Acetylcholine content and viability of cholinergic neurons are influenced by the activity of protein histidine phosphatase.
The first mammalian protein histidine phosphatase (PHP) was discovered in the late 90s of the last century. One of the known substrates of PHP is ATP-citrate lyase (ACL), which is responsible--amongst other functions--for providing acetyl-CoA for acetylcholine synthesis in neuronal tissues. It has been shown in previous studies that PHP downregulates the activity of ACL by dephosphorylation. According to this our present work focused on the influence of PHP activity on the acetylcholine level in cholinergic neurons. The amount of PHP in SN56 cholinergic neuroblastoma cells was increased after overexpression of PHP by using pIRES2-AcGFP1-PHP as a vector. We demonstrated that PHP overexpression reduced the acetylcholine level and induced cell death. The acetylcholine content of SN56 cells was measured by fast liquid chromatography-tandem mass spectrometry method. Overexpression of the inactive H53A-PHP mutant also induced cell damage, but in a significantly reduced manner. However, this overexpression of the inactive PHP mutant did not change the acetylcholine content of SN56 cells significantly. In contrast, PHP downregulation, performed by RNAi-technique, did not induce cell death, but significantly increased the acetylcholine content in SN56 cells. We could show for the first time that PHP downregulation increased the acetylcholine level in SN56 cells. This might be a potential therapeutic strategy for diseases involving cholinergic deficits like Alzheimer's disease.


Intelligent Imaging: Radiomics and Artificial Neural Networks in Heart Failure.
Our previous work with 123iodine meta-iodobenzylguanidine (123I-mIBG) radionuclide imaging among patients with cardiomyopathy reported limitations associated with the prognostic power of global parameters derived from planar imaging [1]. Employing multivariate analysis, we further showed the regional washout associated with territories adjacent to infarcted myocardium obtained from single-photon emission computed tomography imaging (SPECT) yielded superior prognostic power over the other planar and SPECT indices in predicting future cardiac events [1]. The aim of this study was to apply an artificial neural network (Neural Analyser version 2.9.5) to the original data from the same patient cohort to evaluate the most potent prognostic index for future cardiac events among patient with cardiomyopathy. The original data were reevaluated using an artificial neural network (Neural Analyser version 2.9.5). There were 84 input variables in the original 22 patients from clinical data, electrocardiogram (rest, stress, and continuous ambulatory electrocardiogram recording), transthoracic echocardiography, coronary angiogram, sestamibi myocardial perfusion SPECT, planar and SPECT 123I-mIBG, and genetic and biomarkers, detailed in the previous work. A single binary output was a cardiac event or no cardiac event in the follow-up period. Following training and validation phases, the optimal number of inputs was determined to be two with a training loss of 0.025 and selection loss <0.001. The final architecture had inputs of a change in left ventricular ejection fraction (Δ > -10%) and 123I-mIBG planar global washout (>30%), two hidden layers of 6 and 1 node, respectively, and a binary output. Using receiver operator characteristics analysis demonstrated an area under the curve of 0.75 correlating to a sensitivity of 100% and specificity of 50%. The premise that regional washout of 123I-mIBG SPECT from noninfarcted tissue is the best predictor of cardiac events was built on has a sound and logical foundation. By artificial neural network analysis; however, 123I-mIBG planar global washout of >30% was shown to be the best indicator for risk of cardiac event when accompanied by a decline in left ventricular ejection fraction of >10%. Further investigation should be undertaken assessing assimilation into big data and the potential for automated feature extraction from raw image datasets with convolutional neural networks.


Differential regulation of three members of the ATF/CREB family of DNA-binding proteins.
The ATF/CRE binding site can mediate transcriptional activation by cAMP, the adenovirus E1A protein and the human T-cell leukaemia virus 1 (HTLV1) tax protein. A large number of different proteins bind specifically to this element either as homodimers or as heterodimers. Using GAL4-ATF/CREB fusions, we have investigated the regulatory functions of three members of this family. CREB1 (CREB) is strongly activated by cAMP and weakly activated by the E1A protein. In contrast, CREB2 (CRE-BP1, ATF2) is strongly activated by E1A but is insensitive to cAMP stimulation. ATF1 is weakly activated by cAMP but is not activated by E1A. All three proteins are insensitive to activation by the HTLV1 tax protein. The N-terminal region of CREB2, from amino acid residues 19 to 112, is both necessary and sufficient for E1A activation. This region contains a putative C2H2 metal-binding finger, and single amino acid substitutions of the cysteine residues severely decreased CREB2 activity. In contrast, mutations affecting a potential protein kinase A and casein kinase II phosphorylation site within this region had little effect.


Mental health disorders in young urban sexual minority men.
Very few studies have examined mental disorders among male sexual minority youth. We describe demographic correlates, comorbidity, and history of mental disorders and suicidality in a large sample of male sexual minority youth. Structured diagnostic interviews were conducted with 449 racially diverse urban sexual minority males, aged 16-20 years, who were recruited using a social network-driven sampling methodology. Lifetime major depressive episode (MDE) affected 33.2% of the youth. Lifetime conduct disorder (23.6%), alcohol abuse/dependence (19.6%), posttraumatic stress disorder (PTSD; 16.0%), and nicotine dependence (10.7%) were also common. Black participants were less likely than white participants to be diagnosed with lifetime MDE, alcohol abuse/dependence, nicotine dependence, suicidal ideation, and anorexia, as well as past 12-month alcohol abuse/dependence (odds ratios [ORs] range from .08 to .46). Relative to participants identifying as gay, bisexual identified youth were at higher risk for lifetime PTSD (OR = 2.04), and participants who did not identify as gay or bisexual were at higher risk for both lifetime and past 12-month nicotine dependence (OR = 4.36 and 3.46, respectively). Most participants with mental disorders never received treatment, and comorbidity was common. MDE, conduct disorder, alcohol abuse/dependence, PTSD, and nicotine dependence are common and infrequently treated in young sexual minority men. Some within-group disparities emerged, suggesting that factors related to racial background and self-identification may help to understand resilience to the unique stressors experienced by these young men.


A size-tunable nanoplatform: enhanced MMP2-activated chemo-photodynamic immunotherapy based on biodegradable mesoporous silica nanoparticles.
Although immunotherapy is emerging as a revolutionary strategy for cancer therapy, its clinical effect is severely impaired by adaptive immune evasion and inefficient activation of antitumor immune response. Photodynamic therapy and chemotherapy have been shown to efficiently enhance the therapeutic effect of PD-L1 immunotherapy via different mechanisms. However, the lack of a precise drug delivery system seriously impedes the clinical application of combination therapy. To address these restrictions, a matrix metalloproteinases-2 (MMP2)-activated shrinkable nanosystem was developed to potentiate the antitumor efficacy of anti-PD-L1 antibody (aPDL1) delivered along with a chemo-photodynamic therapy. The nanosystem maintains its structure to accelerate tumor accumulation and shrinks down to a smaller size to facilitate tumor penetration and cellular uptake upon arriving in the tumor microenvironment. The exposure of aPDL1 on the surface of the biodegradable mesoporous silica cores (bMSNs) blocks the PD-1/PD-L1 interaction between tumor cells and T cells. Meanwhile, photosensitizer chlorin e6 (Ce6) and paclitaxel (PTX) loaded bMSNs effectively enter tumor cells and induce chemo-photodynamic therapy. The nanosystem elicits a chemo-photodynamic-induced immune response and improves the therapeutic effect of PD-L1 blockade mediated by aPDL1. Furthermore, the nanosystem displays a sustained prohibitive effect on tumor metastasis to distant sites. Our work presents a promising strategy for enhancing the efficacy of cancer immunotherapy.


Extracellular vesicles released by mesenchymal-like prostate carcinoma cells modulate EMT state of recipient epithelial-like carcinoma cells through regulation of AR signaling.
Extracellular vesicles released from cancer cells may play an important role in cancer progression by shuttling oncogenic information into recipient cells. However, our knowledge is still fragmentary and there remain numerous questions regarding the mechanisms at play and the functional consequences of these interactions. We have recently established a mesenchymal-like prostate cancer cell line (22Rv1/CR-1; Mes-PCa). In this study, we assessed the effects of the extracellular vesicles released by these cells on recipient androgen-dependent epithelial VCaP prostate cancer cells. Mes-PCa derived vesicles were found to promote mesenchymal features in the recipient epithelial-like prostate cancer cells. This transformation was accompanied by a modulation of androgen receptor signaling and activation of TGFβ signaling pathway. Moreover, recipient cells acquiring mesenchymal traits displayed enhanced migratory and invasive features as well as increased resistance to the androgen receptor antagonist, enzalutamide. Our results suggest a previously unappreciated role for Mes-PCa secreted vesicles in cancer promotion by transferring cell-mediated signals and promoting phenotypic changes in recipient prostate cancer cells.


Proteolysis of type I inositol 1,4,5-trisphosphate receptor in WB rat liver cells.
A comparison of the basal degradation of type I Ins P3Rs [L- myo -inositol 1,4,5-trisphosphate receptor], measured by pulse-chase analysis or by analysis of immunoreactive Ins P3Rs after cycloheximide addition, indicated that the small pool of newly synthesized radioactive Ins P3Rs degraded relatively rapidly compared with the large pool of mature Ins P3Rs. An antibody (Ab) against a peptide sequence within the IL-3 (third intraluminal loop) of the receptor (IL-3 Ab) was used to identify protected proteolytic fragments that may accumulate in cells. The IL-3 Ab recognized a 56 kDa fragment in both WB rat liver cells and A7R5 smooth-muscle cells. Gel filtration experiments indicated that the 56 kDa fragment was monomeric and, based on reactivity to other Abs, was missing the cytosol-exposed N- and C-terminal segments of the receptor. The addition of the lysosomal protease inhibitor chloroquine resulted in the rapid disappearance of the 56 kDa band. This effect was mimicked by the cysteine protease inhibitors leupeptin, N -acetyl-L-leucyl-L-leucyl-L-methioninal and N -acetyl-leucyl-leucyl-norleucinal. Lactacystin and NH4Cl were less effective. A second fragment of 16 kDa containing the C-terminus accumulated only when the cells were treated with NH4Cl, and not with any of the other inhibitors tested. No N-terminal-reactive fragments were observed. We propose that mature Ins P3R tetramers dissociate into monomers and that the 56 kDa fragment is a cleavage intermediate of the monomer representing the six transmembrane domains. Angiotensin-II-stimulated down-regulation of Ins P3Rs in WB cells has been shown to involve the ubiquitin/proteasome pathway. Angiotensin-II treatment of WB cells neither resulted in the accumulation of any new fragments nor increased the levels of the 56 or 16 kDa fragments. We conclude that basal and agonist-stimulated degradations of Ins P3Rs occur by different pathways. The agonist-mediated pathway involves the concerted removal and proteolysis of the entire receptor molecule from the endoplasmic reticulum membrane without the appearance of intermediate intraluminal fragments.


