conclusively overlies the member of the Omo-Kibish Formation that contains Omo I, with a major explosive eruption of Shala volcano in the Main Ethiopian Rift. By dating the proximal deposits of this eruption, we obtain a new minimum age for the Omo fossils of 233 ± 22 kyr. Contrary to previous arguments6,8, we also show that the KHS Tuff does not correlate with another widespread tephra layer, the Waidedo Vitric Tuff, and therefore cannot anchor a minimum age for the Herto fossils. Shifting the age of the oldest known Homo sapiens fossils in eastern Africa to before around 200 thousand years ago is consistent with independent evidence for greater antiquity of the modern human lineage10.


Effect of infectious bovine rhinotracheitis virus immunization on viral shedding in challenge-exposed calves treated with dexamethasone.
Calves not vaccinated with infectious bovine rhinotracheitis virus (IBRV) became latently infected when challenge exposed and treated with dexamethasone (DM). Calves that shed IBRV after DM treatment were considered to be latently infected. Vaccination with a temperature-sensitive intranasal vaccine or with formalinized IBRV in Freund's complete adjuvant (IBRV-FCA) protected some, but not all, calves against latent infection--indicating a role for the immune response in preventing latent infection. That all latently infected calves were not detected after DM treatment was indicated by the fact that after a 2nd DM treatment of 3 calves treated 6 months previously and not found to shed virus, 1 of the calves was latently infected. Latently infected calves were inoculated with successive doses of IBRV-FCA and treated with DM. Nonvaccinated calves shed virus, whereas vaccinated calves similarly treated did not shed virus. Because both groups had a comparable cell-mediated immune response, as determined by blastogenic response to IBRV, but the vaccinated group had significantly higher virus-neutralizing antibody titers, a role for humoral antibody in preventing viral shedding was indicated.


Induction of resistance to ectromelia virus infection by corynebacterium parvum in murine peritoneal macrophages.
An in vitro model has been developed to study the replication of ectromelia virus in murine macrophages (M phi). Infection of mineral oil-elicited peritoneal M phi cultures with either the virulent (Moscow) or attenuated (Hampstead) strain of ectromelia virus led to productive infections. The kinetics of virus synthesis was similar to those seen following infection of murine fibroblasts. In contrast, peritoneal M phi s activated by intraperitoneal injection of Corynebacterium parvum vaccine were found to be totally refractory to infection by the attenuated strain and significantly more resistant to the virulent strain of ectromelia virus. Administration of C. parvum doses as small as 7 micrograms were sufficient to induce antiviral activity. M phi resistance became maximal at 5-9 days after C. parvum administration; however, M phi resistance was unstable during in vitro culture. Decay of antiviral activity was detected within the first 24 hr of culture and complete virus susceptibility returned after 5 days in culture. Peritoneal exudate cells (PEC) from C. parvum-immunized mice could induce resistance in susceptible M phi cultures during overnight cocultivation. In addition, cell-free culture supernatants from C. parvum-immune PEC could also induce resistance in susceptible M phi cultures, suggesting that a soluble factor, induced by C. parvum immunization and possessing interferon activity, may account for the intrinsic resistance to ectromelia virus by activated M phi s.


Admission Laboratory Values Accurately Predict In-hospital Mortality: a Retrospective Cohort Study.
The greater the severity of illness of a patient, the more likely the patient will have a poor hospital outcome. However, hospital-wide severity of illness scores that are simple, widely available, and not diagnosis-specific are still needed. Laboratory tests could potentially be used as an alternative to estimate severity of illness. To evaluate the ability of hospital laboratory tests, as measures of severity of illness, to predict in-hospital mortality among hospitalized patients, and therefore, their potential as an alternative method to severity of illness risk adjustment. A retrospective cohort study among 38,367 adult non-trauma patients admitted to the University of Maryland Medical Center between November 2015 and November 2017 was performed. Laboratory tests (hemoglobin, platelet count, white blood cell count, urea nitrogen, creatinine, glucose, sodium, potassium, and total bicarbonate (HCO3)) were included when ordered within 24 h from the time of hospital admission. A multivariable logistic regression model to predict in-hospital mortality was constructed using a section of our cohort (n = 21,003). Model performance was evaluated using the c-statistic and the Hosmer-Lemeshow (HL) test. In addition, a calibration belt was constructed to determine a confidence interval around the calibration curve with the purpose of identifying ranges of miscalibration. Patient age and all laboratory tests predicted mortality with good discrimination (c = 0.79). Patients with abnormal HCO3 levels or leukocyte counts at admission were twice as likely to die during their hospital stay as patients with normal results. A good model calibration and fit were observed (HL = 13.9, p = 0.18). Admission laboratory tests are able to predict in-hospital mortality with good accuracy, providing an objective and widely accessible approach to severity of illness risk adjustment.


Characterization of an alpha-tubulin gene of Cryptosporidium parvum.
A gene encoding an alpha-tubulin of Cryptosporidium parvum was isolated and characterized. It had no introns, and encoded a 441-amino acid protein whose predicted ORF represented a typical alpha-tubulin protein with a MW of 50.5 kDa. This tubulin had an amino acid sequence similarity with Apicomplexa Plasmodium falciparum and Toxoplasma gondii higher than 88% and shared a number of conserved motifs.


Non-destructive equations to estimate the leaf area of Styrax pohlii and Styrax ferrugineus.
We developed linear equations to predict the leaf area (LA) of the species Styrax pohlii and Styrax ferrugineus using the width (W) and length (L) leaf dimensions. For both species the linear regression (Y=α+bX) using LA as a dependent variable vs. W × L as an independent variable was more efficient than linear regressions using L, W, L2 and W2 as independent variables. Therefore, the LA of S. pohlii can be estimated with the equation LA=0.582+0.683WL, while the LA of S. ferrugineus follows the equation LA=-0.666+0.704WL.


Effect of N-acetylcysteine on human diaphragm strength and fatigability.
Free radical injury is believed to be important in diaphragm dysfunction. N-Acetylcysteine (NAC) is a potent free radical scavenger shown in animal models to attenuate diaphragm fatigue; however, its effects on human diaphragm function are unknown. We assessed diaphragm function by electrophrenic twitch stimulation (PdiT) and twitch occlusion (to yield Pdimax) in four healthy subjects 35 +/- 3 yr of age (mean +/- SD). We intravenously administered NAC (150 mg/kg in 250 ml D5W) or placebo (CON) (250 ml D5W) in a randomized manner after subjects were premedicated with antihistamines. There were no significant side effects with the infusion. After infusion, we measured baseline Pdimax and PdiT at FRC. Diaphragm fatigue was then induced by subjects breathing through an inspiratory resistive load. Pdimax and PdiT were then measured at 15 to 30 min and 1, 2, 3, 4, and 20-25 h after fatigue. Times to fatigue were 13 +/- 4 min (CON) and 21 +/- 6 min (NAC) (p = 0.04). At 15 min after fatigue, PdiT was reduced to 40% (CON) compared with 30% (NAC) initial PdiT value (p = 0.05). Other twitch characteristics (maximal rate of relaxation and maximal contraction rate) were reduced to a greater degree after placebo compared with NAC. There were no significant differences in the rate of recovery between CON and NAC. Pdimax at 30 min after fatigue was significantly greater with NAC; however, at 1 h after fatigue, Pdimax for CON and NAC were not different, suggesting similar rates of recovery in high-frequency fatigue. These data suggest that NAC may attenuate low-frequency human diaphragm fatigue.


Septicaemia in kwashiorkor.
In blood and stool cultures from 90 Black children with kwashiorkor, the commonest organisms isolated were Gram-negative aerobic rods. The mortality rate was highest in the group who developed septicaemia. In patients with negative blood cultures, the outcome was much more favourable, although the majority of them showed evidence of respiratory and/or bowel infections. It is felt that routine antibiotic therapy is advisable in the management of kwashiorkor.


MicroRNAs in cardiometabolic disease.
Defects in homeostatic regulation of cholesterol and fatty acids are associated with major cardiometabolic risk factors that are prevalent in type 2 diabetes and atherosclerotic cardiovascular disease. Regulatory input is found at many levels; however, recent findings have revealed pivotal roles for small non-coding RNAs (microRNAs) of the endogenous RNA interference pathway in post-transcriptional control of major regulatory mechanisms underpinning cholesterol and energy homeostasis. In addition, aberrant expression of microRNAs has been implicated in marked pathophysiologic events contributing to the progression and development of atherosclerosis, including loss of endothelial integrity, vascular smooth muscle cell proliferation, neointimal hyperplasia, and foam cell formation. This review surveys the impact of microRNA-mediated regulation in biological processes governing the cholesterol/lipoprotein metabolism, fatty acid β-oxidation (eg by miR-122 and miR-33), and endothelial dysfunction related to atherosclerosis. Given the current advances in microRNA-based technologies, the clinical potential of microRNAs as novel therapeutic targets is highlighted as new alternative strategies to ameliorate cardiometabolic diseases.


