[2015 highlights in hospital-based internal medicine by chief residents].
The year 2015 gave us many scientific publications, among whom some will have an impact on our daily practice and some will influence our way of considering some well known diseases. Chief residents in the Service of internal medicine of the Lausanne University hospital, gathered like every year, to share their readings together in order to presentyou a small part of the many publications of 2015, which have been considered to have an impact on our future daily practice.


Genotyping and molecular characterization of hepatitis B virus in liver disease patients in Kenya.
Hepatitis B virus (HBV) genotypes are important in both the clinical manifestation of disease and treatment response. Although Kenya belongs to the African Region (AFR-E) characterized by high mortality and hyperendemicity of HBV, there is a paucity of HBV genotyping data. The aim of this study was to molecularly characterize the basic core promoter/precore (BCP/PC) and complete surface (S) regions of HBV isolated from 61 HBsAg-positive liver disease patients attending Kenyatta National Hospital in Nairobi. HBsAg, HBeAg and viral loads were determined. HBV DNA was amplified and sequenced from 58/61 patients. In addition to the complete genome of two isolates, the BCP/PC and the complete S regions of 43 and 38 isolates, respectively were sequenced. Following phylogenetic analysis of the S region, 38 isolates clustered with subgenotype A1, whereas two isolates clustered with genotype D, one with subgenotype D1 and another as an outlier of the clade containing subgenotype D6 and the D/E recombinant. When the complete genome of the latter isolate was sequenced it clustered with D6. The majority of isolates belonged to serological subtype adw2 and only four to ayw2. Three distinct groups of subgenotype A1, distinguished by different amino acid motifs, circulate in Kenya: two in the African cluster and a monophyletic clade in the "Asian" cluster. HBeAg-negativity was a result of G1896A in genotype D isolates, whereas in subgenotype A1, the HBeAg-negativity was a result of mutations in the Kozak region (1809-1812) or precore start codon (1814-1816). Mutations at positions 1762 and 1764 occurred more frequently in HCC patients (p<0.05). In conclusion, subgenotypes A1, D1 and D6 circulate in liver disease patients in Kenya, with A1 predominating.


[The effect of basic fibroblast growth factor on angiogenesis and on the expression of basic fibroblast growth factor and vascular endothelial growth factor in acute infarcted myocardium].
To evaluate the effect of intramyocardial administration of basic fibroblast growth factor (bFGF) on the angiogenesis and on the expression of bFGF and vascular endothelial growth factor (VEGF) in infarcted myocardium. Twenty-four mongrel dogs were randomized into control group and therapeutic group. Acute myocardial infarction was made by ligation of the left anterior descending coronary artery distal to its first diagonal branch. After coronary artery was occlused, 50 micrograms of basic fibroblast growth factor in 15 ml of normal saline were injected into the infarcted myocardium and its border zone in therapeutic group, whereas the same volume of normal saline alone was used in control dogs. Every 3 dogs in each group was studied on the 1st day, the 3rd day, the 10th day and the 17th day after surgery respectively. With sensitivity encoded technique, cine MR was performed on each dog before euthanasia to evaluate the cardiac function. Angiogenesis and the expression of VEGF and bFGF were evaluated by immunohistochemical studies with factor VIII and the antibodies of VEGF and bFGF. In therapeutic group, left ventricular ejection fraction, improved markedly since the 10th day after injection of bFGF. Microvessel density was higher in the therapeutic group than in the control group except on the first day. VEGF and bFGF expressed more in the therapeutic group. Intramyocardial administration of bFGF is useful in increasing the growth of microvessels and improving the left ventricular function in acute myocardial infarction.


The Dueling Duo: IL10 and TNF Face Off in Microglial Recovery from Endotoxin Challenge.
The molecular mechanisms that restore microglial quiescence after acute stimulation remain largely unexplored, unlike those that drive microglial activation. In this issue of Immunity, Shemer et al. discover that the microglial IL-10 receptor counteracts the pro-inflammatory effects of TNF to allow restoration of microglial quiescence after peripheral endotoxin challenge.