Common anatomical and external coding for hands and feet in tactile attention: evidence from event-related potentials.
Recent studies have suggested that the location of tactile stimuli is automatically recoded from anatomical into external coordinates, independent of the task requirements. However, research has mainly involved the two hands, which may not be representative for the whole body because they are excessively used for the visually guided manipulation of objects and tools. We recorded event-related potentials (ERPs) while participants received tactile stimuli to the hands and feet, but attended only one limb. The hands were placed near the feet either in an uncrossed or a crossed posture, thus varying the spatial distance of each hand from each foot. Centro-parietal ERPs 100-140 msec poststimulus were more positive when stimulating the anatomically same-side hand while attending a foot. They were also more positive when the Euclidean distance between the stimulated hand and the attended foot was small rather than large. When a foot was stimulated and a hand attended, a similar modulation of foot ERPs was observed for the right foot. To assess the spatial distance between two limbs in space, the external location of both must be known. The present ERP results therefore suggest that not only the hands but also other body parts are remapped into external coordinates. The use of both anatomical and external coordinates may facilitate the control of actions toward tactile events and the choice of the most suitable effector.


The Associations between Objectively Measured Physical Activity and Physical Function in Community-Dwelling Older Japanese Men and Women.
The relationships between physical activity (PA) and physical function (PF) among older Japanese adults have been examined before, with some studies reporting that moderate-to-vigorous physical activity (MVPA) is positively associated with PF. However, it is unclear whether the observed associations differ between men and women. In this study, we investigated the associations of objectively measured MVPA, light physical activity (LPA), and sedentary time (ST) with different PF levels in older Japanese men and women. A total of 810 community-dwelling subjects aged 65-75 years were investigated (52.1% women, 47.9% men). The PF variables included grip strength, one-leg standing, usual and maximum walking speeds, and chair-standing time. PA (MVPA, LPA, and ST) and the number of steps taken daily were assessed for seven consecutive days by a tri-axial accelerometer. We determined the sex-specific quartiles of MVPA, LPA, and ST and analyzed their associations with physical function in separate models for each exposure measure. In the crude analysis, MVPA was significantly associated with all PF variables in the men, and with the usual walking speed, max. walking speed, and chair-standing time in the women. Neither LPA nor ST was significantly associated with any PF variables. After adjusting potential confounding factors, significant associations between MVPA and usual walking speed remained in the men and women. Only greater moderate-to-vigorous physical activity (MVPA) was significantly associated with higher levels of PF variables in both men and women. Thus, time spent in moderate-to-vigorous physical activity (MVPA) can help older adults maintain or improve their physical function.


[Col E1 DNA transcription in Escherichia coli RNA-polymerase system in vitro].
The ColEI plasmid DNA transcription in E. coli RNA-polymerase system in vitro was studied. Three RNA types: of 110-140 residues long, 1700 residues long and of the length similar to that of DNA-template were synthesized in the reaction, containing 10 mM MgCl2, 50 mM KCl and 15% glycerol. The transcription was shown to be asymmetric, the DNA H-chain being transcribed. The ColEI DNA region transcribed in vitro was located by the blotting techniques. This region comprised most of the ColEI genome except the colicin EI gene. The addition of mitomycin C to the reaction mixture caused only a little stimulation of colicin EI gene transcription. Four fragments of HaeIII digest of ColEI DNA were shown to have affinity to RNA-polymerase in the absence of NTPs and two fragments to have it in the presence of 3 NTPs (in the RNA initiation conditions). These two fragments seem to contain two strong promoters. One of them is in the HaeIIIA fragment, where the colicin EI gene origin is situated, and another one is the HaeIIIB fragment (in the immunity region).


TREATMENT OF PSYCHOSOMATIC DISORDERS.
Goals, potentialities and limitations of treatment of psychosomatic disorders are reviewed. Removal of a disturbing psychosomatic symptom may be all that can be accomplished. The bulk of patients suffering from psychosomatic disorders should be treated by physicians other than psychiatrists. Difficulties arise, owing to differences in approach, when treatment is carried out by a general physician as well as a psychiatrist. In appraising the prospects of treatment, the age on examination, intelligence, duration of illness, degree of insight, nature of illness, environmental stress and personality structure of the patients should be considered. Psychiatric measures which have been employed include: electroconvulsive therapy, psychotropic drugs, hypnosis, drug abreaction, group therapy, supportive psychotherapy and psychoanalysis. Psychoanalysis provides the best understanding of the psychodynamics of psychosomatic illness but is, for a variety of reasons, applicable only to a small number of patients. Alternations and removal of disturbing symptoms can be accomplished by the other therapeutic means.


Quality measurers of therapeutic communities for substance dependence: an international collaborative study survey in Latin America.
In Latin America, substance related disorders are highly prevalent and one of the treatment strategies is the Therapeutic Communities (TCs), however, in Latin America there is scarce data about this treatment strategies, their quality, drop-out rates and patient satisfaction. Based on a previous study in 5 Latin American countries, the TCs who had a score equal or higher than 9 according to the De Leon criteria which are some fundamental items that the TCs should meet, were selected to carry out a descriptive and retrospective study of qualitative and quantitative characteristics of the TCs. Data from 58 TCs in 5 countries were included, with a sample of 1414 patients interviewed, of which most were single men, with no hospitalization history in a therapeutic community. Marijuana was the most commonly substance used in the 30 days prior to hospitalization, with 78% of interviewees referring alcohol consumption in the last 6 months and an average onset of psychoactive substances at 16 years of age. A 79% of the patients interviewed perceived some improvement during their stay in the TCs. The less fulfilled Quality Indicators by the TCs were "Requesting a professional qualification to former addicts that belonged to the program" and "Work as part of the therapeutic program". Among the reasons for discharge found in the database, 44% were due to therapeutic discharge with fulfillment of the treatment plan and 44% withdraws. The user satisfaction with TCs, in terms of infrastructure and quality are quite high, as the fulfillment of essential quality items, however, the follow up information to evaluate effectiveness of the treatment is poor or in some cases unknown.


Molecular Mechanics of the Moisture Effect on Epoxy/Carbon Nanotube Nanocomposites.
The strong structural integrity of polymer nanocomposite is influenced in the moist environment; but the fundamental mechanism is unclear, including the basis for the interactions between the absorbed water molecules and the structure, which prevents us from predicting the durability of its applications across multiple scales. In this research, a molecular dynamics model of the epoxy/single-walled carbon nanotube (SWCNT) nanocomposite is constructed to explore the mechanism of the moisture effect, and an analysis of the molecular interactions is provided by focusing on the hydrogen bond (H-bond) network inside the nanocomposite structure. The simulations show that at low moisture concentration, the water molecules affect the molecular interactions by favorably forming the water-nanocomposite H-bonds and the small cluster, while at high concentration the water molecules predominantly form the water-water H-bonds and the large cluster. The water molecules in the epoxy matrix and the epoxy-SWCNT interface disrupt the molecular interactions and deteriorate the mechanical properties. Through identifying the link between the water molecules and the nanocomposite structure and properties, it is shown that the free volume in the nanocomposite is crucial for its structural integrity, which facilitates the moisture accumulation and the distinct material deteriorations. This study provides insights into the moisture-affected structure and properties of the nanocomposite from the nanoscale perspective, which contributes to the understanding of the nanocomposite long-term performance under the moisture effect.


Response of the gut microbiota during the Clostridioides difficile infection in tree shrews mimics those in humans.
Clostridioides difficile is a major cause of antibiotic associated diarrhea. Several animal models are used to study C. difficile infection (CDI). The tree shrew has recently been developed as a model of primate processes. C. difficile infection has not been examined in tree shrews. We infected tree shrews with hyper-virulent C. difficile strains and examined the alterations in gut microbiota using 16S rRNA gene sequencing. C. difficile colonized the gastrointestinal tract of tree shrew and caused diarrhea and weight loss. Histopathologic examination indicated structures and mucosal cell destruction in ileal and colonic tissues. The gut microbial community was highly diversity before infection and was dominated by Firmicutes, Fusobacteria, Bacteroidetes, and Proteobacteria. Antibiotic administration decreased the diversity of the gut microbiota and led to an outgrowth of Lactobacillus. The relative abundance of Proteobacteria, Gammaproteobacteria, Enterobacteriales, Lachnospiraceae, Enterobacteriaceae, Escherichia, Blautia, and Tyzzerella increased following C. difficile infection. These taxa could be biomarkers for C. difficile colonization. In general, the disease symptoms, histopathology, and gut microbiota changes following C. difficile infection in tree shrews were similar to those observed in humans.


Advantages of omics approaches for elucidating metabolic changes in diabetic peripheral neuropathy.
Various animal and cell culture models of diabetes mellitus (DM) have been established and utilized to study diabetic peripheral neuropathy (DPN). The divergence of metabolic abnormalities among these models makes their etiology complicated despite some similarities regarding the pathological and neurological features of DPN. Thus, this study aimed to review the omics approaches toward DPN, especially on the metabolic states in diabetic rats and mice induced by chemicals (streptozotocin and alloxan) as type 1 DM models and by genetic mutations (MKR, db/db and ob/ob) and high-fat diet as type 2 DM models. Omics approaches revealed that the pathways associated with lipid metabolism and inflammation in dorsal root ganglia and sciatic nerves were enriched and controlled in the levels of gene expression among these animal models. Additionally, these pathways were conserved in human DPN, indicating the pivotal pathogeneses of DPN. Omics approaches are beneficial tools to better understand the association of metabolic changes with morphological and functional abnormalities in DPN.