Ecofriendly biopolymers and composites: Preparation and their applications in water-treatment.
Over the past few decades, the term polymer has been repeatedly used in several industries for their immense characteristics in different applications. Polymers and their composites which were prepared from chemical monomer sources turned out to be potentially harmful to the environment due to their tedious degradation process. Biopolymers are natural substitutes for synthetic polymers which can be efficiently extricated from natural sources. They are predominantly available as polymeric units as well as monomeric units that are linked covalently. These environment-friendly biopolymers and their composites can be categorized based on their numerous sources, different methods of preparation and their potential form of usage. They were found to be biocompatible and biodegradable which make them exceptionally useful in environment based applications, mainly in the process of water treatment, both potable and wastewater. Further, the biopolymer and biopolymer composites easily fit into different parts of the treatment process by acting as filtration media, adsorbents, coagulants and as flocculants. The primary focus of this review is to provide a comprehensive information of biopolymers and biopolymer composites from synthesis to their usefulness for their productive application in water treatment processes. On the whole, it can be substantiated that the biopolymers were identified to play a notable adversary to the synthetic polymers in treating waters with an indispensable need for an elaborative study in the production of the biopolymers.


Interventions to Increase Physical Activity Among Older Adults: A Meta-Analysis.
To determine the overall effectiveness of interventions designed to increase physical activity (PA) behavior among community-dwelling older adults. Comprehensive literature searching identified eligible PA intervention studies among community-dwelling adults aged 65 and older, or sample mean age of 70. Diverse study characteristics were extracted and outcome data were duplicate coded. Overall mean effect sizes (ESs) were synthesized using a random-effects model. Heterogeneity of effects was analyzed using Q and I(2) statistics. Moderator analyses were conducted using meta-analytic analogues of ANOVA and regression for dichotomous and continuous moderators, respectively. ESs were calculated from 13,829 primary study subjects. The overall mean ES for two-group posttest comparisons was 0.18 (95% CI 0.10-0.26, p < .001). This represents a difference of 620 steps/day or 73 min of PA/week between treatment and control groups. Significant moderators included the use of theory, how interventions were delivered, and cognitive plus behavioral-type intervention components. Non-significant moderators include the type of interventionist, delivery setting, and various measures of intervention dose. PA interventions significantly improved PA behavior among community-dwelling older adults. Effective PA interventions may be efficiently delivered using already available resources and personnel. Future PA intervention research should be theoretically based, incorporate more diverse subjects, and compare intervention delivery methods.


Idiopathic disseminated bacillus Calmette-Guérin infection: a French national retrospective study.
Disseminated bacillus Calmette-Guérin (BCG) infection after inoculation of live vaccine is considered to result from impaired immunity of the child. However, in half of the cases, regarded as idiopathic, no well-defined immunodeficiency condition can account for the infection. The objective of the present study is to report the prevalence, clinical features, associated infections, and outcomes of children with idiopathic disseminated BCG infection. National retrospective survey during the period from 1974 through 1994 in France. All neonatology and pediatrics units in primary care and referral centers throughout France. Data were collected from 595 (82%) of 721 units, 377 (93%) of 407 centers, and 320 (93%) of 345 cities. Selection criteria included BCG infection, dissemination to at least two areas beyond the inoculation site, and no well-defined immunodeficiency condition. Sixteen children (8 girls and 8 boys), born to families unrelated to each other but often consanguinous (5 of 16) or abroad (5 of 16). The minimal prevalence rate was estimated at 0.59 cases per 1 million vaccinated children born in France. Clinical features included fever and cachexia, disseminated BCG infection to lymph nodes (15 of 16), skin (13 of 16), soft tissues (11 of 16), lungs (11 of 16), spleen (11 of 16), liver (11 of 16), and bones (9 of 16). Eight children had associated or subsequent severe opportunistic infection (50%), with either nontyphi Salmonella enterica serotypes (7 of 16) or Mycobacterium abscessus (1 of 16). The outcome was poor: 8 children (50%) died; the cause of death was BCG infection for most children (7 of 8); 8 survived until the last follow-up (50%). Idiopathic disseminated BCG infection is a rare but severe complication of BCG vaccination. The infection probably results from an as yet unknown genetically determined immunodeficiency condition that affects the killing of intracellular bacteria such as BCG and Salmonella.


Limitations of diffusion-weighted imaging in the diagnosis of postoperative infections.
Diffusion-weighted imaging (DWI) has assumed a rapidly emerging role in the diagnosis of intracranial infection; however, its usefulness in the recognition of postoperative infection has been largely unexplored. We sought to determine the ability of DWI to accurately detect a broad range of postneurosurgical infections as well as identify individual factors that may limit its applicability. We retrospectively identified 65 patients who had undergone surgery for the confirmed diagnosis of infection between August 2001 and February 2005 and had received preoperative magnetic resonance imaging evaluation, including DWI. Fifty patients developed infections after a primary neurosurgical procedure ("postoperative" infections), whereas 15 infections occurred without antecedent intervention ("spontaneous" infections). Logistic regression analysis was used to identify factors associated with false-negative DWI findings. Additionally, we investigated the false-positive rate of DWI by retrospectively reviewing a series of 30 consecutive patients who underwent craniotomy and received postoperative DWI. Spontaneously developing cranial infections exhibited evidence of restricted diffusion in 14 out of 15 (93%) patients; however, infections that occurred postoperatively were associated with a significant false-negative rate using DWI (36%; P < 0.01). Within the subset of patients with postoperative infection, location of infection significantly correlated with the DWI false-negative rate. Infections located extradurally were less likely to demonstrate restricted diffusion compared with those located primarily within the subdural or intraparenchymal spaces. Additionally, false-positive DWI findings were observed in 11 of the 30 patients (37%) who had DWI obtained postoperatively in the absence of infection. Utilization of DWI for the diagnosis of infection after primary neurosurgical intervention is associated with an elevated false-negative rate. The absence of restricted diffusion is not sufficient to exclude the presence of pyogenic postcraniotomy infection and should not be used as the principle determinant of patient management in this clinical setting.


In vivo impairment of neutrophil recruitment during lentivirus infection.
Evidence indicates that the lentivirus, HIV, infection affects neutrophil response to bacteria and bacterial products in vitro. We used a novel model of rapid onset immunosuppression following infection with a similar lentivirus, feline immunodeficiency virus (FIV), in cats to examine neutrophil function within the microvasculature in vivo and to determine the steps that are impaired in the neutrophil recruitment cascade. In uninfected cats and cats infected neonatally with FIV, the mesentery was exteriorized, but remained autoperfused during intravital microscopy for 4 h. When the tissue was superfused with 10 micro g/ml of LPS for 4 h, intravital microscopy displayed a profound increase in neutrophil rolling at both 8 and 12 wk of age in uninfected cats. At 12 wk of age, FIV-infected animals showed a profound decrease in the number of rolling neutrophils. In vitro studies revealed that neutrophils from infected and uninfected animals rolled equally well on surrogate selectin substrata. In addition, in vivo neutrophil adhesion and emigration out of the vasculature were severely reduced, and in vitro neutrophil chemotaxis from FIV-infected animals was significantly impaired in response to fMLP or IL-8. However, FIV infection of neutrophils could not be detected. In summary, in vivo lentivirus infection with immunosuppression leads to a severe impairment in neutrophil rolling, adhesion, and emigration in response to bacterial stimulants potentially involving both endothelial and neutrophil dysfunction. These in vivo studies also indicate that neutrophil dysfunction should be taken into account when treating infections and tissue injury.


Elucidating dynamic protein-protein interactions and ubiquitination in NF-κB signaling pathways.
The Nuclear factor-kappaB (NF-κB) family of transcription factors plays critical roles in inflammatory responses and host defense; however, uncontrolled NF-κB activation can be deleterious by promoting autoimmune diseases and cancers. Lysine K63 (K63)-linked polyubiquitination has emerged as an important regulatory mechanism in NF-κB signaling by regulating dynamic protein-protein interactions that trigger NF-κB signaling. RIP1 and TRAF6 serve as key substrates of K63-linked polyubiquitin chains in tumor necrosis factor receptor (TNFR) and interleukin-1 receptor (IL-1R) pathways respectively as a mechanism to recruit TAK1 and IKK kinases by associated ubiquitin-binding adaptor molecules. Activation of IKKβ by TAK1 induces IκBα phosphorylation, degradation, and downstream NF-κB activation. The ubiquitin-editing enzyme A20 maintains transient NF-κB activation by opposing the K63-linked polyubiquitination of RIP1 and TRAF6. A20 inducibly interacts with the adaptor molecule TAX1BP1 and the E3 ligases Itch and RNF11 to form an A20 ubiquitin-editing enzyme complex. Notably, loss-of-function somatic mutations or polymorphisms in human A20 are associated with B-cell lymphomas or a variety of autoimmune diseases as a result of dysregulated NF-κB activation. In this chapter, we summarize the protocols routinely used in our laboratories to examine ubiquitination and NF-κB signaling.