Migration despite stabilization of an embolized transcatheter heart valve: A word of caution.
This case report describes an initially stabilized transcatheter heart valve that embolized in the ascending aorta, leading to a postprocedural acute type A aortic dissection.


Older adults present better back endurance than young adults during a dynamic trunk extension exercise.
Poor back endurance is a predictor of low back pain. Few studies have investigated back muscle fatigue in older people. The purpose of this study was to compare the back muscle fatigue by endurance time and perceived effort between young and older adults during dynamic exercise. Sixteen older and 16 young adults, all healthy, participated in this study. The subjects performed a fatiguing trunk extension-flexion exercise on a Roman chair until exhaustion. Endurance time and perceived muscle fatigue (Borg CR-10 scale) were used as fatigue criteria. The older adults were significantly (T<formula>_{(30)}</formula> = -2,073; p = 0.039) more resistant to back muscle fatigue (time in mean 133 ± 52 s) than the young adults (mean 97 ± 27 s). In general, both groups had the same perception of high-level fatigue during the exercise bout (T<formula>_{(29)}</formula> = 1.73; p=0.092). The older adults presented better back endurance than young adults during a dynamic trunk extension exercise. These results have implications for back endurance in the primary prevention of low back pain in both young and older adults.


Design and construction of a new human naïve single-chain fragment variable antibody library, IORISS1.
Human monoclonal antibodies are a powerful tool with increasingly successful exploitations and the single chain fragment variable format can be considered the building block for the implementation of more complex and effective antibody-based constructs. Phage display is one of the best and most efficient methods to isolate human antibodies selected from an efficient and variable phage display library. We report a method for the construction of a human naïve single-chain variable fragment library, termed IORISS1. Many different sets of oligonucleotide primers as well as optimized electroporation and ligation reactions were used to generate this library of 1.2×10(9) individual clones. The key difference is the diversity of variable gene templates, which was derived from only 15 non-immunized human donors. The method described here, was used to make a new human naïve single-chain fragment variable phage display library that represents a valuable source of diverse antibodies that can be used as research reagents or as a starting point for the development of therapeutics. Using biopanning, we determined the ability of IORISS1 to yield antibodies. The results we obtained suggest that, by using an optimized protocol, an efficient phage antibody library can be generated.


The efficacy of simultaneous bilateral axillary brachial plexus block under the guidance of neurostimulator or ultrasound: a prospective study.
This study was designed to investigate the risk of local anesthetic toxicity and efficacy of simultaneous bilateral axillary brachial plexus block performed under the guidance of ultrasound or a neurostimulator. One hundred and twenty patients who were anesthetized with bilateral axillary plexus block simultaneously between February 2012 and March 2014 were enrolled in the study. The patients were anesthetized under the guidance of a neurostimulator (group N, n = 60) or ultrasound (group U, n = 60). The block performance time, procedure-related pain, adverse events, total and free plasma concentrations of ropivacaine, and other data were recorded. The comparison was analyzed statistically. The block performance time, and onset of the sensory and motor block, of group N was longer than that of group U (p < 0.001). The procedure-related pain of group N was more serious than that of group U (p < 0.05). The patient satisfaction rate of group U was higher than that of group N (p < 0.05). The total plasma concentrations of ropivacaine in group N were comparable to those of group U, except for the value at 50 min after injection (p < 0.05). The free plasma concentrations of ropivacaine of group N at 5 min were significantly higher than that of group U (p < 0.001). No apparent serious adverse events were observed perioperatively in both groups. Simultaneous bilateral axillary brachial plexus block guided by neurostimulator or ultrasound in bilateral distal upper extremity surgery seems to have a low risk of local anesthetic toxicity and to be effective. The ultrasound-guided block is superior in terms of providing the same degree of anesthesia with shorter duration, less pain, and faster onset of sensory and motor blockades, which is important in clinical practice.