Chemicals inhaled from spray cleaning and disinfection products and their respiratory effects. A comprehensive review.
Spray cleaning and disinfection products have been associated with adverse respiratory effects in professional cleaners and among residents doing domestic cleaning. This review combines information about use of spray products from epidemiological and clinical studies, in vivo and in vitro toxicological studies of cleaning chemicals, as well as human and field exposure studies. The most frequent chemicals in spray cleaning and disinfection products were compiled, based on registrations in the Danish Product Registry. The chemicals were divided into acids, bases, disinfectants, fragrances, organic solvents, propellants, and tensides. In addition, an assessment of selected cleaning and disinfectant chemicals in spray products was carried out. Chemicals of concern regarding respiratory effects (e.g. asthma) are corrosive chemicals such as strong acids and bases (including ammonia and hypochlorite) and quaternary ammonium compounds (QACs). However, the evidence for respiratory effects after inhalation of QACs is ambiguous. Common fragrances are generally not considered to be of concern following inhalation. Solvents including glycols and glycol ethers as well as propellants are generally weak airway irritants and not expected to induce sensitization in the airways. Mixing of certain cleaning products can produce corrosive airborne chemicals. We discuss different hypotheses for the mechanisms behind the development of respiratory effects of inhalation of chemicals in cleaning agents. An integrative assessment is needed to understand how these chemicals can cause the various respiratory effects.


Gonadotropin-suppressive therapy in girls with early and fast puberty affects the pace of puberty but not total pubertal growth or final height.
Early and fast puberty (EFP) in girls, defined as pubertal onset at age 8-9 yr, with an accelerated course, may cause compromised final height (FHt) and psychosocial distress. Treatment with a gonadotropin-suppressive agent is controversial, because the improvement in FHt is equivocal and there may be risk of obesity. We analyzed the data of 126 girls with EFP: 63 treated with GnRH analog (GnRHA) since Tanner stage 3, for 2-4 yr; and 63 untreated. Age at onset of puberty; accelerated time of transition from Tanner stage 2 to 3 (<1.3 yr); and clinical, hormonal and sonographic findings were similar in the 2 groups. The girls given GnRHA treatment had a significantly prolonged pubertal course, compared with the accelerated course in the untreated girls (4.7 +/- 0.4 vs. 2.45 +/- 0.4 yr, P < 0.001). After therapy, they reached Tanner stages 4 and 5 and FHt at a significantly older age than the untreated group (P < 0.001), and their menarche was delayed (12.8 +/- 0.6 vs. 10.8 +/- 0.5 yr, P < 0.001). However, the different pace of puberty in the 2 groups did not change the total pubertal growth and the bone maturation rate. The Ht gain from Tanner stage 3 to 4 (10.4 +/- 2.7 vs. 11.2 +/- 3.1 cm) and from Tanner stage 4 to FHt (8.2 +/- 2.7 vs. 8.8 +/- 3.6 cm) was similar in the treated and untreated girls, as were absolute Ht and bone age at each pubertal stage. The weight gain of the treated girls was more pronounced during treatment (P = 0.0016), but it was arrested after discontinuation of therapy; and by the time FHt was reached, the body mass index was similar in the 2 groups. The treated and untreated girls achieved a similar mean FHt, which was not significantly different from their respective mean target Ht (THt). Individual analysis revealed that 70% of the treated girls and 67% of the untreated girls attained their THt range (THt +/- 0.5 SD) or surpassed it. In conclusion, treatment with GnRHA affected only the pace of EFP. The similar Ht gain and bone maturation rate at each pubertal stage in the treated and untreated girls may suggest that the total pubertal growth is not dependent on pubertal duration and pace and is probably determined already at the onset of the normal pubertal development. The treatment did not compromise the FHt and did not cause long-lasting obesity. Therefore, GnRHA therapy may be suggested for use in girls who have psychosocial difficulties in coping with EFP.


GC/MS analytical procedure for the characterization of glycerolipids, natural waxes, terpenoid resins, proteinaceous and polysaccharide materials in the same paint microsample avoiding interferences from inorganic media.
An innovative GC/MS procedure for the characterization of organic materials in samples from works of art was developed. It is based on a multistep chemical pretreatment of the samples based on the ammonia extraction of proteins and polysaccharide materials, in order to separate them from lipid and resinous materials. The extraction is then followed by the separation and purification of proteinaceous and polysaccharide materials before hydrolysis, based on the use of monolithic sorbent tip technology with a C4 stationary phase. Lipids and resins are saponified/salified separately. Three fractions are generated and analyzed separately by GC/MS, thus enabling a quantitative analysis to be performed on aldoses and uronic acids, amino acids, mono- and dicarboxylic aliphatic acids, to determine polysaccharide, proteinaceous, and glycerolipid materials and molecular pattern recognition for the natural resin and wax components. With this analytical procedure, for the first time, glycerolipids, natural waxes, and proteinaceous, resinous, and polysaccharide materials can be simultaneously characterized in the same microsample from painted works of art. This new analytical approach prevents any analytical difficulties arising when the sample is divided into several different aliquots to be chemically processed separately, in order to characterize the various classes of organic materials. The procedure was successfully applied to samples from paintings from the Bamiyan Buddhas and a panel painting from the 15th century, highlighting the occurrence of glycerolipids, animal and plant resins, proteinaceous and polysaccharide materials.


Domestic violence screening and intervention programmes for adults with dental or facial injury.
Domestic violence exists in all communities across the world. Healthcare services have a pivotal role in the identification, assessment and response to domestic violence. As the face is a common target in assault, dentists and oral and maxillofacial surgeons are in a unique position to screen for domestic violence in the context of presentation of dental and facial injury. Owing to lack of training, dentists and oral and maxillofacial surgeons may not be the best persons to give advice to someone experiencing domestic violence. Improper advice such as encouragement to leave an abusive relationship may escalate the frequency of violence. It may be more appropriate to refer to specialist agencies for intervention and support. It would, therefore be useful to know whether screening and intervention programmes are effective. (1) To assess the benefits and harms of intervention programmes employed to reduce and or prevent domestic violence in adults with dental and/or facial injuries. (2) To assess the benefits and harms of screening and the use of different screening tools in the detection of the proportion of adult victims of domestic violence who present with dental and/or facial injury. The following electronic databases were searched: the Cochrane Oral Health Group Trials Register (to 18 May 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 2), MEDLINE via OVID (1950 to 18 May 2010), EMBASE via OVID (1980 to 18 May 2010), PsycINFO via OVID (1950 to 18 May 2010), LILACS via BIREME (1982 to 18 May 2010) and CINAHL via EBSCO (1980 to 18 May 2010). There were no restrictions regarding language or date of publication. Randomised controlled trials (RCTs) involving adults aged 16 years and over presenting with dental and/or facial injury relating to domestic violence in any healthcare setting. Screening of eligible studies was conducted in duplicate and independently by two reviewers. Results were to be expressed as random effects models using mean differences for continuous outcomes and relative risk for dichotomous outcomes with 95% confidence interval. Heterogeneity was to be investigated including both clinical and methodological factors. No eligible RCTs were identified. There is no evidence from RCTs to support or refute that screening for domestic violence in adults with dental or facial injury is beneficial nor that it causes harm. Screening tools to detect domestic violence exist but no RCTs have specifically evaluated their effectiveness for patients presenting with facial and or dental injuries. There is also lack of evidence (from RCTs) that intervention programmes are effective at reducing frequency of physical assaults and at reducing the severity of facial injuries.


Pre-Appointment Nurse Navigation: Patient-Centered Findings From a Survey of Patients With Breast Cancer.
Research indicates that nurse navigators can play key roles in promoting empowerment for patients with cancer through advocacy, educational support, resource navigation, and psychosocial care. This study attempted to elucidate the efficacy of nurse navigation in patient knowledge, care coordination, and well-being before a breast oncology appointment. Staff provided a nine-question survey to 50 newly referred patients before their initial appointment. After survey completion, patients had the option to participate in an open-ended interview about their experience. A greater proportion of patients with initial nurse navigation than those without felt informed before their appointment and thought that their care was effectively coordinated. Although some patients without nurse navigation experienced delays and confusion in scheduling their appointment, no patients with nurse navigators reported such issues.


Concealed fertility and extended female sexuality in a non-human primate (Macaca assamensis).
In numerous primates living in mixed-sex groups, females display probabilistic cues of fertility to simultaneously concentrate paternity to dominant males while diluting it amongst others as a means to reduce the risk of infanticide and to increase male care for offspring. A few species, however, lack these cues and potentially conceal fertility from males; yet, to date, little is known about mating patterns and their underlying proximate mechanisms in such species. Here, we investigated mating activity and sexual consortships relative to female reproductive state in wild Assamese macaques (Macaca assamensis), a species where females lack prominent anogenital swellings and copulation calls. During two mating seasons (2837 contact hours) we recorded sexual and social behaviors, sexual consortships, and collected 1178 fecal samples (n = 15 females) which were analyzed for progestogen concentrations to assess female reproductive state and to determine the timing of ovulation and conception. Although mostly conceiving in their first ovarian cycle, females were sexually receptive throughout the entire 4-month mating season, and within-cycle mating frequencies were not increased during fertile phases. Dominant males did not monopolize fertile matings, and consortships by high-ranking males lasted for long periods, which were not exclusively linked to female fertile phases. Furthermore, females copulated promiscuously but not randomly, i.e. for almost every female, matings were concentrated to a certain male, irrespective of male rank. Collectively, we demonstrate that fertility is undisclosed to males. The extreme extended female sexuality facilitated by concealed fertility may allow females to create differentiated mating relationships within a promiscuous mating system. Our study provides important new insight into the plasticity of female sexuality in non-human primates.


HIV serostatus disclosure in the Democratic Republic of the Congo: a systematic review.
HIV status disclosure among people living with HIV/AIDS has been shown to have a number of both personal and public health benefits, but rates of HIV status disclosure remain low in many African countries, including the Democratic Republic of the Congo (DRC). This systematic review uses the Disclosure Process Model to examine the factors involved in serostatus disclosure and nondisclosure to various persons in the lives of people living with HIV/AIDS (PLWHA) in the DRC, as well as the specific outcomes of their disclosure or nondisclosure. MEDLINE/PubMed, Embase, Web of Science, Global Health, and PsycINFO were searched and research studies were included if: (i) the study discussed disclosure of HIV status; (ii) the study population included HIV-infected people in DRC; and (iii) the study was published in English. Fourteen articles met the inclusion criteria and were included in the study. Factors contributing to nondisclosure were generally associated with high stigma of HIV in adults and concern for emotional wellbeing when disclosing to HIV positive minors. Factors contributing to disclosure among adults were increased social support and religion. In disclosing to HIV positive minors, increasing age and health benefits were identified as approach goals that supported disclosure. The findings highlight the importance of understanding the avoidance and approach goals involved in HIV status disclosure among populations living in the DRC. Interventions and future research directed at increasing HIV disclosure among Congolese PLWHA should move beyond individual-level to consider multilevel factors including circumstantial social behaviors.