Isolation, identification, and transcriptional specificity of the heat shock sigma factor sigma32 from Caulobacter crescentus.
We report the identification of the Caulobacter crescentus heat shock factor sigma32 as a 34-kDa protein that copurifies with the RNA polymerase holoenzyme. The N-terminal amino acid sequence of this protein was determined and used to design a degenerate oligonucleotide as a probe to identify the corresponding gene, rpoH, which encodes a predicted protein with a molecular mass of 33,659 Da. The amino acid sequence of this protein is similar to those of known bacterial heat shock sigma factors of Escherichia coli (41% identity), Pseudomonas aeruginosa (40% identity), and Citrobacter freundii (38% identity). The isolated C. crescentus gene complements the growth defect of an E. coli rpoH deletion strain at 37 degrees C, and Western blot (immunoblot) analysis confirmed that the gene product is related to the E. coli sigma32 protein. The purified RpoH protein in the presence of RNA polymerase core enzyme specifically recognizes the heat shock-regulated promoter P1 of the C. crescentus dnaK gene, and base pair substitutions in either the -10 or -35 region of this promoter abolish transcription. S1 nuclease mapping indicates that rpoH transcripts originate from two promoters, P1 and P2, under the normal growth conditions. The P2 promoter is similar to the sigma32 promoter consensus, and the P2-specific transcript increases dramatically during heat shock, while the P1-specific transcript remains relatively constant. These results suggest that although the structure and function of C. crescentus sigma32 appear to be very similar to those of its E. coli counterpart, the C. crescentus rpoH gene contains a novel promoter structure and may be positively autoregulated in response to environmental stress.


Practical aspects of weekly docetaxel administration schedules.
Docetaxel (Taxotere; Aventis Pharmaceuticals Inc.; Bridgewater, NJ) is a highly effective chemotherapeutic agent with proven efficacy in a number of solid tumors. However, myelosuppression can be a substantial concern when docetaxel is administered every 3 weeks. Myelosuppression can be particularly problematic in older patients and those being treated with palliative intent. Weekly dosing of docetaxel has been investigated in an effort to reduce toxicity and has been identified as a safe and effective regimen in clinical trials. Weekly docetaxel is generally administered at doses ranging from 30-40 mg/m(2)/week for 6 of 8 weeks or for 3 of 4 weeks. With weekly dosing, though efficacy is comparable, myelosuppression is substantially less, and the overall tolerability profile is better than with every-3-week dosing. Fatigue is a common toxicity associated with weekly docetaxel; other adverse effects that are seen in a minority of patients include hyperlacrimation, nail toxicity, and alopecia. These side effects are dose related and can generally be managed through dose reductions or alterations in the weekly schedule. Because of the favorable tolerability profile, weekly docetaxel is under investigation in combination with other chemotherapeutic agents and with novel targeted agents in a variety of tumor types. The results of these ongoing studies will further define the place of weekly docetaxel in cancer therapy.


Improved functional connectivity network estimation for brain networks using multivariate partial coherence.
Graphical networks and network metrics are widely used to understand and characterise brain networks and brain function. These methods can be applied to a range of electrophysiological data including electroencephalography, local field potential and single unit recordings. Functional networks are often constructed using pair-wise correlation between variables. The objective of this study is to demonstrate that functional networks can be more accurately estimated using partial correlation than with pair-wise correlation. We compared network metrics derived from unconditional and conditional graphical networks, obtained using coherence and multivariate partial coherence (MVPC), respectively. Graphical networks were constructed using coherence and MVPC estimates, and binary and weighted network metrics derived from these: node degree, path length, clustering coefficients and small-world index. Network metrics were applied to simulated and experimental single unit spike train data. Simulated data used a 10x10 grid of simulated cortical neurons with centre-surround connectivity. Conditional network metrics gave a more accurate representation of the known connectivity: Numbers of excitatory connections had range 3-11, unconditional binary node degree had range 6-80, conditional node degree had range 2-13. Experimental data used multi-electrode array recording with 19 single-units from left and right hippocampal brain areas in a rat model for epilepsy. Conditional network analysis showed similar trends to simulated data, with lower binary node degree and longer binary path lengths compared to unconditional networks. We conclude that conditional networks, where common dependencies are removed through partial coherence analysis, give a more accurate representation of the interactions in a graphical network model. These results have important implications for graphical network analyses of brain networks and suggest that functional networks should be derived using partial correlation, based on MVPC estimates, as opposed to the common approach of pair-wise correlation.


In vitro mutagenesis and SOS repair.
SOS repair in Escherichia coli (E. coli) utilizes inducible gene products to "fix" mutations in the genome. It has been supposed that an "error prone" system is induced which makes errors in the course of bypassing lesions. An alternative model has been proposed by Bridges and Woodgate which suggests that it is the elongation step rather than the insertion opposite a damaged site which is critical in SOS mutagenesis. A variety of in vitro evidence supports this more recent model. DNA polymerases can be shown to insert bases opposite non-instructional lesions in DNA. It can be demonstrated that it is the elongation rather than the insertion step which is rate limiting in such in vitro reactions. An in vitro mutagenesis system can be devised using a processive polymerase with a reduced 3'----5' exonuclease activity. This system mimics the mutagenic specificity seen in vivo.


Efficient coupling of Sec23-Sec24 to Sec13-Sec31 drives COPII-dependent collagen secretion and is essential for normal craniofacial development.
The COPII coat assembles on endoplasmic reticulum membranes to coordinate the collection of secretory cargo with the formation of transport vesicles. During COPII assembly, Sar1 deforms the membrane and recruits the Sec23-Sec24 complex (Sec23/24), which is the primary cargo-binding adaptor for the system, and Sec13-Sec31 (Sec13/31), which provides a structural outer layer for vesicle formation. Here we show that Sec13 depletion results in concomitant loss of Sec31 and juxtanuclear clustering of pre-budding complexes containing Sec23/24 and cargo. Electron microscopy reveals the presence of curved coated profiles on distended endoplasmic reticulum, indicating that Sec13/31 is not required for the generation or maintenance of the curvature. Surprisingly, export of tsO45-G-YFP, a marker of secretory cargo, is unaffected by Sec13/31 depletion; by contrast, secretion of collagen from primary fibroblasts is strongly inhibited. Suppression of Sec13 expression in zebrafish causes defects in proteoglycan deposition and skeletal abnormalities that are grossly similar to the craniofacial abnormalities of crusher mutant zebrafish and patients with cranio-lenticulo-sutural dysplasia. We conclude that efficient coupling of the inner (Sec23/24) and outer (Sec13/31) layers of the COPII coat is required to drive the export of collagen from the endoplasmic reticulum, and that highly efficient COPII assembly is essential for normal craniofacial development during embryogenesis.


A proposed structural connectivity matrices approach for the superior fronto-occipital fascicle in the Harvard-Oxford Atlas comparative framework following the Pandya comparative extrapolation principle.
A key set of connections necessary for the most complex brain functions are the long association cortico-cortical fiber tracts. These pathways have been described by the Dejerines and others using post mortem histological or brain dissection techniques. Given methodological limitations, these fiber connections have not been delineated completely in humans. Although the stem portions of fiber tracts have been identified in humans, their precise origins and terminations remain to be determined. By contrast, the origins and terminations as well as the stems of long cortico-cortical association fiber pathways in monkeys have been detailed in the macaque monkey brain using experimental tract tracing methods. Deepak Pandya made major contributions to the delineation of fiber tracts in the monkey brain. In the early 1990s, he compared his observations in monkeys with the original descriptions in humans by the Dejerines. With the advent of diffusion-weighted imaging, Dr. Pandya extended this line of investigation to the human brain with Dr. Nikos Makris. In this translational analysis of long association cortico-cortical fiber tracts, they applied a principle of extrapolation from monkey to human. In the present study, we addressed the reasoning and the complex methodology in translating brain structural connectivity from monkey to human in one cortico-cortical fiber tract, namely the superior fronto-occipital fascicle, which was delineated in both species by Dr. Pandya and colleagues. Furthermore, we represented this information in the form of connectional matrices in the context of the HOA2.0-ComPaRe framework, a homological monkey-to-human translational system used in neuroimaging.


Spatial variability in the concentrations of metals in beached microplastics.
Heavy metals and microplastics have been considered as threats to the marine environment and the interactions between these two pollutants are poorly understood. This study investigates the interactions between metals adsorbed in pellets collected randomly from 19 beaches along the coast of São Paulo State in southeastern Brazil, comparing these levels with those in virgin pellets. The samples were analyzed for Al, Cr, Cu, Fe, Mn, Sn, Ti and Zn by inductively coupled plasma optical emission spectroscopy (ICP-OES). The polymers were solubilized via acid digestion. The highest levels occurred with Fe (227.78mgkg-1 - Itaguaré) and Al (45.27mgkg-1 - Guaraú) in the same areas, which are closer to the Port of Santos. The metal adsorption on pellets collected is greater than that on virgin pellets. In this context, pellets can be considered to be a carrier for the transport of metals in the environment, even in small quantities.