Early right ventricular response to cardiac resynchronization therapy: impact on clinical outcomes.
Right ventricular (RV) dysfunction has been associated with a worse outcome in heart failure patients undergoing CRT. However, evidence on the RV response to CRT is controversial and there are no data regarding the early effects of CRT on RV function (RVF). We sought to investigate whether a CRT device favourably influences the RVF acutely after implantation, impacting on long-term outcomes. Patients who successfully underwent CRT device implantation from January 2005 to January 2014 were retrospectively analysed. RV dysfunction was defined by an RV fractional area change <35%. Post-procedural echocardiographic evaluation was performed at a median time of 2 days (interquartile range 1-6 days). The primary endpoint was a composite of all-cause mortality and urgent heart transplantation. A total of 194 patients with available pre- and post-procedural RVF assessment were included. Sixty-two (32%) presented an impaired RVF before the procedure. Of them, 32% showed prompt normalization of RVF following CRT. This occurred in parallel with a large improvement in pulmonary arterial pressure, mitral regurgitation, E/E' ratio, and diastolic function. Pre-implantation independent predictors of early RVF normalization were LBBB (P = 0.034) and higher systolic blood pressure (P = 0.026). Improvement in RVF was independently associated with a better long-term prognosis at multivariable analysis [hazard ratio 0.124; 95% confidence interval 0.016-0.966, P = 0.04). Acute normalization of RVF can be observed after CRT along with haemodynamic improvement, and therefore can be used as an independent predictor of transplant-free survival.


Glial migratory streams in the developing hindbrain: a slice culture approach.
Compared to our knowledge of neurogenesis, relatively little is known about glial cell specification and migration during central nervous system development. We have established a novel chick hindbrain slice preparation which permits examination of gliogenesis in its native environment, providing a means to study the signaling pathways involved in glial cell specification and migration during development. Cells in the hindbrain slice preparations mature in a manner which is similar to in vivo developmental timing and patterning paradigms. To demonstrate the utility of this approach, we examined the effect of the retinoic acid signaling pathway on cells in these slices, showing that addition of exogenous trans-retinoic acid to slice cultures promotes expression of a marker of mature astrocytes, glial fibrillary acidic protein (GFAP), while the inhibition of endogenous retinoic acid synthesis reduces GFAP expression; the results suggest a role for retinoic acid in modulating glial differentiation. Using these hindbrain slice cultures, we have used two different approaches to label glial progenitors specifically at the ventricular zone and have observed for the first time the ventrally-directed migration of these cells from the ventricular zone of the hindbrain. This slice culture system is thus an innovative and robust tool for examining glial cell migration and the extracellular molecular and signaling pathways which regulate glial differentiation.


Mycorrhizal fungi show regular community compositions in natural ecosystems.
Dissimilarity overlap curve analysis has shown that 'universality' is a common feature in many complex microbial communities, suggesting that the same taxa interact in a similar manner when shared between communities. We present evidence that arbuscular mycorrhizal fungi, common plant root symbionts, show universal community compositions in natural ecosystems and that this pattern is conserved even at larger spatial scales. However, universality was not detected in agricultural ecosystems potentially implying that agricultural symbiont communities are formed in a different manner.