Iron-Catalyzed Ring-Closing C-O/C-O Metathesis of Aliphatic Ethers.
Among all metathesis reactions known to date in organic chemistry, the metathesis of multiple bonds such as alkenes and alkynes has evolved into one of the most powerful methods to construct molecular complexity. In contrast, metathesis reactions involving single bonds are scarce and far less developed, particularly in the context of synthetically valuable ring-closing reactions. Herein, we report an iron-catalyzed ring-closing metathesis of aliphatic ethers for the synthesis of substituted tetrahydropyrans and tetrahydrofurans, as well as morpholines and polycyclic ethers. This transformation is enabled by a simple iron catalyst and likely proceeds via cyclic oxonium intermediates.


Myth, Manners, and Medical Ritual: Defensive Medicine and the Fetish of Antibiotics.
Given the global crisis of antimicrobial resistance, the continued misuse of antibiotics is perplexing, particularly despite persistent attempts to curb usage. This issue extends beyond traditional "wastage" areas, of livestock and community medicine, to hospitals, raising questions regarding the current principles of hospital practice. Drawing on five focus group discussions, we explore why doctors act in the ways they do regarding antibiotics, revealing how practices are done, justified, and perpetuated. We posit that antibiotic misuse is better understood in terms of social relations of fear, survival and a desire for autonomy; everyday rituals, performances, and forms of professional etiquette; and the mixed obligations evident in the health sector. Moreover, that antibiotic misuse presents as a case study of the broader problematic of defensive medicine. We argue that the impending global antibiotic crisis will involve understanding how medicine is built around certain logics of practice, many that are highly resistant to change.


Brain Responses at Encoding Predict Limited Verbal Memory Retrieval by Persons with Schizophrenia.
Special attention has been given to verbal memory deficits in schizophrenia because they are apparent in healthy biological relatives of affected individuals, indicating a link to genetic risk for the disorder. Despite a growing consensus that encoding abnormalities contribute to poor verbal memory in the disorder, few studies have directly examined how neural responses during encoding contribute to later memory performance. We evaluated event-related potentials (ERPs) during encoding of verbal material by patients with schizophrenia, healthy first-degree biological relatives of patients, and healthy controls. The extent to which N1, N400, and anterior and parietal Late Positive Components (LPCs) explained encoding accuracy and later memory of material was investigated. Encoding accuracy was associated with asymmetry in anterior LPCs toward right frontal brain regions and was most evident in relatives. N1 was abnormal at encoding in schizophrenia and differentially accounted for later memory performance. In controls better recall of verbal material was predicted by a larger early occipital (N1) encoding response; however, in patients with schizophrenia smaller N1 encoding responses were related to better recall. Interestingly, better recognition of verbal material across groups was also predicted by smaller N1 amplitudes during encoding of word stimuli. Separable patterns of electrophysiological response during encoding appear to differentially support recall and recognition of material from memory. Similar patterns of electrophysiological response across patient and relative groups suggest that those who carry genetic liability for schizophrenia share deviations in the neural activity related to encoding of material into episodic memory.


[Morphometric and histochemical characteristic of cluster organization of the neurons of rat spinal nerve sensory ganglion and of sympathetic trunk cervicothoracic ganglion].
The topographic pattern of neurons in spinal nerve sensory ganglion and of sympathetic trunk cervicothoracic ganglion was investigated at adult rats (n = 12). Results of the work have shown, that these organs are characterized by a heterogeneity of the neurons according to their morphometric (Nissl's stain) and histochemical (acetylcholinestherase and NADPH-diaphorase activity) parameters. The common feature of ganglia organization was demonstrated by the clustered pattern of neuron topography. Clusters were formed on a principle of heterogeneity, uniting from 3-4 to 9-10 neurons. The application of a combined histochemical method has allowed to identify the histo-functional charactristics of neurons within the clusters of the ganglia studied, which were also detected by standard histological methods.


Nuclear factor kappaB mediates the inhibitory effects of interleukin-1 on growth hormone-inducible gene expression.
Hepatic expression of growth hormone (GH)-inducible genes serine protease inhibitor (Spi 2.1) and insulin-like growth factor (IGF)-I are inhibited by interleukin (IL)-1. The current study examines the role of the nuclear factor kappaB (NFkappaB) pathway and suppressor of cytokine signaling (SOCS)-3 expression as potential mechanisms for IL-1-mediated GH resistance. CWSV-1 hepatocytes were cotransfected with Spi 2.1 or IGF-1 promoter luciferase constructs and empty pCMV4 vector or dominant negative inhibitor-kappaBalpha (IkappaBalpha)S/A construct. Cells were treated with or without IL-1 and then stimulated with or without recombinant human GH. Cell extracts were assayed for luciferase activity and protein, normalized and expressed as fold-induction. CWSV-1 cells transfected with pCMV4 or IkappaBalphaS/A were treated with or without IL-1 then SOCS-3 mRNA was measured. Finally, CWSV-1 cells were cotransfected with a SOCS-3 promoter construct with or without pCMV4 or IkappaBalphaS/A and then stimulated with or without IL-1 to investigate SOCS-3 promoter activity. CWSV-1 cells cotransfected with pCMV4 demonstrated a three- to fivefold induction of Spi 2.1 or IGF-1 promoter activity after GH stimulation that was almost completely inhibited by IL-1. Cotransfection with IkappaBalphaS/A increased GH-inducible Spi 2.1 and IGF-1 promoter activity, but the inhibitory effects of IL-1 on both promoters were attenuated by cotransfection with IkappaBalphaS/A. IL-1 stimulated SOCS-3 mRNA expression and promoter activity. Cotransfection with IkappaBalphaS/A increased IL-1-inducible SOCS-3 promoter activity, but not SOCS-3 mRNA or protein. Signaling via the NFkappaB pathway is responsible for the inhibitory effects of IL-1 on GH-inducible gene expression by a mechanism that does not seem to involve increased SOCS-3 expression.


Conservative Secondary Shell Substitution In Cyclooxygenase-2 Reduces Inhibition by Indomethacin Amides and Esters via Altered Enzyme Dynamics.
The cyclooxygenase enzymes (COX-1 and COX-2) are the therapeutic targets of nonsteroidal anti-inflammatory drugs (NSAIDs). Neutralization of the carboxylic acid moiety of the NSAID indomethacin to an ester or amide functionality confers COX-2 selectivity, but the molecular basis for this selectivity has not been completely revealed through mutagenesis studies and/or X-ray crystallographic attempts. We expressed and assayed a number of divergent secondary shell COX-2 active site mutants and found that a COX-2 to COX-1 change at position 472 (Leu in COX-2, Met in COX-1) reduced the potency of enzyme inhibition by a series of COX-2-selective indomethacin amides and esters. In contrast, the potencies of indomethacin, arylacetic acid, propionic acid, and COX-2-selective diarylheterocycle inhibitors were either unaffected or only mildly affected by this mutation. Molecular dynamics simulations revealed identical equilibrium enzyme structures around residue 472; however, calculations indicated that the L472M mutation impacted local low-frequency dynamical COX constriction site motions by stabilizing the active site entrance and slowing constriction site dynamics. Kinetic analysis of inhibitor binding is consistent with the computational findings.


Magnetic resonance imaging in the encephalopathic term newborn.
Neonatal encephalopathy is a neurological emergency with heterogeneous etiologies and several management challenges. Neonatal encephalopathy of hypoxic-ischemic origin is associated with high rate of neonatal morbidity and mortality, and the long-term neurodevelopmental outcome of survivors with moderate to severe encephalopathy is poor. Magnetic resonance imaging now provides new insights on the diagnosis and prognosis of this condition. Typical patterns of brain injury have been recognized and in contemporary cohorts of newborns these patterns reflect different risk factors and clinical presentation, as well as specific patterns of neurodevelopmental outcome. Magnetic resonance spectroscopy, diffusion-weighted imaging, and diffusion tensor imaging are advanced MR techniques that are increasingly used in the assessment of encephalopathic newborns, providing innovative perspectives on neonatal brain metabolism, microstructure, and connectivity. These techniques have been particularly helpful in elucidating the unique time course of neonatal brain injury and in providing quantitative biomarkers for prognostication. To better refine the prognostic value of these new imaging tools, standardization of protocols, imaging modalities and scan timing are needed across centers. It is hoped that these techniques will permit earlier identification of newborns at risk of neurodevelopmental impairment and complement ongoing trials of emerging therapies such as hypothermia and novel pharmacological agents with neuroprotective properties.


A modified ATP benchmark for evaluating the cleaning of some hospital environmental surfaces.
Hospital cleaning continues to attract patient, media and political attention. In the UK it is still primarily assessed via visual inspection, which can be misleading. Calls have therefore been made for a more objective approach to assessing surface cleanliness. To improve the management of hospital cleaning the use of adenosine triphosphate (ATP) in combination with microbiological analysis has been proposed, with a general ATP benchmark value of 500 relative light units (RLU) for one combination of test and equipment. In this study, the same test combination was used to assess cleaning effectiveness in a 1300-bed teaching hospital after routine and modified cleaning protocols. Based upon the ATP results a revised stricter pass/fail benchmark of 250 RLU is proposed for the range of surfaces used in this study. This was routinely achieved using modified best practice cleaning procedures which also gave reduced surface counts with, for example, aerobic colony counts reduced from >100 to <2.5 cfu/cm(2), and counts of Staphylococcus aureus reduced from up to 2.5 to <1 cfu/cm(2) (95% of the time). Benchmarking is linked to incremental quality improvements and both the original suggestion of 500 RLU and the revised figure of 250 RLU can be used by hospitals as part of this process. They can also be used in the assessment of novel cleaning methods, such as steam cleaning and microfibre cloths, which have potential use in the National Health Service.