Co-expression of plexin-B1 and Met in human breast and ovary tumours enhances the risk of progression.
Plex-B1, the receptor of Sema4D, has been implicated in tumour growth, angiogenesis and metastasis. The binding of Sema4D to Plex-B1 can trigger the activation of Met tyrosine kinase, thereby promoting cell dissociation and invasive growth. We tested the hypothesis that the expression of Plex-B1, either alone or in association with Met, can be of predictive value for tumour progression. The expression and distribution of Plex-B1 and Met were investigated by immunohistochemistry and immunofluorescence in 50 human neoplasias originating in the breast and ovary, and correlated with clinical-pathological data at diagnosis. Plex-B1 and Met were individually expressed in 14% and in 24% of the tumours, respectively. Plex-B1 and Met were co-expressed in 24/50 cases (48%), and in the majority of these (83%) Met was tyrosine phosphorylated. The expression of Plex-B1 or Met alone showed no significant correlation with tumour aggressiveness, whereas advanced stage tumours (III-IV) frequently showed Plex-B1-Met double-positive (9/13). Tumours co-expressing Plex-B1 and Met were characterised by worse grading and higher incidence of lymph node metastases. Out of 22 tumours with lymph node metastases, as many as 19 were Plex-B1 and Met double-positive (p=0.0008), and 17 expressed phosphorylated Met (p=0.002). Plex-B1 assumes a predictive value for unfavourable outcome when co-expressed with Met.


Disseminated Geotrichum capitatum infection with predominant liver involvement in a patient with non Hodgkin's lymphoma.
Geotrichum capitatum is an emerging opportunistic pathogen which causes invasive disease in immunocompromized patients. We describe a patient with non Hodgkin's lymphoma and disseminated infection by G. capitatum with predominant liver involvement, which was proven by repeated positive blood cultures and a liver biopsy. Staining liver biopsy demonstrated the presence of hyphal elements consistent with G. capitatum. Combined antimycotic treatment with amphotericin B and 5-flucytosine did not eradicate the mycotic infection as shown by the persistence of liver lesions.


Analysis of soybean protein-derived peptides and the effect of cultivar, environmental conditions, and processing on lunasin concentration in soybean and soy products.
Soybean, an important source of food proteins, has received increasing interest from the public because of its reported health benefits. These health benefits are attributed to its components, including isoflavones, saponins, proteins, and peptides. Lunasin, Bowman-Birk inhibitor, lectin, and beta-conglycinin are some of the biologically active peptides and proteins found in soybean. This article provides a comprehensive review on the recently used techniques in the analysis and characterization of food bioactive peptides, with emphasis on soybean peptides. The methods used to isolate and purify lunasin from defatted soybean flour were ion-exchange chromatography, ultrafiltration, and gel filtration chromatography. The identity of lunasin was established by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Western blot, matrix-assisted laser desorption ionization-time of flight, and liquid chromatography. The results on the effect of soybean cultivar and environmental factors on lunasin concentration are also reported. The highest lunasin concentration, 11.7 +/- 0.3 mg/g flour, was found in Loda soybean cultivar grown at 23 degrees C; the lowest concentration, 5.4 +/- 0.4 mg/g flour, was found in Imari soybean cultivar grown at 28 degrees C. Lunasin concentration was affected by cultivar-temperature, cultivar-soil moisture, and cultivar-temperature-soil moisture interactions. The variation on lunasin concentration suggests that its content can be improved by breeding, and by optimization of growing conditions. In summary, bioactive peptides can be accurately identified and quantified by using different techniques and conditions. In addition, lunasin concentration in soybean depends mainly on cultivar and to some extent on environmental factors, particularly temperature. Lunasin concentration in soy products was also affected by processing conditions.


[Mitral Valve Replacement with a Low-Profile Bioprosthesis in Combination with Septal Myectomy for Hypertrophic Obstructive Cardiomyopathy;Report of a Case].
An 83-year-old woman diagnosed with hypertrophic obstructive cardiomyopathy was referred to our hospital. Her echocardiogram revealed diffuse left ventricular hypertrophy, severe mitral valve regurgitation with systolic anterior motion of the mitral valve, and left ventricular obstruction with a peak outflow gradient of 142 mmHg. Cardiac catheterization revealed a peak pressure gradient of 60 mmHg across the left ventricular outflow tract. Because of the patient's advanced age, as well as uncertainty regarding our ability to resolve her mitral regurgitation, we performed mitral valve replacement with a St. Jude Medical Epic porcine low-profile bioprosthesis in combination with septal myectomy. The patient's postoperative course was uneventful. At 1 year after the operation, her functional status was New York Heart Association class I. The echocardiogram showed the peak outflow gradient markedly decreased to 9 mmHg.


Resistance of cytotoxic T lymphocytes to lysis by a clone of cytotoxic T lymphocytes.
To investigate how cytotoxic T lymphocytes (CTL) avoid killing themselves when they destroy target cells, we compared 20 different cell lines as target cells, including several CTL cell lines, for their susceptibility to lysis by CTL. Variations in recognition of this diverse set of target cells was circumvented by attaching to all of them a monoclonal antibody to the antigen-specific receptor of a cloned CTL cell line (clone 2C) and using the 2C cell line as the standard aggressor or effector cell. All of the nine tumor cell lines and the four noncytolytic T-helper cell lines tested as targets were highly susceptible to lysis by the aggressor CTL, but seven cytotoxic T-cell lines (six CTL and one T-helper cell line with cytotoxic activity) were largely resistant. These results, and the use of the lectin Con A as an alternative means for triggering CTL activity, point clearly to a level of resistance that could enable CTL to avoid their own destruction when they lyse target cells. The resistance of the cytolytic T cells did not appear to be accompanied by a similar resistance to complement-mediated lysis, indicating that mechanisms of CTL-mediated and complement-mediated lysis are not identical.


Ecological mechanisms underlying arthropod species diversity in grasslands.
Arthropods are an important component of grassland systems, contributing significantly to biodiversity and ecosystem structure and function. Climate, fire, and grazing by large herbivores are important drivers in grasslands worldwide. Arthropod responses to these drivers are highly variable and clear patterns are difficult to find, but responses are largely indirect with respect to changes in resources, species interactions, habitat structure, and habitat heterogeneity resulting from interactions among fire, grazing, and climate. Here, we review these ecological mechanisms influencing grassland arthropod diversity. We summarize hypotheses describing species diversity at local and regional scales and then discuss specific factors that may affect arthropod diversity in grassland systems. These factors include direct and indirect effects of grazing, fire, and climate, species interactions, above- and belowground interactions, and landscape-level effects.


Genetic markers may predict disease behavior in patients with ulcerative colitis.
Recent studies have suggested that HLA DRB1*0103 and allele 2 of the interleukin 1 receptor antagonist (IL-1RA) gene predict severe and extensive ulcerative colitis, respectively. The aim of this study was to test these hypotheses in patients undergoing surgery for their colitis. HLA DRB1 and DQB1 genotyping was performed in 99 patients and 472 controls. Genotyping for polymorphisms of genes encoding tumor necrosis factor alpha and IL-1RA was performed in 107 patients and 89 controls. Measurement of antineutrophil cytoplasmic antibody (ANCA) was performed in 72 patients and 58 healthy subjects by fixed neutrophil enzyme-linked immunosorbent assay and indirect immunofluorescence. The DRB1*0103 allele was increased in patients (14.1% vs. 3.2% in controls; P < 1 x 10[-5]). This association was greatest in patients with extensive disease (15.8%; P < 0.0001) or extraintestinal manifestations (22.8%; P < 0.0001): mouth ulcers (25.8%; P < 0.0001), arthritis (27.2%; P < 0.0001), and uveitis (35.7%; P < 0.0001). The DRB1*04 alleles were reduced in patients (P = 0.005). Differences were noted between extensive and distal disease in the frequency of allele 2 of IL-1RA (10.9% in distal vs. 28.6% in extensive; P = 0.01) and allele 2 homozygosity. ANCA was detected in 76.4% of patients. Carriage of IL-1RA allele 2 and tumor necrosis factor 2 allele was increased in ANCA-positive patients. Genetic markers may predict disease behavior in ulcerative colitis.


Conservative Management of Major Anastomotic Leaks Occurring after Primary Repair in Esophageal Atresia with Fistula: Role of Extrapleural Approach.
We are reporting single-institution's experience regarding the role of conservative management in 38 cases of minor and major anastomotic leaks [AL] occurring after primary surgery of esophageal atresia [EA] with tracheo-esophageal fistula [TEF] during last 17 years between 2000 and 2017. In this retrospective review, we are sharing our experience and protocol of management of AL with more emphasis to evaluate: (a) role of conservative treatment in major AL (b) role of extra-pleural approach in enhancing the success rate in conservative treatment in major AL (c) to define the criteria for major & minor leaks and (d) to evaluate the role of ventilation in primary EA surgery to control AL. All these cases were operated through extra-pleural approach and out of total 203 cases, 38[18.7%] developed anastomotic leaks. In 29 of the 38 cases [14.3%], leak was minor and in 9 cases [4.4%] the leak was a major one. All these cases of leaks were managed conservatively. All cases of major and minor leaks showed spontaneous healing except one case of minor leak that died before healing due to major cardiac anomaly. For minor leaks, average healing time was 9.5 days while for major leaks it was 17.4 days. Overall mortality was 14.8% and there was no mortality directly attributable to major or minor leak. During follow up, the incidence of stricture was 40% in cases having anastomotic leaks, while in cases without a leak, the incidence of stricture was 23.3%. These all cases of stricture responded to regular dilatations. We believe in cases of major AL, where primary repair is done by EP approach, a conservative treatment should be the treatment of choice. With this conservative approach of management of major AL, we not only save the native esophagus, the best conduit, but there is also less morbidity and mortality.