Noradrenergic function and hypothalamic-pituitary-adrenal axis activity in adolescents with major depressive disorder.
Levels of plasma norepinephrine (NE), free 3-methoxy-4-hydroxyphenylglycol (MHPG), and cortisol in adolescents with major depressive disorder (10 girls, 1 boy; mean +/- SD age = 16.4 +/- 1.6 years, range = 14-19 years) did not differ significantly from those in a group of healthy adolescents (17 girls, 12 boys; mean +/- SD age = 15.9 +/- 1.5 years, range = 12-18 years). No correlations were observed between these variables and age within the adolescent groups. However, when the adolescent data were viewed in combination with data previously obtained for an adult population (De Villiers et al., 1987), significant positive correlations between the variables were observed within the patient group. A moderate positive correlation with age was also observed for patients' NE and free MHPG levels. No such correlations were observed for the combined control group. When groups were partitioned into three age categories, it became apparent that differences in the three variables between the patient and the control groups were restricted to elderly subjects (greater than 50 years). In adults (21-50 years old), only the patients' NE levels were significantly elevated. These findings suggest that duration of illness may be important in determining the full expression of the biochemical abnormality in major depression.


Interference of B lymphocyte tolerance by prolactin in rheumatic autoimmune diseases.
Systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic sclerosis (SSc) are the most common rheumatic autoimmune diseases/disorders (RADs) that affect autologous connective tissues as a result of the breakdown of the self-tolerance mechanisms of the immune system. Prolactin, a glycoprotein hormone, has been known for its crucial role in the pathogenesis of these rheumatic autoimmune diseases. In addition to regulating lymphocyte proliferation and antibody synthesis, prolactin is also responsible for regulating cytokine production. Moreover, it contributes to the breakdown of central and peripheral tolerance mechanisms of B lymphocytes. Given the crucial role of prolactin in the pathogenesis of the mentioned RADs, prolactin may contribute to their pathogenesis by the breakdown of tolerance. In the present study, the key role of prolactin to the breakdown of B lymphocyte tolerance and its possible implication for the pathogenesis of these diseases is discussed. Current literature supports prolactin's role in the breakdown of B lymphocyte central and peripheral tolerance mechanisms, such apoptosis, receptor editing, and also anergy. Therefore, prolactin may contribute to the pathogenesis of RADs by the breakdown of B lymphocyte tolerance. However, more investigations, particularly in RA and SSc animal models, are required to precisely address the pathologic role of prolactin.


A survey of participants in a mass CPR training course.
To determine demographic data and reasons for CPR course taking among 891 participants of a mass CPR training event, a questionnaire was distributed at the time of the course. Of the 728 persons completing this initial survey, 379 (52.6%) were less than 20 years of age. Only 41 (5.6%) took the course because of a family member or close relative with cardiac disease. Of this subgroup, seven (17.1%) had taken a previous CPR course, compared with 25.7% for the entire population. Thirty-eight percent of the 60-and-over age group mentioned cardiac disease as their reason for taking the course, compared to only 2.1% for the under-20 age group. To assess recall and actual performance of CPR, a follow-up survey was mailed to all participants six months after the course. Seventy-two percent were still confident in their ability to perform CPR, although no one had performed the technique on a real victim; 61.9% thought there should have been more manikin practice time; 92.2% still had their CPR refresher card. Only 32.3% would perform CPR on a known AIDS patient. This survey provides demographic and personal data that should be considered when planning future large-scale CPR training programs.


High-speed scanning of planar images showing 123I-MIBG uptake using a whole-body CZT camera: a phantom and clinical study.
The heart-to-mediastinum ratio (HMR) obtained in myocardial sympathetic innervation imaging using 123I-metaiodobenzylguanidine (MIBG) is used for heart failure or Lewy body diseases (LBD). Discovery NM/CT 670 CZT, a novel whole-body scanner, enables direct HMR measurements in planar images, in contrast to cardiac-dedicated CZT-based cameras which require specific post-processing reconstruction. We sought to investigate the clinical utility of the Discovery NM/CT 670 CZT for myocardial innervation imaging and the potential time reduction. Following preliminary phantom examinations, 123I-MIBG planar imaging was performed in 36 patients with suspected or known LBD to measure HMRs with a collection time of 300 s. Images for different collection times were subsequently reframed using already acquired data, and changes in HMRs were evaluated. The HMRs for patients with versus without clinically diagnosed LBD were 1.63 ± 0.08 versus 2.21 ± 0.08 at early phase (p < 0.001) and 1.54 ± 0.09 versus 2.08 ± 0.09 at delayed phase (p < 0.001). The difference of HMRs (300 s - other collection time) became greater as the collection time became shorter. There was good consistency in HMRs between the 300-s images (reference) and the 200-s (intra-class correlation (ICC) coefficients > 0.99), 100-s (ICC coefficients > 0.97), and 50-s (ICC coefficients > 0.89) images. In planar images with a whole-body CZT-based camera, the HMRs of patients with LBD were significantly lower than those without. HMRs with the collection time of 50 s and longer showed good consistency with those of 300 s in the ICC analysis. These findings indicate a clinical utility of this novel scanner for HMR measurements and potential time reductions.