Involvement of Noxa in cellular apoptotic responses to interferon, double-stranded RNA, and virus infection.
Double-stranded RNA (dsRNA) accumulates in virally infected cells, leading to induction of genes encoding proteins involved in signaling, apoptosis, protein synthesis/processing, and cell metabolism. Noxa is a BH3-containing mitochondrial protein that contributes to apoptosis by disrupting mitochondrial outer membrane integrity. Here we demonstrate potent induction of Noxa expression by exposure of cells to dsRNA, interferon (IFN), and virus. Noxa induction was confirmed by using reverse transcriptase-PCR and immunoblot analyses in multiple human tumor cell lines. Importantly, Noxa regulation by IFN and dsRNA was independent of p53, thereby identifying a novel mechanism of Noxa induction. Ectopic expression of Noxa in HT1080 fibrosarcoma cells enhanced cellular sensitivity to viral or dsRNA/actinomycin D-induced apoptosis, typified by enhanced cytochrome c release from the mitochondrial to the cytosolic fraction and increased cleavage of caspases 3 and 9. Point and deletion mutations of Noxa confirmed that both the BH3 domain and the mitochondrial-targeting domain were necessary for enhanced cellular apoptotic responses to dsRNA, IFN, or virus. Treatment of cells with dsRNA or virus, but not etoposide, induced interaction between Noxa and Bax that required an intact Noxa BH3 domain. Interestingly, the Noxa mitochondrial-targeting domain deletion mutant interacted with Bax in a dsRNA-dependent manner and redirected Bax away from the mitochondria, thus acting as a dominant-negative protein. Together, these data suggest that Noxa is an important component of the innate immune response of cells to viral infection, leading to enhanced cellular apoptosis that may play a role in limiting viral dissemination.


MS cortical lesions on DIR: not quite what they seem?
Accurate identification and localization of cortical gray matter (CGM) lesions in MS is important when determining their clinical relevance. Double inversion recovery (DIR) scans have been widely used to detect MS CGM lesions. Phase sensitive inversion recovery (PSIR) scans have a higher signal to noise, and can therefore be obtained at a higher resolution within clinically acceptable times. This enables detection of more CGM lesions depicting a clearer cortical and juxtacortical anatomy. In this study, we systematically investigated if the use of high resolution PSIR scans changes the classification of CGM lesions, when compared with standard resolution DIR scans. 60 patients [30 RR(Relapsing remitting) and 15 each with PP(Primary progressive) and SP(Secondary progressive) MS] were scanned on a 3T Philips Achieva MRI scanner. Images acquired included DIR (1×1×3 mm resolution) and PSIR (0.5×0.5×2 mm). CGM lesions were detected and classified on DIR as intracortical (IC) or leucocortical (LC). We then examined these lesions on corresponding slices of the high resolution PSIR scans and categorized them as IC, LC, Juxtacortical white matter (JC-WM, abutting but not entering cortex) and other white matter (WM, not juxtacortical). Classifications using both scans were noted. 282 IC and 483 LC were identified on DIR. Of the IC lesions, 61% were confirmed as IC on PSIR, 35.5% were reclassified as LC and 3.5% as JC-WM or other WM only. Of the LC DIR lesions, 43.9% were confirmed at LC on PSIR, 16.1% were reclassified as IC and 40% as JC-WM or other WM only. Overall, 50% (381/765) of CGM lesions seen on DIR were reclassified, and 26.5% (203/765) affected WM only. When compared with higher resolution PSIR, a significant proportion of lesions classified as involving CGM on DIR appear to either contain more white matter than expected or to not involve CGM at all.


Uptake of Preventive Services Among Patients With and Without Multimorbidity.
Patients with multiple chronic conditions (multimorbidity) are seen commonly in primary care practices and often have suboptimal uptake of preventive care owing to competing treatment demands. The complexity of multimorbidity patterns and their impact on receiving preventive services is not fully understood. This study identifies multimorbidity combinations associated with low receipt of preventive services. This was a retrospective cohort study of U.S. community health center patients aged ≥19 years. Electronic health record data from 209 community health centers for the January 1, 2014-December 31, 2017 study period were analyzed in 2018-2019. Multimorbidity patterns included physical only, mental health only, and physical and mental health multimorbidity patterns, with no multimorbidity as a reference category. Electronic health record-based preventive ratios (number of months services were up-to-date/total months the patient was eligible for services) were calculated for the 14 preventive services. Negative binomial regression models assessed the relationship between multimorbidity physical and/or mental health patterns and the preventive ratio for each service. There was a variation in receipt of preventive care between multimorbidity groups: individuals with mental health only multimorbidity were less likely to be up-to-date with cardiometabolic and cancer screenings than the no multimorbidity group or groups with physical health conditions, and the physical only multimorbidity group had low rates of depression screening. This study provided critical insights into receipt of preventive service among adults with multimorbidity using a more precise method for measuring up-to-date preventive care delivery. Findings would be useful to identify target populations for future intervention programs to improve preventive care.


Different Perspectives on Predictability and Preventability of Surgical Readmissions.
Although unscheduled readmissions are increasingly being used as a quality indicator, only few readmission studies have focused on surgical patient populations. An observational study "CURIOS@" was performed at three centers in the Netherlands. Readmitted patients and treating doctors were surveyed to assess the discharge process during index admission and their opinion on predictability and preventability of the readmission. Risk factors associated with predictability and preventability as judged by patients and their doctor were identified. Cohen's kappa was calculated to measure pairwise agreement of considering readmission as predictable/preventable. PRISMA root cause categories were used to qualify the reasons for readmission. In 237 unscheduled surgical readmissions, more patients assessed their readmissions to be likely preventable compared with their treating doctors (28.7% versus 6.8%; kappa, 0.071). This was also reflected in poor consensus about risk factors and root causes of these readmissions. When patients reported that they did not feel ready for discharge or requested their doctor to allow them to stay longer at discharge during index admission, they deemed their readmission more likely predictable and preventable. Doctors focused on measurable factors such as the clinical frailty scale and biomarkers during discharge process. Health-care worker failures were strongly associated with preventable readmissions. There is no consensus between readmitted patients and treating doctors about predictability and preventability of readmissions, nor about associated risk factors and root causes. Patients should be more effectively involved in their discharge process, and the relevance of optimal communication between them should be emphasized to create a safe and efficient discharge process.


Impact of smokeless tobacco packaging on perceptions and beliefs among youth, young adults, and adults in the U.S: findings from an internet-based cross-sectional survey.
Research demonstrates that tobacco packaging elements (including health warning labels, descriptive characteristics, and corporate branding) are associated with knowledge of health risks and product appeal with cigarettes. Yet, little research has assessed this with smokeless tobacco (SLT) packaging. This study evaluates the association between three SLT packaging elements with knowledge of health risks and perceptions of novelty and appeal. Additionally, we assess how effects of these messages may differ across age groups, including youth (14-17 years), young adults (18-25 years), and older adults (26-65 years). 1000 participants were administered a web-based survey in 2010 and shown three sets of SLT packs in random order, varied by descriptor (flavor descriptor vs. none), warning label format (graphic vs. text), and corporate branding (branded vs. plain packaging). Participants rated the packs compared with "no difference" on appeal, novelty, and risk perceptions associated with product use. Chi-square tests were used to test for significant differences in pack selections. Multinomial regression was employed to evaluate the association between effects of packaging elements and participant age. More respondents selected the pack with the graphic warning label as the pack to make them consider the health risks associated with SLT use, attract their attention, and be least attractive to a smoker. The product with the text warning label was the product someone their age would want to be seen using and would appeal to peers. The SLT pack with the flavor descriptor was not associated with health risks associated with product use. The pack with corporate branding was selected as more appealing, to attract attention, and one they would want to be seen using; the plain pack was less attractive to smokers. Youth and young adults were more likely to indicate that pack elements affected their perceptions of appeal and risk associated with SLT products. These results suggest that SLT pack characteristics have a measurable effect on perceptions of health risk and product appeal. Future research should assess these findings in the context of harm reduction. Specifically, research is needed to determine whether pack elements on SLT products can effectively convey risk and harm.


Effects of SGLT2 inhibitors on weight loss in patients with type 2 diabetes mellitus.
SGLT2 (sodium-glucose cotransporter type 2) inhibitors are a new class of drugs which reversibly block the glucose reabsorption that occurs in the kidneys. Since their mechanisms of action do not rely on insulin secretion, they constitute a complementary alternative to the classic treatment of type 2 diabetes mellitus. A glycemic level reduction in patients who used SGLT2 inhibitors due to the reversible block of their transporters could be observed. Associated with this, there was a reduction in body weight and blood pressure (BP) caused by osmotic diuresis. Few adverse effects and low drug interaction combined with antihyperglycemic effects are some of the benefits of these inhibitors widely discussed in clinical trials. Patients with history of urogenital infections or those on diuretics must be carefully evaluated before the administration of these drugs. While a promising class of drugs indicated as a treatment for patients with type 2 diabetes mellitus, SGLT2 inhibitors should not be prescribed for individuals with severe renal or hepatic impairment. Therefore, as there are only a few situations in which they should not be indicated, the efficacy, safety and tolerability of these inhibitors allow them to be used in a wide range of patients. Nevertheless, further researches are required so that the possible long-term risks can be studied and the benefits associated with their use can be more objectively elucidated.


Treatment of presumed hypotension in very low birthweight neonates: effects on regional cerebral oxygenation.
Previous studies have correlated poor neurological outcomes with hypotension. Treatment of hypotension in very low birthweight (VLBW) infants is common, and most often is based solely on the blood pressure measurement. Whether treatment improves cerebral oxygenation is unclear. To determine if treatment of hypotension in VLBW neonates results in an increase in cerebral oxygenation. In this single centre observational study, neonates <30 weeks and <1500 grams, blood pressure and regional cerebral oximetry (rCSO2) with near infrared spectroscopy were continuously monitored and digitally recorded. If patients were treated for hypotension during the first 3 days of life, effects of treatment on blood pressure and regional cerebral saturation were determined. Twenty-eight of 50 patients were treated by the medical team for hypotension, of which 22 had accurate data recorded for analysis. Both normal saline 10 ml/kg, and dopamine 2.5-5 mcg/kg per min significantly increased blood pressure, (saline 26.8±3.5 to 28.8±4.2 mm Hg, p<0.005; dopamine 27.6±1.9 to 29.5±3.2 mm Hg, p<0.02). Pre-treatment values of rCSO2 were similar to published normative values and treatment with either normal saline or dopamine had no effect on rCSO2. These results suggest that treating hypotension in VLBW neonates based solely on a blood pressure measurement of less than 30 mm Hg, while increasing blood pressure, may not increase cerebral oxygenation, possibly because many of these patients are in the autoregulatory zone for cerebral blood flow.