[Laboratory and clinical studies of cefdinir 5% and 10% fine granules in pediatric field].
We have carried out laboratory and clinical studies on cefdinir (CFDN) 5% and 10% fine granule preparations. The results are summarized as follows. CFDN 5% fine granule preparation was given via oral route to each of 2 children in the fasting state at a single dose of 3 mg/kg. After administration, the mean peak plasma level of CFDN was 0.76 micrograms/ml at 4 hours and the mean half-life was 1.77 hours. The mean urinary excretion rate of CFDN was 31.5% in the first 12 hours after oral administration. CFDN 10% fine granule preparation and CFDN 100 mg capsule were given via oral route 3 children and to another child in the fasting state at single doses of 3 mg/kg and 2.63 mg/kg, respectively. After administration of 10% granules the mean peak plasma level of CFDN was 0.73 micrograms/ml at 2 hours and the mean half-life was 1.62 hours. The peak serum level obtained after administration of CFDN 100 mg capsule was 0.91 micrograms/ml at 2 hours and the half-life was 1.08 hours. The mean urinary excretion rate obtained with CFDN 10% fine granules was 26.2% in the first 8 hours after oral administration and the urinary excretion rate obtained with CFDN 100 mg capsule was 19.7% in the first 12 hours after oral administration. Treatment with CFDN 5% fine granules was made for a total of 48 cases of pediatric bacterial infections including 21 cases of tonsillitis, 12 cases of scarlet fever, 3 cases of pharyngitis, 5 cases of impetigo, 1 case of subcutaneous abscess, 1 case of furuncle, 5 cases of UTI. Results obtained were excellent in 30 cases, good in 18 cases. Treatment with CFDN 10% fine granules was made for a total of 16 cases of pediatric bacterial infections including 6 cases of tonsillitis, 3 cases of pneumonia, 4 cases of scarlet fever, 2 cases of impetigo, 1 case of UTI. Results obtained were excellent in 8 cases, good in 7 cases, poor in 1 case. No significant side effects due to the drugs were observed except 2 cases (1 case with 5% preparation and another with 10%) with eosinophilia, 3 cases (all with 5%) with diarrhea and 1 case each of elevated GOT & GPT (with 5%) and elevated GOT, GPT & Al-P (with 10%).


Explaining Individual Differences in Motor Behavior by Intrinsic Functional Connectivity and Corticospinal Excitability.
Motor performance varies substantially between individuals. This variance is rooted in individuals' innate motor abilities, and should thus have a neural signature underlying these differences in behavior. Could these individual differences be detectable with neural measurements acquired at rest? Here, we tested the hypothesis that motor performance can be predicted by resting motor-system functional connectivity and motor-evoked-potentials (MEPs) induced by non-invasive brain stimulation. Twenty healthy right handed subjects performed structural and resting-state fMRI scans. On a separate day, MEPs were measured using transcranial magnetic stimulation (TMS) over the contrateral primary motor cortex (M1). At the end of the session, participants performed a finger-tapping task using their left non-dominant hand. Resting-state functional connectivity between the contralateral M1 and the supplementary motor area (SMA) predicted motor task performance, indicating that individuals with stronger resting M1-SMA functional connectivity exhibit better motor performance. This prediction was neither improved nor reduced by the addition of corticospinal excitability to the model. These results confirm that motor behavior can be predicted from neural measurements acquired prior to task performance, primarily relying on resting functional connectivity rather than corticospinal excitability. The ability to predict motor performance from resting neural markers, provides an opportunity to identify the extent of successful rehabilitation following neurological damage.


Antiresorptives overlapping ongoing teriparatide treatment result in additional increases in bone mineral density.
During teriparatide (TPTD) treatment, high levels of bone formation are accompanied by an increase in bone resorption. The aim of this work was to test if coadministration of raloxifene (RAL) or alendronate (ALN) following 9 months of ongoing TPTD therapy would reopen the anabolic window, thereby exerting additional benefit on bone mineral density (BMD). Postmenopausal women (n = 125) with severe osteoporosis on TPTD treatment for 9 months were randomized into three open-label groups for a further 9 months: ALN (70 mg/week) in addition to TPTD; RAL (60 mg/d) in addition to TPTD; or no medication in addition to TPTD. Amino-terminal propeptide of type I procollagen (P1NP) and cross-linked C-telopeptide (CTX), and areal and volumetric BMD at the lumbar spine and hip were assessed. During the combination period, P1NP concentrations did not change on TPTD monotherapy (693% ± 371%, p < 0.0001) and decreased in the ALN (360% ± 153%, p < 0.0001) and RAL (482% ± 243%, p < 0.0001) combination groups; whereas CTX did not change on TPTD monotherapy (283% ± 215%, p < 0.0001), decreased to the starting level in the ALN combination group (17% ± 72%, p = 0.39), and remained elevated in the RAL combination group (179% ± 341%, p < 0.0001). The increase in lumbar spine BMD was 5% ± 6.3% in the ALN and 6% ± 5.2% in the RAL combination groups compared with 2.8% ± 9.3% in the TPTD monotherapy group (p = 0.085 and p = 0.033, respectively). The increase of trabecular lumbar spine BMD for both the ALN and RAL combination groups was superior to TPTD monotherapy. Total hip BMD changes were 4% ± 5.3% for the ALN combination group and 1.4% ± 5.1% for the TPTD monotherapy (p = 0.032), and 1.4% ± 3.4% (p = 0.02) for the RAL combination group. With the exception of no differences in the trabecular compartment of femoral neck, volumetric BMD changes in the ALN combination group for all other comparisons were significantly superior to the two other groups. Our data suggest that ALN when added to TPTD 9 months after initiation of TPTD monotherapy results in a more robust increase in BMD, probably due to a reopening of the anabolic window. The clinical relevance of the BMD increase is unknown.


Low to moderate maternal alcohol use before and during pregnancy, and neurobehavioural outcome in the newborn infant.
Of 2002 randomly selected pregnant women recruited prospectively over a three-year period for an extensive questionnaire survey, a stratified subsample of 665 mothers was selected for mother-infant follow-up on the basis of pre-pregnancy alcohol intake. Infant outcome was assessed by detailed clinical examination and application of a modified Einstein Neonatal Behavioural Assessment Schedule (ENBAS) performed at 24 to 72 hours of age. Of the infant responses to 25 ENBAS items, only tonus showed a small but significant relationship to pre-pregnancy maternal alcohol intake. The authors conclude that low to moderate maternal alcohol intake has no significant effect on newborn neurological status.


Disruptiveness, peer experiences and adolescent smoking: a long-term longitudinal approach.
This study examined links of peer experiences (i.e. social status and affiliation with disruptive peers) throughout childhood with respect to adolescent smoking trajectories, after controlling for childhood disruptiveness. Specifically, we tested four models regarding links of peer experiences and deviant behaviours. Prospective community sample. A total of 312 children, aged 6.17 years at baseline. Growth parameters of own disruptive behaviour, disruptive behaviour of friends and social status measured at ages 7-12 years as predictors of smoking assessed at ages 13-15 years, while controlling for own disruptive behaviour at age 6 years. We found three groups with distinct profiles of smoking. One group displayed hardly any or no smoking at all; a second group showed a trajectory of increased smoking; and a third group that showed high smoking rates initially and increased in smoking intensity over time. Results support the assumption of the selection model that the link between disruptive peers and smoking is spurious and due to shared variances with own early disruptiveness. Moreover, support was found for the popularity-socialization model supporting the assumption that age-related increases in social status are associated with smoking. The findings emphasize that early disruptiveness is predictive of later smoking. In addition, it was shown that smoking becomes less deviant over time, in line with group norms. Future prevention programmes should emphasize the need to change these norms.


First Report of a de novo 10q23.31q23.33 Microdeletion: Obesity, Intellectual Disability and Microcephaly.
Intellectual disability (ID) is characterized by limited or insufficient development of mental abilities, including intellectual functioning impairments, such as learning and understanding cause-effect relationships. Some cases have ID as the only finding and are called isolated cases. Conversely, cases accompanied by facial dysmorphism, microcephaly, autism spectrum disorder, epilepsy, obesity, and congenital anomalies are called syndromic developmental delay (DD)/ID. Isolated and syndromic DD/ID cases show extreme genetic heterogeneity. Genetic etiology can be detected in approximately 40% of the cases, whereas chromosomal abnormalities are observed in 25%. Obesity is a multifactorial disease in which both genetic and environmental factors play important roles. The role of heredity in obesity has been reported to be between 40 and 70%. Array-based comparative genomic hybridization (array-CGH) can detect CNVs in the whole genome at a higher resolution than conventional cytogenetic methods. Array-CGH is currently recommended as the first-tier genetic test for ID cases worldwide. In the present study, we aimed to evaluate clinical, radiological, and genetic analyses of a 12-year and 4-month-old girl with microcephaly, ID, and obesity. In the array-CGH analysis, a 3.1-Mb deletion, arr[GRGh37] 10q23.31g23.33 (92745793_95937944)×1 was detected, and this alteration was evaluated to be pathogenic. We consider that haploinsufficiency of the candidate genes (GPR120, KIF11, EXOC6, CYP26A1, CYP26C1, and LGI1) in the deletion region may explain microcephaly, ID, obesity, seizures, and ophthalmological findings in our patient. The investigation of 10q23.31q23.33 microdeletion in cases with syndromic obesity may contribute to molecular genetic diagnosis.