Concurrence of the triple-X syndrome and expression of the fragile site Xq27.3.
The Xq27.3 fragile site was found to be expressed in an XXX woman, who was mentally and physically normal, and in her son who was mentally retarded and showed behavioural and physical features characteristic of the fragile X syndrome.


Urethral substitution using vein graft for hypospadias repair.
Complex hypospadias surgery requires abundant and stretchable tissues for urethroplasty. Genital skin is ideal for this purpose but is often unavailable in re-do cases. Extragenital tissues have their drawbacks such as the limited length of buccal and bladder mucosa, and contracture of skin grafts. Tubularization and on-lay techniques comprise one or two longitudinal suture lines that are the source of complications. We investigate the possibility of using a saphenous vein graft to construct a long, wide, stretchable and pre-tubularized neourethra that is not compromised by the longitudinal suture line. A male patient with proximal hypospadias for which surgical correction had failed underwent the operation. The patient had a penoscrotal meatus and was circumcised. A saphenous vein graft was passed through a tunnel created on the ventral aspect of the penis, and was anastomosed to the urethra proximally and the distal opening of the tunnel at the tip of the penis. After 12 months, the patient had a forward stream, no dilatation of the neourethra, and no penile curvature upon morning erection (as reported by the parents). This initial experience with saphenous vein urethroplasty shows that the technique is feasible, and may provide a reliable and practical alternative to the current techniques.


Affluence boosted intelligence? How the interaction between cognition and environment may have produced an eighteenth-century Flynn effect during the Industrial Revolution.
Cognition played a pivotal role in the acceleration of technological innovation during the Industrial Revolution. Growing affluence may have provided favourable environmental conditions for a boost in cognition, enabling individuals to tackle more complex (industrial) problems. Dynamical systems thinking may provide useful tools to describe sudden transitions like the Industrial Revolution, by modelling the recursive feedback between psychology and environment.


Impact of the chronic use of benzodiazepines prescribed for seizure control on the anxiety levels of patients with epilepsy.
In a cross-sectional study, we evaluated the impact of the chronic use of benzodiazepines (BDZ) prescribed for seizure control on the anxiety levels of patients with temporal lobe epilepsy. We assessed the anxiety level of 99 patients with temporal lobe epilepsy with (n=15) or without (n=84) BDZ for seizure control, using the Beck Anxiety Inventory (BAI) or the Hamilton Anxiety Scale (HAMA). Independent risk factors for high anxiety levels were being a female patient (O.R.=2.93; 95% C.I.=1.05-8.16; p=0.039), having uncontrolled seizures (O.R.=4.49; 95% C.I.=1.66-12.11; p=0.003) and having a history of a psychiatric disorder (O.R.=4.46; 95% C.I.=1.63-12.21; p=0.004). However, there were no statistically significant differences in anxiety levels between patients utilizing or not utilizing BDZ prescribed exclusively for seizure control. We concluded that in our study, patients with chronic use of BDZ prescribed exclusively for seizure control showed similar anxiety levels than patients who were not using this class of drug. Additional studies are needed to define better strategies for the treatment of anxiety disorders in epilepsy.