Germline BRCA1 and BRCA2 testing for breast cancer survivors.
Background For patients with early breast cancer, knowledge of germline BRCA1/2 status increasingly influences management as well as informing future cancer risk for patients and their families. As access to germline testing expands, it is important that this benefit is extended to survivors as well as to the newly diagnosed. Methods In collaboration with our breast unit colleagues and by embedding a Senior Genetic Counsellor in the virtual multidisciplinary meeting, we identified patients suitable for genetics review 5 years after their breast cancer diagnosis. Results Between May 2015 and December 2018, 2044 patients were discussed, of whom 769 patients were identified for notes review by Genetics. Of these, 275 had already undergone testing and 47 had confirmed germline pathogenic variants in BRCA1/2 A further 463 were recommended for referral. One hundred and eighty patients were subsequently offered testing with 161 accepting (161/180, 89%). Nine patients were found to harbour pathogenic variants in either BRCA1 or BRCA2 (9/161, 6%). Of the initial 2044 patients reviewed, 2.7% (56/2044) are now known to carry germline pathogenic variants. Conclusion The survivorship setting provides an opportunity for genetic review underpinned by collaborative working between cancer specialists and the genetics team.


Perturbing Neural Representations of Working Memory with Task-irrelevant Interruption.
Working memory maintains information so that it can be used in complex cognitive tasks. A key challenge for this system is to maintain relevant information in the face of task-irrelevant perturbations. Across two experiments, we investigated the impact of task-irrelevant interruptions on neural representations of working memory. We recorded EEG activity in humans while they performed a working memory task. On a subset of trials, we interrupted participants with salient but task-irrelevant objects. To track the impact of these task-irrelevant interruptions on neural representations of working memory, we measured two well-characterized, temporally sensitive EEG markers that reflect active, prioritized working memory representations: the contralateral delay activity and lateralized alpha power (8-12 Hz). After interruption, we found that contralateral delay activity amplitude momentarily sustained but was gone by the end of the trial. Lateralized alpha power was immediately influenced by the interrupters but recovered by the end of the trial. This suggests that dissociable neural processes contribute to the maintenance of working memory information and that brief irrelevant onsets disrupt two distinct online aspects of working memory. In addition, we found that task expectancy modulated the timing and magnitude of how these two neural signals responded to task-irrelevant interruptions, suggesting that the brain's response to task-irrelevant interruption is shaped by task context.


Thermochemistry of germanium and organogermanium compounds.
This article reviews the current state of thermochemistry (enthalpies of formation) of germanium and organogermanium compounds. While the emphasis is on data from experimental measurements, results of quantum chemical (ab initio) calculations are also included. We provide a set of current best values for GeX4 compounds (X = H, Me, F, Cl, Br, I) as well as mixed GeXnY4-n compounds. Also included are Ge/C/H, Ge/C/H/O and Ge/C/H/N compounds and Ge2 and Ge3 containing molecules. Further inclusions are data for species such as GeX3 (free radicals), GeX2 (germylenes) and π-bonded molecules which play prominent roles as intermediates in many thermal and photochemical reactions of germanium compounds. Bond dissociation enthalpies are derived for most commonly encountered Ge-X bonds. The evaluation of preferred values is assisted by exploiting relationships (increments, substituent effects) within specific series and between series.


Alcohol and cardiovascular health: the razor-sharp double-edged sword.
An extensive body of data shows concordant J-shaped associations between alcohol intake and a variety of adverse health outcomes, including coronary heart disease, diabetes, hypertension, congestive heart failure, stroke, dementia, Raynaud's phenomenon, and all-cause mortality. Light to moderate alcohol consumption (up to 1 drink daily for women and 1 or 2 drinks daily for men) is associated with cardioprotective benefits, whereas increasingly excessive consumption results in proportional worsening of outcomes. Alcohol consumption confers cardiovascular protection predominately through improvements in insulin sensitivity and high-density lipoprotein cholesterol. The ethanol itself, rather than specific components of various alcoholic beverages, appears to be the major factor in conferring health benefits. Low-dose daily alcohol is associated with better health than less frequent consumption. Binge drinking, even among otherwise light drinkers, increases cardiovascular events and mortality. Alcohol should not be universally prescribed for health enhancement to nondrinking individuals owing to the lack of randomized outcome data and the potential for problem drinking.


Safety and stability of open-door cervical expansive laminoplasty.
Cervical expansive laminoplasty has been utilized for over 20 years. This retrospective analysis investigated the safety and incidence of postoperative instability of patients undergoing a modified expansive laminoplasty. One hundred five patients underwent a modified cervical expansive laminoplasty and had at least a 6-month follow-up. These 105 patients were followed for a mean of 18.6 months (range 6-89 months). All patients remained in a rigid cervical collar for 8-12 weeks after the laminoplasty. Postoperative cervical plain radiographs were obtained on postoperative day 1, an average of 9.6 weeks postoperatively (range 8-12 weeks) and an average of 10.1 months (range 6-12 months) postoperatively. Thirty-five patients underwent further radiographs >18 months postoperatively. Laminoplasty was performed in 82 patients with progressive cervical spondylotic myelopathy, 4 patients with ossification of the posterior longitudinal ligament, 7 patients for posterior approach to a cervical neoplasm, and 12 patients for early posttraumatic decompression. The canal/vertebral body ratio showed a significant increase from 0.78 to 1.02 (paired t test, p < 0.001). Postoperatively, no incidence of graft dislodgement or segmental instability was diagnosed in any patient. Modified open-door expansive laminoplasty is an effective way of expanding the spinal canal. Its associated low incidence of postoperative instability and kyphotic deformity should make this procedure a desirable substitute for cervical laminectomy under many circumstances.


Effect of Tai Chi on mononuclear cell functions in patients with non-small cell lung cancer.
Tai Chi is the Chinese traditional medicine exercise for mind-body health. The objective of this study is to investigate the effect of Tai Chi Chuan (TCC) exercise on the proliferative and cytolytic/tumoricidal activities of peripheral blood mononuclear cells (PBMCs) in postsurgical non-small cell lung cancer (NSCLC) patients. Patients (n = 27) were randomly divided into the control group (n = 13) and the TCC group (n = 14). TCC group participated in Tai Chi 24-type exercise for 16 weeks, 60-min every time, and three times a week. Peripheral blood was collected and PBMCs isolated before and after the 16-week TCC, PBMC proliferation and co-culture of PBMCs with the NSCLC cell line A549 were performed for proliferation and cell cytolysis assays. Analysis of NKT cells, NK cells, and CD123+ and CD11c + dendritic cells were also performed. (1) After 16-week of TCC, cell proliferation increased significantly as compared with the control. (2) PBMCs from the TCC group also demonstrated enhanced cytolytic/oncolytic activity against A549 cells. (3) Significant differences were also found in NK cell percentage at t = 16 weeks, post-pre changes of NKT and DC11c between groups. Regular Tai Chi exercise has the promise of enhancing PBMC proliferative and cytolytic activities in NSCLC patients. Our results affirm the value of a future trial with a larger scale and longer duration for cancer survivors. ChiCTR-TRC-11001404 .


Voluntary adoption of social welfare-enhancing behavior: Mask-wearing in Spain during the COVID-19 outbreak.
With the spread of COVID-19, more countries now recommend their citizens to wear facemasks in public. The uptake of facemasks, however, remains far from universal in countries where this practice lacks cultural roots. In this paper, we aim to identify the barriers to mask-wearing in Spain, a country with no mask-wearing culture. We conduct one of the first nationally representative surveys (n = 4,000) about this unprecedented public health emergency and identify the profile of citizens who are more resistant to face-masking: young, educated, unconcerned with being infected, and with an introverted personality. Our results further indicate a positive correlation between a social norm of mask-wearing and mask uptake and demonstrate that uptake of facemasks is especially high among the elderly living in localities where mask-wearing behavior is popular. These results are robust when controlling for respondents' demographics, time spent at home, and occupation fixed effects. Our findings can be useful for policymakers to devise effective programs for improving public compliance.


Effects of changing milk replacer feedings from twice to once daily on Holstein calf innate immune responses before and after weaning.
The objectives of this study were to determine the effects of switching Holstein calves to once-daily feeding during the fourth week of life (24 ± 2.3 d of age; once-fed n=22; twice-fed n=22) on innate immune responses, and to evaluate whether carry-over effects occurred when the calves were weaned during the seventh week of life. Peripheral blood samples were taken immediately before the change in feeding strategy (24 d of age) and at 27, 31, 45, 48, 52, and 66 d of age and were analyzed for circulating cortisol, haptoglobin, total leukocyte counts, neutrophil:mononuclear cells, and hematocrit percentage. Heparinized whole blood was also stimulated with lipopolysaccharide (LPS) for 24h and the concentration of tumor necrosis factor-α (TNF-α) in the supernatant was analyzed. Neutrophil L-selectin and β(2)-integrin expression were analyzed by flow cytometry. Simultaneous neutrophil phagocytic and oxidative burst responses to a heat-killed Escherichia coli were quantified by dual-color flow-cytometry. Treatment (once-daily or twice daily feeding) had no effect on pre- or postweaning performance. Once-fed calves tended to have more circulating neutrophils at 27 d of age, greater expression of L-selectin on neutrophils at 31 and 45 d of age, and greater intensity of phagocytosis at 45 d of age. Once-fed calves secreted less TNF-α in LPS-stimulated whole blood cultures at 45 d of age compared with twice-fed calves and this tended to persist through the immediate postweaning period. None of the other immune parameters differed after weaning between the preweaning feeding strategies. Consolidating calf milk replacer into one feeding during the fourth week of life was likely a mild and acute stressor, as evidenced by transient neutrophilia in the absence of suppressed functional capacities of neutrophils. Future research should address the mechanism and immunological significance of the persistent decreased TNF-α response in once-fed calves.