Single-tooth replacement: factors affecting different prosthetic treatment modalities.
The choice between several treatment options for replacing a single missing tooth is influenced by clinical, dentist- and patient-immanent factors. This study aimed to determine the patient factors that would affect the treatment decision to replace a single missing tooth and to assess the satisfaction with several options. 200 volunteers involved (121 females and 79 males) divided into four groups, Group A: consisted of patients with conventional fixed partial dentures or patients with resin bonded fixed partial dentures. Group B: consisted of patients who received removable partial dentures while Group C: consisted of patients who received a single implant supported crown, and a control group D: consisted of patients who received no treatment. Data were collected using a questionnaire. The highest percentage of males within groups (58%) was within the removable prostheses category. The majority of the subjects in the study reported that the main reason for replacing a missing tooth was for esthetic and function. Most important factor affecting the choice between treatment modalities was damaging the neighboring teeth. Pain, post operative sensitivity and dental phobia were important factors in choosing the prosthesis type and affected the control group patients not to have any treatment. The highest satisfaction percentage among groups studied was recorded for dental implants then FPD groups, while the least percentage were in both the control and RPD groups, for all aspects of function, esthetic and speech efficiency. The final choice between FPD, RPD and implant depended on several factors which affected the decision making; among these is cost and patients' awareness of the different treatment options.


The relationship between quality of life and health-related quality of life in young males with Duchenne muscular dystrophy.
This study investigated the relationship between quality of life (QoL) and health-related quality of life (HRQoL) and assessed factors other than health that contribute to differences in QoL in young males with Duchenne muscular dystrophy (DMD). In this cross-sectional study, QoL and HRQoL measures were completed by 98 parents and 85 children. The Quality of My Life (QoML) questionnaire measured QoL and HRQoL as single-items, and the Pediatric Quality of Life 4.0 Generic Core (PedsQL) questionnaire was used as a multidimensional measure of HRQoL. Simple regression was used to examine the relationship between single-item measures of HRQoL and QoL. Multivariable regression was used to investigate factors that may contribute to difference in QoL and HRQoL. While ratings of QoL and HRQoL were significantly correlated with one another, HRQoL only accounted for 21% and 44% of the variability in QoL by child- and parent-reports respectively. None of the factors measured contributed ratings of the child's QoL to be much higher than HRQoL. QoL and HRQoL are related but distinct constructs as rated by children with DMD and their parents. Further research is needed to elucidate factors outside HRQoL that contribute to QoL. Quality of life (QoL) and health-related quality of life are distinct concepts rated by young males with Duchenne muscular dystrophy (DMD) and their parents. Factors outside of 'health' contribute to overall QoL in the paediatric population with DMD. This article's abstract has been translated into Spanish and Portuguese. Follow the links from the abstract to view the translations.


A case of the Neu-Laxova syndrome: prenatal ultrasonographic monitoring in the third trimester and the histopathological findings.
A diagnosis of the Neu-Laxova syndrome was made by ultrasonography in the third trimester of pregnancy. Initial ultrasonographic examination, at approximately 28 wk gestation, showed intrauterine growth retardation (IUGR), hypoechoic skeletal structures, kyphosis, feeble fetal activity, and restricted limb movement. Subsequent sonograms showed microcephaly with a receding forehead and prominent eyes, generalised edema and flexion deformities of limbs. Late third trimester findings included polyhydramnios, swelling and webbing of the knee and elbow joints, and severe edema of the hands and feet, giving the impression of absent digits. The clinical features of this case are consistent with group II of Curry's classification of the Neu-Laxova syndrome [Curry, 1982]. The histopathological findings, a triad of dermatological features, poor cortex formation of the long bones, and central nervous system (CNS) dysgenesis, are discussed. In view of the 25% recurrence rate, at risk pregnancies should be carefully monitored by ultrasonography: at 6-8 wk for accurate dating, at 12-16 weeks for active fetal limb movement, and at 16-24 wk for facial and skeletal anomalies, the detection of IUGR, and polyhydramnios.


Perspectives on reasons for non-adherence to medication in persons with schizophrenia in Ethiopia: a qualitative study of patients, caregivers and health workers.
Levels of non-adherence to antipsychotic medication in persons with schizophrenia in rural African settings have been shown to be comparable to those found in high-income countries. Improved understanding of the underlying reasons will help to inform intervention strategies relevant to the context. A qualitative study was conducted among persons with schizophrenia (n = 24), their caregivers (n = 19), research field workers (n = 7) and health workers (n = 1) involved in the ongoing population-based cohort study, 'The Butajira Study on Course and Outcome of Schizophrenia and Bipolar Disorder', based in rural Ethiopia. Six focus group discussions and 9 in-depth interviews were conducted to elicit perspectives on non-adherence to antipsychotic medication. Thematic analysis was used to identify prominent perspectives. Predominant reasons for non-adherence specific to a low-income country setting included inadequate availability of food to counter appetite stimulation and the perceived strength of antipsychotic medications. The vital role of the family or other social support in the absence of a statutory social safety net was emphasised. Expectations of cure, rather than need for continuing care, were reported to contribute to non-adherence in the longer-term. Many of the factors associated with non-adherence in high-income countries were also considered important in Ethiopia, including lack of insight, failure to improve with treatment, medication side effects, substance abuse, stigma and dissatisfaction with the attitude of the care provider. This study identifies additional barriers to medication adherence faced by persons with schizophrenia in Ethiopia compared to those in high-income countries. In this era of scaling up of mental health care, greater attention to provision of social and financial assistance will potentially improve adherence and thereby enable patients to benefit more fully from medication.


Psychiatric consultation with regard to requests for euthanasia or physician-assisted suicide.
The objective of this article is to describe the practice of psychiatric consultation with regard to explicit requests for euthanasia or physician-assisted suicide in the Netherlands. Written questionnaires were sent to an unselected sample of 673 Dutch psychiatrists, about half of all such specialists in the Netherlands. The response rate was 83%. Of the respondents, 36% (199 of 549) had at least once been consulted about a patient's request for physician-assisted death. The annual number of such psychiatric consultations is estimated to be 400 (about 4% of all requests for physician-assisted death). About one in four consultations is initiated by another psychiatrist. Consultants were mainly asked to assess whether the patient had a treatable mental disorder (68%) or whether the patient's request was well considered (66%). Assessment of the influence of transference and countertransference was less frequently sought (24%). Of the 221 consultation cases described, 67 (30%) ended in euthanasia or assisted suicide, whereas another 124 (56%) did not. In most, but not all, cases where the patient's request for physician-assisted death was refused, the respondent had judged that the request was not well considered or that the patient had a treatable mental disorder, or that the decision-making was influenced by transference and countertransference. We conclude that psychiatric consultation for patients requesting physician-assisted death in the Netherlands is rare, as in other countries. The issue of psychiatric consultation with regard to requests for physician-assisted death, especially in patients with a physical disease, needs to be further addressed.


Annual report on surveillance for avian influenza in poultry and wild birds in Member States of the European Union in 2021.
European Union (EU) Member States (MSs) are required to carry out surveillance for avian influenza (AI) in poultry and wild birds and notify the results to the responsible authority. In addition, Iceland, Norway, Switzerland and the United Kingdom (Northern Ireland) also implement ongoing surveillance programmes to monitor incursions of avian influenza viruses (AIVs) in poultry and wild birds. EFSA received a mandate from the European Commission to collate, validate, analyse and summarise the data resulting from these AI surveillance programmes in an annual report. The present report summarises the results of the surveillance activities carried out in MSs and the aforementioned countries in 2021. Overall, 24,290 poultry establishments (PEs) were sampled, of which 27 were seropositive for influenza A(H5) and 4 for A(H7) viruses. Seropositive PEs were found in 10 MSs and, as per previous years, the highest percentages of seropositive PEs were found in establishments raising waterfowl game birds and breeding geese. Out of these 31 seropositive PEs, 3 tested positive by polymerase chain reaction (PCR) for influenza A(H5) viruses: 1 for highly pathogenic avian influenza virus (HPAIV), 1 for low pathogenic avian influenza virus (LPAIV) and 1 with unknown virus pathogenicity. In addition, 16 countries reported PCR test results from 1,858 PEs which did not correspond to the follow-up testing of a positive serology event (e.g. in some PEs, PCR tests were used for screening). Sixty-five of these PEs in 10 MSs were found positive for AIVs. Apart from poultry, 31,382 wild birds were sampled, with 2,314 wild birds testing positive for HPAIVs by PCR. Twenty-two countries reported HPAIV-positive wild birds and most positive samples were identified as highly pathogenic avian influenza (HPAI) A(H5N8) virus. In addition, 328 wild birds tested positive for LPAIVs of the A(H5/H7) subtypes and 362 wild birds tested positive for non-A(H5/H7) subtype AIVs.