IL-4 and IL-13 induce protection of porcine endothelial cells from killing by human complement and from apoptosis through activation of a phosphatidylinositide 3-kinase/Akt pathway.
Vascular endothelial cells (EC) perform critical functions that require a balance of cell survival and cell death. EC death by apoptosis and EC activation and injury by the membrane attack complex of complement are important mechanisms in atherosclerosis and organ graft rejection. Although the effects of various cytokines on EC apoptosis have been studied, little is known about their effects on complement-mediated EC injury. Therefore, we studied the abilities of various cytokines to induce protection of porcine aortic EC against apoptosis and killing by human complement, a model of pig-to-human xenotransplantation. We found that porcine EC incubated with IL-4 or IL-13, but not with IL-10 or IL-11, became protected from killing by complement and apoptosis induced by TNF-alpha plus cycloheximide. Maximal protection required 10 ng/ml IL-4 or IL-13, developed progressively from 12 to 72 h of incubation, and lasted 48-72 h after cytokine removal. Protection from complement was not associated with reduced complement activation, C9 binding, or changes in CD59 expression. Inhibition of PI3K prevented development of protection; however, inhibition of p38 MAPK or p42/44 MAPK had no effect. IL-4 and IL-13 induced rapid phosphorylation of Akt. Although protection was inhibited by an Akt inhibitor and a dominant negative Akt mutant transduced into EC, it was induced by transduction of EC with the constitutively active Akt variant, myristylated Akt. We conclude that IL-4 and IL-13 can induce protection of porcine EC against killing by apoptosis and human complement through activation of the PI3K/Akt signaling pathway.


Current techniques for high-resolution mapping of behavioral circuits in Drosophila.
Understanding behavior requires unraveling the mysteries of neurons, glia, and their extensive connectivity. Drosophila has emerged as an excellent organism for studying the neural basis of behavior. This can be largely attributed to the extensive effort of the fly community to develop numerous sophisticated genetic tools for visualizing, mapping, and manipulating behavioral circuits. Here, we attempt to highlight some of the new reagents, techniques and approaches available for dissecting behavioral circuits in Drosophila. We focus on detailing intersectional strategies such as the Flippase-induced intersectional Gal80/Gal4 repression (FINGR), because of the tremendous potential they possess for mapping the minimal number of cells required for a particular behavior. The logic and strategies outlined in this review should have broad applications for other genetic model organisms.


Beyond the target area: an integrative view of tDCS-induced motor cortex modulation in patients and athletes.
Transcranial Direct Current Stimulation (tDCS) is a non-invasive technique used to modulate neural tissue. Neuromodulation apparently improves cognitive functions in several neurologic diseases treatment and sports performance. In this study, we present a comprehensive, integrative review of tDCS for motor rehabilitation and motor learning in healthy individuals, athletes and multiple neurologic and neuropsychiatric conditions. We also report on neuromodulation mechanisms, main applications, current knowledge including areas such as language, embodied cognition, functional and social aspects, and future directions. We present the use and perspectives of new developments in tDCS technology, namely high-definition tDCS (HD-tDCS) which promises to overcome one of the main tDCS limitation (i.e., low focality) and its application for neurological disease, pain relief, and motor learning/rehabilitation. Finally, we provided information regarding the Transcutaneous Spinal Direct Current Stimulation (tsDCS) in clinical applications, Cerebellar tDCS (ctDCS) and its influence on motor learning, and TMS combined with electroencephalography (EEG) as a tool to evaluate tDCS effects on brain function.