Fructose induced neurogenic hypertension mediated by overactivation of p38 MAPK to impair insulin signaling transduction caused central insulin resistance.
Type 2 diabetes are at a high risk of complications related to hypertension, and reports have indicated that insulin levels may be associated with blood pressure (BP). Fructose intake has recently been reported to promote insulin resistance and superoxide formation. The aim of this study is to investigate whether fructose intake can enhance superoxide generation and impair insulin signaling in the NTS and subsequently elevate BP in rats with fructose-induced hypertension. Treatment with fructose for 4 weeks increased the BP, serum fasting insulin, glucose, homeostatic model assessment-insulin resistance, and triglyceride levels and reduced the serum direct high-density lipoprotein level in the fructose group. The Tempol treatment recovered the fructose-induced decrease in nitric oxide production in the NTS. Immunoblotting and immunofluorescence analyses further showed that fructose increased the p38- and fructose-induced phosphorylation of insulin receptor substrate 1 (IRS1S307) and suppressed AktS473 and neuronal nitric oxide synthase phosphorylation. Similarly, fructose was able to impair insulin sensitivity and increase insulin levels in the NTS. Fructose intake also increased the production of superoxide in the NTS. The results of this study suggest that fructose might induce central insulin resistance and elevate BP by enhancing superoxide production and activating p38 phosphorylation in the NTS.


Recent advances in asymmetric total synthesis of prostaglandins.
Prostaglandins (PGs) are a series of hormone-like chemical messengers and play a critical role in regulating physiological activity. The diversified therapeutic activities and complex molecular architectures of PGs have attracted special attention, and huge progress has been made in asymmetric total synthesis and discovery of pharmaceutically useful drug candidates. In the last 10 years, several powerful syntheses have emerged as new solutions to the problem of building PGs and represent major breakthroughs in this area. This review highlights the advances in methodologies for the asymmetric total synthesis of prostaglandins. The application of these methodologies in the syntheses of medicinally useful prostaglandins is also described. The study has been carefully categorized according to the key procedures involved in the syntheses of various prostaglandins, aiming to give readers an easy understanding of this chemistry and provide insights for further improvements.


Covalent immobilization of antimicrobial agents on titanium prevents Staphylococcus aureus and Candida albicans colonization and biofilm formation.
Biofilm-associated implant infections represent a serious public health problem. Covalent immobilization of antimicrobial agents on titanium (Ti), thereby inhibiting biofilm formation of microbial pathogens, is a solution to this problem. Vancomycin (VAN) and caspofungin (CAS) were covalently bound on Ti substrates using an improved processing technique adapted to large-scale coating of implants. Resistance of the VAN-coated Ti (VAN-Ti) and CAS-coated Ti (CAS-Ti) substrates against in vitro biofilm formation of the bacterium Staphylococcus aureus and the fungal pathogen Candida albicans was determined by plate counting and visualized by confocal laser scanning microscopy. The efficacy of the coated Ti substrates was also tested in vivo using an adapted biomaterial-associated murine infection model in which control-Ti, VAN-Ti or CAS-Ti substrates were implanted subcutaneously and subsequently challenged with the respective pathogens. The osseointegration potential of VAN-Ti and CAS-Ti was examined in vitro using human bone marrow-derived stromal cells, and for VAN-Ti also in a rat osseointegration model. In vitro biofilm formation of S. aureus and C. albicans on VAN-Ti and CAS-Ti substrates, respectively, was significantly reduced compared with biofilm formation on control-Ti. In vivo, we observed over 99.9% reduction in biofilm formation of S. aureus on VAN-Ti substrates and 89% reduction in biofilm formation of C. albicans on CAS-Ti substrates, compared with control-Ti substrates. The coated substrates supported osseointegration in vitro and in vivo. These data demonstrate the clinical potential of covalently bound VAN and CAS on Ti to reduce microbial biofilm formation without jeopardizing osseointegration.


Translational aspects of blood-brain barrier transport and central nervous system effects of drugs: from discovery to patients.
The development of CNS drugs is associated with high failure rates. It is postulated that too much focus has been put on BBB permeability and too little on understanding BBB transport, which is the main limiting factor in drug delivery to the brain. An integrated approach to collecting, understanding, and handling pharmacokinetic-pharmacodynamic information from early discovery stages to the clinic is therefore recommended in order to improve translation to human drug treatment.


An alternatively-spliced mRNA in the carboxy terminus of the neurofibromatosis type 1 (NF1) gene is expressed in muscle.
The gene for neurofibromatosis type 1 (NF1) was identified by positional cloning and found to contain two alternatively spliced exons. The first described alternatively spliced exon (exon 23a) is located within the GAP-related domain of the gene and inserts an additional 63 nucleotides into the NF1 mRNA. The second alternatively spliced exon (exon 48a) is located near the extreme carboxy terminus of the gene and inserts an additional 54 nucleotides into the mRNA. This second isoform, termed 3'ALT, was originally detected while screening a fetal brain cDNA library. Examination of its expression by reverse-transcribed RNA PCR demonstrates high level of expression in cardiac muscle, skeletal muscle and smooth muscle. Trace levels of expression are detected in brain and nerve. The 3'ALT isoform is expressed in fetal cardiac muscle, adult left ventricle and cardiac Purkinje cells. Further confirmation of the existence of this isoform was obtained by blotting the PCR products with a radiolabeled oligonucleotide entirely derived from sequences contained within exon 48a and by direct sequencing of the PCR products. Additionally, this isoform is expressed in muscle tissues from other vertebrate species. The expression of this isoform in muscle suggests that the NF1 gene may play additional tissue-specific roles in muscle development and signal transduction.


Sonographic findings in gastric leiomyosarcoma.
Ultrasonography in two cases of gastric leiomyosarcoma demonstrated predominantly solid masses with multiple echo-free cystic areas. Metastases to the liver showed similar sonographic findings. In both cases, ultrasonography was of value in assessing the extragastric extent of the lesion.


alpha-Helical solenoid model for the human involucrin.
Involucrin is a key component of the cross-linked envelope of terminally differentiated keratinocytes. The human molecule largely consists of 10 residue repeats and forms a thin 460 A long rod. Summarized experimental data and a detailed stereochemical analysis made with computer modeling resulted in a structural model for the involucrin molecule. The suggested structure is a left-handed alpha-helical solenoid built of a tandem array of helix-turn-helix folds. The structure enables us to explain the whole set of experimental data and residue conservations within the repeats. It is ideally suited to serve as a scaffold for cell envelope assembly and proposes a possible mode of the intermolecular interactions of involucrin during cell cornification.


The Effect of Atrial Fibrillation on Inpatient Outcomes of Patients with Acute Pancreatitis: A Two-year National Inpatient Sample Database Study.
Limited published data exist regarding the association of atrial fibrillation (AF) and acute pancreatitis. To test our hypothesis that AF increases mortality and clinical outcomes in patients with acute pancreatitis, we conducted a cross-sectional data review of the National Inpatient Sample (NIS) database. The NIS database was reviewed for the collection of data on patient hospitalizations in 2016 and 2017. Patients diagnosed with acute pancreatitis with and without concomitant AF were included in the analysis. The International Classification of Diseases, 10th revision coding system was used for the variables of interest. The Stata software program (StataCorp LLC, College Station, TX, USA) was used to perform statistical analyses. The chi-squared test or analysis of variance was used to identify differences in demographic characteristics between the groups. The study population included two groups of patients: those with acute pancreatitis only (n = 542,440) and those with both acute pancreatitis and AF (n = 32,790). The group with acute pancreatitis and AF had a two- to threefold higher rate of mortality [adjusted odds ratio (OR): 2.59; 95% confidence interval (CI): 2.04-3.28] and increased length of stay (adjusted OR: 1.28; 95% CI: 1.08-1.48). Also, significantly higher odds of sepsis (adjusted OR: 2.49; 95% CI: 2.06-3.01), congestive heart failure (adjusted OR: 3.16; 95% CI: 2.87-3.49), acute coronary syndrome (adjusted OR: 1.61; 95% CI: 1.17-2.21), stroke (adjusted OR: 3.94; 95% CI: 1.42-10.93), and acute kidney injury (adjusted OR: 1.42; 95% CI: 1.30-1.55) were observed in patients with acute pancreatitis and AF relative to in patients with acute pancreatitis only. Our results suggest AF increases mortality in patients with acute pancreatitis and that patients with acute pancreatitis and AF are at greater risk of worse clinical outcomes.


Steps parameters of elderly patients hospitalised for an acute medical illness in a Swiss University Hospital: a monocentric observational pilot-study.
Objective mobility goals for elderly hospitalised medical patients remain debated. We therefore studied steps parameters of elderly patients hospitalised for an acute illness, to determine goals for future interventional trials and medical practice. Observational study conducted from February to November 2018 in a medical ward of the Lausanne University Hospital, Switzerland. We measured the step parameters of consecutive medical patients aged ≥65 years admitted for an acute medical illness using a wrist accelerometer (Geneactiv). We also collected demographic, somatic and functional factors. Overall, 187 inpatients had their step parameters (daily step count, walking cadence and bout duration) measured with accelerometers worn for a mean of 3.6 days (standard deviation [SD] 3.2). Elderly inpatients (81.5 years, SD 8.5) walked a median of 603 steps daily (interquartile range [IQR] 456-809), at a median cadence of 100 steps/minute (IQR 99-101) with median walking bouts of 33 seconds (IQR 27-37) and with 70% of the walking bouts lasting less than 30 seconds. Patients walking ≥600 steps were younger (80.4 years, SD 8.9 vs 82.8 years,SD 7.9, p = 0.050) and had a longer length of stay (7.8 days, SD 5.1 vs 6.1 days, SD 4.1, p = 0.011) than those walking <600 steps. Patients at high risk of bed sores walked less (564 steps, IQR 394-814 vs 626, IQR 526-840) than those with a lower risk of sores. During a hospitalisation for an acute medical illness, patients aged ≥65 years walk a mere 603 steps daily and most of the time for periods of less than 30 seconds. This information should be used to build up future interventional trials or to set mobility goals for patients hospitalised in Swiss hospitals.