Ulinastatin improves myocardial ischemia-reperfusion injury in rats through endoplasmic reticulum stress-induced apoptosis pathway.
To investigate the protective role of ulinastatin (UTI) on myocardial ischemia-reperfusion (I/R) injury in rats via endoplasmic reticulum stress (ERS)-induced apoptosis pathway. A total of 60 rats were randomly divided into normal group (n=20), myocardial I/R model group (model group, n=20), and myocardial I/R model+UTI treatment group (treatment group, n=20). The myocardial function indicators [creatinine (Scr) and creatine kinase (CK)] were detected. Enzyme-linked immunosorbent assay (ELISA) was performed to measure serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and matrix metalloproteinase-9 (MMP-9). Meanwhile, the contents of reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA) in rat left ventricular tissues were determined by ELISA as well. The cardiac function indexes were determined via magnetic resonance imaging (MRI) and echocardiography (ECG). Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) staining assay was carried out to detect the apoptosis of myocardial tissues. Additionally, the expression levels of endoplasmic reticulum stress and apoptosis genes were measured through quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) assay and Western blotting analysis, respectively. Serum levels of alanine aminotransferase (ALT), CK, and Scr in model group were significantly higher than those in normal group (p<0.05). Besides, rats in model group had significantly lowered SOD, ejection fraction (EF, %), and fractional shortening (FS, %) than those in normal group (p<0.05). In addition, remarkably increased contents of TNF-α, IL-6, MMP-9, MDA, and ROS, as well as higher left ventricular end-diastolic diameter (LVEDd) and left ventricular end-systolic diameter (LVESd) were observed in model group in comparison with normal group (p<0.05). TUNEL staining results revealed that there were more apoptotic cells in model group than that in the other two groups (p<0.05). Expression levels of cysteine aspartic acid-specific protease 12 (Caspase-12) and glucose-regulated protein 78 (GRP78) were evidently higher in model group than those in normal group (p<0.05), while the expression level of B-cell lymphoma 2 (Bcl-2) was clearly lower in model group than that in normal group (p<0.05). UTI treatment partially reversed the above expression changes (p<0.05). UTI has a protective effect against myocardial I/R injury in rats by repressing the occurrence of ERS-induced apoptosis.


A Novel Percutaneous Snare-Assisted Manipulation and Repositioning of a ProtekDuo Cannula in a COVID-19 Acute Respiratory Distress Syndrome.
Venovenous extracorporeal membrane oxygenation [VV-ECMO] has gained increasing notoriety during the COVID-19 pandemic as a salvation therapy for fulminant respiratory failure. Various configurations can present unique challenges in management. For instance, the ProtekDuo cannula is a 29Fr to 31Fr dual-lumen cannula inserted by way of the right internal jugular vein that allows for right atrium to pulmonary artery bypass with an attached oxygenator, essentially resulting in VV-ECMO. Understanding that these different configurations inevitably dictate the types of complications that can arise during the circuit implantation and management is imperative. However, in a hemodynamically unstable patient, time or resources may not permit standard maneuvers for management. In conclusion, we present an innovative, percutaneous approach which allowed the restoration of flow and oxygenation in a decompensating ProtekDuo patient without having to explant/disconnect the circuit or implant a new VV-ECMO circuit.


[EPIGENETIC ENZYMES AS THERAPEUTIC TARGETS FOR TREATING BRAIN DISORDERS].
At present, epigenetic regulation is considered as a dynamic mechanism by means of which cells realize adaptive response to signals from both the inner medium and environment. DNA methylation, as bidirectional balance of the activity of histone-acetylation and -deacetylation (HDAC) enzymes, determines the conformation of chromatin thus playing the main role in "appropriate" gene expression. HDACs represent emerging therapeutic targets in the context of treating various forms of neurological and mental illness. A wide range of brain diseases are associated with imbalance between protein acetylation levels and tran- scriptional dysfunctions. Increasing evidence supports the notion that histone hypoacetylation and transcriptional dysfunction are involved in a large number of neurodegenerative conditions in vivo and in vitro. Histone deacetylase inhibitors (HDACIs) that affect the acetylation status of histones and other important cellular proteins--have been recognized as potentially useful therapeutic means for a broad range of human disorders. This review summarizes the current state of development of HDACIs based therapeutics and their application for the treatment of human brain neurodegenerative, ischemic, and cognitive pathologies. Treatment with various HDACIs can correct these deficiencies and has emerged as a promising new strategy for therapeutic intervention based on the experimental search and clinical testing of HDACIs representing compounds of various classes.


Extracellular remodelling during oncogenic Ras-induced epithelial-mesenchymal transition facilitates MDCK cell migration.
Epithelial-mesenchymal transition (EMT) describes a process whereby immotile epithelial cells escape structural constraints imposed by cellular architecture and acquire a phenotype characteristic of migratory mesenchymal cells. Implicated in carcinoma progression and metastasis, EMT has been the focus of several recent proteomics-based studies aimed at identifying new molecular players. To gain insights into extracellular mediators associated with EMT, we conducted an extensive proteomic analysis of the secretome from MDCK cells following oncogenic Ras-induced EMT (21D1 cells). Using Orbitrap technology and a label-free quantitative approach, differential expression of several secreted modulators were revealed. Proteomic findings were further substantiated by mRNA transcript expression analysis with 71% concordance. MDCK cells undergoing Ras-induced EMT remodel the extracellular matrix (ECM) via diminished expression of basement membrane constituents (collagen type IV and laminin 5), up-regulation of extracellular proteases (MMP-1, kallikreins -6 and -7), and increased production and secretion of ECM constituents (SPARC, collagen type I, fibulins -1 and -3, biglycan, and decorin). Collectively, these findings suggest that hierarchical regulation of a subset of extracellular effectors may coordinate a biological response during EMT that enhances cell motility. Transient silencing of MMP-1 in 21D1 cells via siRNA-mediated knockdown attenuated cell migration. Many of the secretome proteins identified broaden our understanding of the EMT process.


No increased risk of short-term complications after radical cystectomy for muscle-invasive bladder cancer among patients treated with preoperative chemotherapy: a nation-wide register-based study.
Preoperative chemotherapy is underused in conjunction with radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) due to concerns for complications and delay of surgery. Prospective data on short-term complications from population-based settings with frequent use of preoperative chemotherapy and standardised reporting of complications is lacking. We identified 1,340 patients who underwent RC between 2011 and 2015 in Sweden due to MIBC according to the Swedish Cystectomy Register. These individuals were followed through linkages to several national registers. Propensity score adjusted logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for complications and death within 90 days of surgery, comparing patients receiving preoperative chemotherapy or not. Minimum two cycles of preoperative chemotherapy were given to 519 (39%) of the patients, who on average tended to be younger, have higher education, better physical status, and more advanced bladder cancer than patients not receiving chemotherapy. After adjusting for these and other parameters, there was no association between treatment with preoperative chemotherapy and short-term complications (OR 1.06 95% CI 0.82-1.39) or mortality (OR 0.75 95% CI 0.36-1.55). We observed a risk reduction for gastrointestinal complications among patients who received preoperative chemotherapy compared with those who did not (OR 0.49 95% CI 0.30-0.81). This nation-wide population-based observational study does not suggest that preoperative chemotherapy, in a setting with high utilisation of such treatment, is associated with an increased risk of short-term complications in MIBC patients treated with radical cystectomy.


Integrative analysis of a cross-loci regulation network identifies App as a gene regulating insulin secretion from pancreatic islets.
Complex diseases result from molecular changes induced by multiple genetic factors and the environment. To derive a systems view of how genetic loci interact in the context of tissue-specific molecular networks, we constructed an F2 intercross comprised of >500 mice from diabetes-resistant (B6) and diabetes-susceptible (BTBR) mouse strains made genetically obese by the Leptin(ob/ob) mutation (Lep(ob)). High-density genotypes, diabetes-related clinical traits, and whole-transcriptome expression profiling in five tissues (white adipose, liver, pancreatic islets, hypothalamus, and gastrocnemius muscle) were determined for all mice. We performed an integrative analysis to investigate the inter-relationship among genetic factors, expression traits, and plasma insulin, a hallmark diabetes trait. Among five tissues under study, there are extensive protein-protein interactions between genes responding to different loci in adipose and pancreatic islets that potentially jointly participated in the regulation of plasma insulin. We developed a novel ranking scheme based on cross-loci protein-protein network topology and gene expression to assess each gene's potential to regulate plasma insulin. Unique candidate genes were identified in adipose tissue and islets. In islets, the Alzheimer's gene App was identified as a top candidate regulator. Islets from 17-week-old, but not 10-week-old, App knockout mice showed increased insulin secretion in response to glucose or a membrane-permeant cAMP analog, in agreement with the predictions of the network model. Our result provides a novel hypothesis on the mechanism for the connection between two aging-related diseases: Alzheimer's disease and type 2 diabetes.