Validation of the orthopedic frailty score for measuring frailty in hip fracture patients: a cohort study based on the United States National inpatient sample.
The Orthopedic Frailty Score (OFS) has been proposed as a tool for measuring frailty in order to predict short-term postoperative mortality in hip fracture patients. This study aims to validate the OFS using a large national patient register to determine its relationship with adverse outcomes as well as length of stay and cost of hospital stay. All adult patients (18 years or older) registered in the 2019 National Inpatient Sample Database who underwent emergency hip fracture surgery following a traumatic fall were eligible for inclusion. The association between the OFS and mortality, complications, and failure-to-rescue (FTR) was determined using Poisson regression models adjusted for potential confounders. The relationship between the OFS and length of stay and cost of hospital stay was instead determined using a quantile regression model. An estimated 227,850 cases met the study inclusion criteria. There was a stepwise increase in the rate of complications, mortality, and FTR for each additional point on the OFS. After adjusting for potential confounding, OFS 4 was associated with an almost ten-fold increase in the risk of in-hospital mortality [adjusted IRR (95% CI): 10.6 (4.02-27.7), p < 0.001], a 38% increased risk of complications [adjusted IRR (95% CI): 1.38 (1.03-1.85), p = 0.032], and an almost 11-fold increase in the risk of FTR [adjusted IRR (95% CI): 11.6 (4.36-30.9), p < 0.001], compared to OFS 0. Patients with OFS 4 also required a day and a half additional care [change in median length of stay (95% CI): 1.52 (0.97-2.08), p < 0.001] as well as cost approximately $5,200 more to manage [change in median cost of stay (95% CI): 5166 (1921-8411), p = 0.002], compared to those with OFS 0. Patients with an elevated OFS display a substantially increased risk of mortality, complications, and failure-to-rescue as well as a prolonged and more costly hospital stay.


Novel dnaG mutation in a dnaP mutant of Escherichia coli.
Reexamination of the dnaP18 mutant strain of Escherichia coli revealed that the mutation responsible for the arrest of DNA replication and cell growth at high temperatures resides in the dnaG gene rather than in the dnaP locus as previously thought; this mutation has been designated dnaG2903.


TNFalpha DNA vaccination prevents clinical manifestations of experimental antiphospholipid syndrome.
Naked DNA encoding TNFalpha was introduced to BALB/c mice with experimental antiphospholipid syndrome (APS) induced by beta2GPI. Administration of naked DNA encoding TNFalpha resulted in the generation of immunological memory to its gene product, associated with elevated circulating anti-TNFalpha antibodies. Enriched IgG fraction of the mouse anti-TNFalpha was biologically active since it prevented endothelial cell activation by TNFalpha e.g., inhibition of monocyte adhesion to activated endothelial cells (HUVEC). Mice immunized with beta2GPI, vaccinated with TNFalpha DNA at an early stage of disease development, showed decreased titres of circulating anti-beta2GPI antibodies as compared to the group of mice vaccinated with a control naked DNA. The reduction of antiphospholipid antibody production was followed by amelioration of the foetal loss, increased platelet count to normal values as well as normalization of the prolonged aPTT. APS mice which were introduced to the TNFalpha DNA vector at a later stage of the disease development, showed less improvement in their clinical manifestations. The current study suggests a way in which a DNA vaccine can be employed for induction of a protective immunity in experimental APS.


Glucocorticosteroids attenuate aspirin-precipitated adverse reactions in aspirin-intolerant patients with asthma.
We evaluated the effects of corticosteroid pretreatment on the intensity of adverse reactions to aspirin during carefully controlled aspirin challenges in 13 aspirin-sensitive asthmatics. Two studies were performed. First, using a double-blind crossover design, we administered to five patients 75 mg prednisone daily or placebo for two days preceding the challenge. No consistent protection against adverse reactions was achieved. In the second study, a 10-day pretreatment with 15 mg oral prednisolone and topical intrabronchial and intranasal beclomethasone offered total clinical protection against bronchospasm produced by threshold doses of aspirin in five of eight patients. In two others, the bronchospasm provoked was less severe, and only in one patient did its intensity remained unchanged. There was a significant reduction in fall of mean pulmonary function tests following the second aspirin challenge, which was performed after ten days of steroid treatment. Steroids given for ten days also prevented significantly nasal discharge and nasal blockade. When diagnostic challenge tests with aspirin are carried out in asthmatic patients on long-term corticosteroid therapy, there is an increased possibility of false negative results.