WNT5A regulates adipose tissue angiogenesis via antiangiogenic VEGF-A165b in obese humans.
Experimental studies have suggested that Wingless-related integration site 5A (WNT5A) is a proinflammatory secreted protein that is associated with metabolic dysfunction in obesity. Impaired angiogenesis in fat depots has been implicated in the development of adipose tissue capillary rarefaction, hypoxia, inflammation, and metabolic dysfunction. We have recently demonstrated that impaired adipose tissue angiogenesis is associated with overexpression of antiangiogenic factor VEGF-A165b in human fat and the systemic circulation. In the present study, we postulated that upregulation of WNT5A is associated with angiogenic dysfunction and examined its role in regulating VEGF-A165b expression in human obesity. We biopsied subcutaneous and visceral adipose tissue from 38 obese individuals (body mass index: 44 ± 7 kg/m2, age: 37 ± 11 yr) during planned bariatric surgery and characterized depot-specific protein expression of VEGF-A165b and WNT5A using Western blot analysis. In both subcutaneous and visceral fat, VEGF-A165b expression correlated strongly with WNT5A protein (r = 0.9, P < 0.001). In subcutaneous adipose tissue where angiogenic capacity is greater than in the visceral depot, exogenous human recombinant WNT5A increased VEGF-A165b expression in both whole adipose tissue and isolated vascular endothelial cell fractions (P < 0.01 and P < 0.05, respectively). This was associated with markedly blunted angiogenic capillary sprout formation in human fat pad explants. Moreover, recombinant WNT5A increased secretion of soluble fms-like tyrosine kinase-1, a negative regulator of angiogenesis, in the sprout media (P < 0.01). Both VEGF-A165b-neutralizing antibody and secreted frizzled-related protein 5, which acts as a decoy receptor for WNT5A, significantly improved capillary sprout formation and reduced soluble fms-like tyrosine kinase-1 production (P < 0.05). We demonstrated a significant regulatory nexus between WNT5A and antiangiogenic VEGF-A165b in the adipose tissue of obese subjects that was linked to angiogenic dysfunction. Elevated WNT5A expression in obesity may function as a negative regulator of angiogenesis.NEW & NOTEWORTHY Wingless-related integration site 5a (WNT5A) negatively regulates adipose tissue angiogenesis via VEGF-A165b in human obesity.


Trade and health: how World Trade Organization (WTO) law affects alcohol and public health.
The alcohol field is becoming more aware of the consequences of world trade law for alcohol policies. However, there is a need for greater clarity about the different effects of trade on alcohol-related harm. A comprehensive review of all literature on alcohol and world trade [including World Trade Organization (WTO) disputes on alcohol], supported by a more selective review of other relevant cases, academic reports and the grey literature on trade and health. The burden of WTO law on alcohol policies depends upon the type of policy in question. Purely protectionist policies are likely to be struck down, which may lead to increases in alcohol-related harm. Partly protectionist and partly health-motivated policies are also at risk of being struck down. However, purely health-motivated policies are likely to be defended by the WTO-and to the extent that policy makers misunderstand this, they are needlessly avoiding effective ways of reducing alcohol-related harm. WTO agreements contain genuine and substantial risks to alcohol policies, and various ways of minimizing future risks are suggested. However, the 'chilling effect' of mistakenly overestimating these constraints should be avoided. Health policy makers should decide on which policies to pursue based primarily on considerations of effectiveness, ethics and politics rather than legality. As long as any effect of these policies on trade is minimized, they are overwhelmingly likely to win any challenges at the WTO.


Reactive modifications of the autonomous time structure in the human organism.
The spectrum of biological rhythms exhibits characteristic principles of biological time structure which also rule the functional behaviour. With increasing period lengths the rhythms become increasingly complex. In the long-wave section the rhythmic functions find their corresponding cycles in the environment, whereas the shorter waves represent only endogenous autonomous rhythms, which maintain an internal time order by means of frequency- and phase-coordination. Under resting conditions and in a state of complete adaptation only a few spontaneous rhythms dominate in the spectrum. However, under loading conditions as well as in pathological situations further periodicities come up. The spectrum of rhythms can be divided into certain blocks, with the period lengths predominating in each of these whole number frequency ratios forming a harmonic system. Frequency- and phase coordination establish a system of co-action which favours the functional economy of the organism. A tripartite organization of the autonomous rhythms involves different functional behaviours with regard to frequency, amplitude, and phase. Slower rhythms act upon the faster rhythms preferably by modulating their frequencies, while changes of the faster rhythms influence the slower ones by enhancing their amplitudes, multiplying their period lengths and shifting their phases. In principle the reactions of living systems are periodically structured. Reactive periodicity brings to appearance an endogenous time structure, which prefers whole number relationships with the spontaneous rhythms. The phase position of reactive periods depends on the stimulus. The amplitudes dampen down with increasing compensation. From the medical point of view so-called circaseptan (about 7 days) reactive periods are of predominant interest. This periodicity can be observed in numerous adaptive and compensating processes. It does not depend on the external week cycle and was already known to the antiquity.


Qualitative methods in PhD theses from general practice in Scandinavia.
Qualitative methodology is gaining increasing attention and esteem in medical research, with general practice research taking a lead. With these methods, human and social interaction and meaning can be explored and shared by systematic interpretation of text from talk, observation or video. Qualitative studies are often included in Ph.D. theses from general practice in Scandinavia. Still, the Ph.D. programs across nations and institutions offer only limited training in qualitative methods. In this opinion article, we draw upon our observations and experiences, unpacking and reflecting upon values and challenges at stake when qualitative studies are included in Ph.D. theses. Hypotheses to explain these observations are presented, followed by suggestions for standards of evaluation and improvement of Ph.D. programs. The authors conclude that multimethod Ph.D. theses should be encouraged in general practice research, in order to offer future researchers an appropriate toolbox.


Delayed muscle development in small pig fetuses around birth cannot be rectified by maternal early feed restriction and subsequent overfeeding during gestation.
Intrauterine variations in nutrient allowance can alter body composition and tissue features of the porcine offspring around birth. This study aimed to determine the effects of fetal weight variations between littermates and of maternal dietary regimen during gestation on fetal muscle traits just before birth. Fourteen pregnant gilts were reared under a conventional (control, CTL; n=7) or an experimental (treatment, TRT; n=7) dietary regimen during gestation. The dietary treatment provided 70% of the protein and digestible energy contents of the CTL diet during the first 70 days of gestation and then, 115% of the protein and digestible energy contents up to farrowing. At 110 days of gestation, sows were sacrificed and one fetus having a low (824±140 g) and one having a normal (1218±192 g) BW per litter were sampled. Irrespective of maternal dietary regimen, the longissimus muscle of the small fetuses exhibited higher expression levels of DLK1/Pref1 and NCAM1/CD56, two genes known to be downregulated during normal skeletal muscle development. Expression levels of the embryonic isoform of the myosin heavy chain (MyHC), both at the mRNA and at the protein levels, were also higher in small fetuses. In addition, the ratios of perinatal to embryonic and of adult fast to developmental MyHC isoforms were generally lower in light fetuses compared with their medium-weight littermates. These modifications suggest a delayed myofiber development in spontaneous growth-retarded fetuses. Finally, GLUT1 was expressed to a lesser extent in the muscle of small v. normal fetuses, suggesting decreased ability for glucose uptake in muscle. Initial feed restriction and subsequent overfeeding of sows during gestation led to a lower expression of the myogenic factor MYOD1, a prerequisite for myogenic initiation in skeletal muscle. This maternal strategy was also associated with a lower expression level of insulin-like growth factor 1 receptor (IGFR) but an upregulation of IGF2. This suggests an altered susceptibility of muscle cells to IGFs' signal in fetuses from treated sows. Altogether, intrauterine growth restriction impaired fetal muscle development, and restricted feeding followed by overfeeding of gestating sows did not allow small fetuses to recover normal contractile and metabolic characteristics.


Prevalence and risk factors of frailty in older patients with chronic heart failure: a systematic review and meta-analysis.
To provide a summary of the available evidence concerning prevalence and risk factors of frailty in elderly patients with CHF. PubMed, Embase, Web of Science, CINAHL, The Cochrane Library, China National Knowledge Infrastructure Database (CNKI), Chinese Biomedical Database (Sinomed), Weipu Database (VIP), and Wanfang database were searched from inception to July 2023. This study strictly followed the PRISMA guidelines. The quality of the included studies was rated by the Agency for Healthcare and Research and Quality and the Newcastle-Ottawa Scale. A total of 21 original studies were included, involving 4,797 patients. Meta-analysis results showed that the prevalence of frailty in older patients with heart failure was 38% (95%CI: 0.32-0.44). Age, cardiac function grading, left atrial diameter, left ventricular ejection fraction, hemoglobin, polypharmacy, BNP, nutritional risk, and hospitalization day are the influential factors of frailty in older patients with CHF. The prevalence of frailty in older patients with CHF is high, and clinical medical personnel should identify and intervene early to reduce or delay the frailty in older patients with CHF as much as possible.


Alcohol adsorption on softwood lignin from aqueous solutions.
Lignin prepared by acid and enzyme hydrolysis of a softwood mixture adsorbs acetone, butanol, and other alcohols while showing only a slight uptake of glucose. Adsorption of butanol is independent of temperature in the range of 30-65 degrees C. The Polanyi theory fits adsorption for the linear alcohols methanol through hexanol with values of DeltaS and Delta(mu) ranging from 2.6 to 26 J mol(-1) K(-1)and -0.8 to -8 kJ/mol. The adsorption capacity is given by Q (g alcohol/g lignin) = KC(*). Where C(*) is the equilibrium alcohol concentration (g/mL), K = epsilon(W)exp (Delta/R), and epsilon(w) is the porosity of the lignin (0.23-0.42 mL/g). The value of the adsorption capacity constant K for n-butanol ranges from 1.3 to 2.7 mL/g on sorbent containing 26-72% lignin, while ethanol is 0.5-0.73, acetone is 0.62-1.0, and glucose is 0.35. Adsorption is shown to occur through combined hydrophobic and hydrophilic interactions of the alkyl and hydroxyl groups, respectively, of the adsorbate with the lignin. Consequently, for the alcohols methanol to hexanol, we present the capacity constant K[=K(R) + K(OH)] as a sum of an alky! adsorption constant (0.1-9.5 mL/g) and a hydrophilic (0.40-0.50 mL/g) contribution. This approach may be applicable to organic acids. Lignin's sorbent properties have potential to moderate product inhibition in the anaerobic acetone-butanol-ethanol (ABE) fermentation.