Local governance and community financing of primary care: evidence from Nepal.
Improved community participation in the financing of primary health care (PHC) is important for sustaining quality and availability of care in developing countries. This study asks whether the social status of members on a local support committee is associated with community contributions to PHC. A survey of PHC financing was conducted at 42 health facilities in two rural districts of Nepal (Jumla and Nawal Parasi). Complete data were available for 37 clinics. At each health facility, a trained interviewer collected information from the clinic administrator about the caste characteristics of the Village Development Committees (VDC) and the financial contributions made by VDCs towards the operation of the health facilities. Bivariate and multivariate logistic regression assessed the likelihood of financial contribution as it related to the caste and gender composition of the VDC as well as other characteristics of the VDC and the facility. VDCs with a majority of committee members in castes other than the highest two had higher odds of contributing to the health centre. We conclude that local development committees with a greater representation of middle and low caste members are more likely to contribute financially to the local health facility. Future research must determine the factors that lead some villages to include low caste villagers in local government.


Decoding signals for membrane protein assembly using alkaline phosphatase fusions.
We have used genetic methods to investigate the role of the different domains of a bacterial cytoplasmic membrane protein, MalF, in determining its topology. This was done by analyzing the effects of MalF topology of deleting various domains of the protein using MalF-alkaline phosphatase fusion proteins. Our results show that the cytoplasmic domains of the protein are the pre-eminent topogenic signals. These domains contain information that determines their cytoplasmic location and, thus, the orientation of the membrane spanning segments surrounding them. Periplasmic domains do not appear to have equivalent information specifying their location and membrane spanning segments do not contain information defining their orientation in the membrane. The strength of cytoplasmic domains as topogenic signals varies, correlated with the density of positively charged amino acids within them.


Evidence on Virtual Reality-Based Therapies for Psychiatric Disorders: Meta-Review of Meta-Analyses.
Among all diseases globally, mental illnesses are one of the major causes of burden. As many people are resistant to conventional evidence-based treatments, there is an unmet need for the implementation of novel mental health treatments. Efforts to increase the effectiveness and benefits of evidence-based psychotherapy in psychiatry have led to the emergence of virtual reality (VR)-based interventions. These interventions have shown a wide range of advantages over conventional psychotherapies. Currently, VR-based interventions have been developed mainly for anxiety-related disorders; however, they are also used for developmental disorders, severe mental disorders, and neurocognitive disorders. This meta-review aims to summarize the current state of evidence on the efficacy of VR-based interventions for various psychiatric disorders by evaluating the quality of evidence provided by meta-analytical studies. A systematic search was performed using the following electronic databases: PubMed, PsycINFO, Web of Science, and Google Scholar (any time until February 2020). Meta-analyses were included as long as they quantitatively examined the efficacy of VR-based interventions for symptoms of a psychiatric disorder. To avoid overlap among meta-analyses, for each subanalysis included within this meta-review, only one analysis provided from one meta-analysis was selected based on the best quality of evidence. The search retrieved 11 eligible meta-analyses. The quality of evidence varied from very low to moderate quality. Several reasons account for the lower quality evidence, such as a limited number of randomized controlled trials, lack of follow-up analysis or control group, and the presence of heterogeneity and publication bias. Nonetheless, evidence has shown that VR-based interventions for anxiety-related disorders display overall medium-to-large effects when compared with inactive controls but no significant difference when compared with standard evidence-based approaches. Preliminary data have highlighted that such effects appear to be sustained in time, and subjects may fare better than active controls. Neurocognitive disorders also appear to improve with VR-based approaches, with small effects being found for various clinical outcomes (eg, cognition, emotion). Finally, there are insufficient data to classify VR-based interventions as an evidence-based practice for social skills training in neurodevelopmental disorders and compliance among patients with schizophrenia. VR provides unlimited opportunities by tailoring approaches to specific complex problems and individualizing the intervention. However, VR-based interventions have not shown superiority compared with usual evidence-based treatments. Future VR-based interventions should focus on developing innovative approaches for complex and treatment-resistant symptoms that are difficult to address with traditional treatments. Future research should also aim to gain a better understanding of the potential factors that may mediate VR outcomes to improve treatment.


Gray matter volume modifications in migraine: A cross-sectional and longitudinal study.
To explore cross-sectional and longitudinal gray matter (GM) volume changes in patients with migraine and their association with patients' clinical characteristics and disease activity. Brain T2-weighted and 3-dimensional T1-weighted scans were acquired from 73 episodic migraineurs and 46 age- and sex-matched nonmigraine controls at baseline. Twenty-four migraineurs and 25 controls agreed to be reexamined after a mean follow-up of 4 years. Using a general linear model and SPM12, a whole-brain analysis was performed to assess GM volume modifications. At baseline, compared to controls, patients with migraine showed lower cerebellar GM volume and higher volume of regions of the frontotemporal lobes. At follow-up, migraineurs were significantly older than controls. Over the follow-up, migraineurs developed an increased volume of frontotemporoparietal regions, which was more prominent in patients with a higher baseline disease activity: long disease duration and high attack frequency. Migraineurs also developed decreased GM volume of visual areas, which was related to higher pain severity. Patients with an increased attack frequency at follow-up experienced both increased and decreased volume of nociceptive regions. In migraineurs, reduced GM volume of extrastriate visual areas during the follow-up was significantly correlated to baseline disease activity: shorter disease duration and lower attack frequency. In this cohort, the migraine brain changes dynamically over time, and different pathophysiologic mechanisms can occur in response to patients' disease severity. The interaction between predisposing brain traits and experience-dependent responses might vary across different nociceptive and visual areas, thus leading to distinct patterns of longitudinal GM volume changes.


Disabled and nondisabled infants' interactions with their mothers.
This study investigated social interactions between infants and mothers, comparing dyads with physically disabled infants and dyads with nondisabled infants. The groups were matched on mental and motor development, sex, socioeconomic status, birth order, and maternal education. Each infant-mother dyad was videotaped at home during a 10-minute period of free play, and blind observers subsequently transcribed infants' and mothers' behaviors. In general, the groups were remarkably similar in their interaction patterns. However, a few differences emerged: Mothers of infants with physical disabilities were significantly more commanding than were comparison mothers. Nondisabled infants tended to engage in more eye contact than did infants with physical disabilities. And whereas mothers of nondisabled infants responded to interactive play with interactive play, mothers of infants with physical handicaps tended to respond with commands and verbalizations. These results suggest reciprocal influences between infants and mothers in both groups and highlight emerging maternal behavior patterns that may interfere with the development of communication and independence in handicapped young children.


Cone-rod dystrophy in the Guinea baboon.
Three stages of macular degeneration associated with diffuse cone-rod dystrophy have been described in a Guinea baboon (P papio) colony. Clinically, the affected animals displayed abnormal behavior associated with decreased vision. Ophthalmoscopically, the lesion in the macula was the only change observable in early cases; retinal vessel attenuation and optic disc pallor were seen only in the advanced cases. The hyperfluorescence of the maculae was the result of loss of pigment in the pigmented epithelium. Electrophysiology supported a cone-rod sequence of this retinal dystrophy. Histologic examination confirmed the theory that the dystrophy began in the cone outer segment but eventually involved all the photoreceptors.


Widespread cis-regulatory convergence between the extinct Tasmanian tiger and gray wolf.
The extinct marsupial Tasmanian tiger, or thylacine, and the eutherian gray wolf are among the most widely recognized examples of convergent evolution in mammals. Despite being distantly related, these large predators independently evolved extremely similar craniofacial morphologies, and evidence suggests that they filled similar ecological niches. Previous analyses revealed little evidence of adaptive convergence between their protein-coding genes. Thus, the genetic basis of their convergence is still unclear. Here, we identified candidate craniofacial cis-regulatory elements across vertebrates and compared their evolutionary rates in the thylacine and wolf, revealing abundant signatures of convergent positive selection. Craniofacial thylacine-wolf accelerated regions were enriched near genes involved in TGF beta (TGFB) and BMP signaling, both of which are key morphological signaling pathways with critical roles in establishing the identities and boundaries between craniofacial tissues. Similarly, enhancers of genes involved in craniofacial nerve development showed convergent selection and involvement in these pathways. Taken together, these results suggest that adaptation in cis-regulators of TGF beta and BMP signaling may provide a mechanism to explain the coevolution of developmentally and functionally integrated craniofacial structures in these species. We also found that despite major structural differences in marsupial and eutherian brains, accelerated regions in both species were common near genes with roles in brain development. Our findings support the hypothesis that, relative to protein-coding genes, positive selection on cis-regulatory elements is likely to be an essential driver of adaptive convergent evolution and may underpin thylacine-wolf phenotypic similarities.