Impact of the segment-specific region of the 3'-untranslated region of the influenza A virus PB1 segment on protein expression.
The 12 and 13 terminal nucleotides in the 3'- and 5'-untranslated regions (UTRs) of the influenza A virus genome, respectively, are important for the transcription of the viral RNA and the translation of mRNA. However, the functions of the segment-specific regions of the UTRs are not well known. We utilized an enhanced green fluorescent protein (eGFP) flanked at both ends by different UTRs (from the eight segments of H1N1 PR8/34) as a reporter gene to evaluate the effects of these UTRs on protein expression in vitro. The results showed that the protein expression levels of NP-eGFP, NS-eGFP, and HA-eGFP were higher than those of the other reporters and that the protein level of PB1-eGFP remained at a relatively low amount 48-h post-transfection. The results revealed that the UTRs of all segments differently affected the protein expression levels and that the effect of the UTRs of PB1 segment on protein expression was significant. The deletion of "UAAA" and "UAAACU" motifs in the PB1-3'-UTR significantly increased the protein expression level by 49.8 and 142.6%, respectively. This finding suggests that the "UAAACU" motif in the PB1-3'-UTR is at least partly responsible for the low protein expression level. By introducing the "UAAACU" motif into other 3'-UTRs (PA, NS, NP, and HA) at similar locations, the eGFP expression was reduced as expected by 56, 61, 22, and 22%, respectively. This result further confirmed that the "UAAACU" motif of the PB1-3'-UTR can inhibit protein expression. Our findings suggest that the segment-specific regions in the UTRs and not just the conserved regions of the UTRs play an important role in the viral protein expression. Additionally, the reported findings may also shed light on novel regulatory mechanism for the influenza A virus genome.


Midface retrusion.
Experience with 162 patients for whom a midface advancement was performed over the last 10 years is reported. The series includes cases of primary maxillary hypoplasia, post-cleft deformities, and major craniofacial anomalies. The indications and techniques applicable to each particular deformity are discussed and final results are analyzed. The overall facial esthetic concept is emphasized to ensure achievement of not only a good functional result, but also a pleasant appearance.


Evaluation of the antioxidant effect of melatonin by flow injection analysis-luminol chemiluminescence.
The antioxidant effect of melatonin was evaluated by using a flow injection analysis chemiluminescence (FIA-CL) method to measure alone its direct antioxidant behaviour in aqueous solutions. Inhibition by melatonin, DL-tryptophan or serotonin (5-hydroxytryptamine, 5-HT) of the steady CL emissions of various oxidants with luminol was measured. LogIC(50) values of melatonin were calculated: -2.6+/-0.1M for superoxide (O(2) radical(-)), -3.0+/-0.02 M, for hydrogen peroxide (H(2)O(2)), -4.7+/-0.04 M, for hypochlorous anion ((-)OCl), -2.8+/-0.1M, for hydoxyl (radical OH) and -2.0+/-0.03 M, for peroxynitrite (ONOO(-)). Thus melatonin exerted a limited direct antioxidant activity towards reactive oxygen species (ROS) in aqueous solutions, broadly comparable to that of tryptophan, but less than that of serotonin and of major antioxidants such as ascorbic acid. This suggests that where the benefits of melatonin are correctly attributed to antioxidant behaviour, this is mediated largely through antioxidant enzymes. The pharmacological implications are discussed.


Early Treatment of Shoulder Pathology Is Necessary but Not Enough Is Being Performed.
Delayed treatment of shoulder instability results in bone loss requiring more-complicated surgery, in turn resulting in less-optimal outcomes. Similarly, delayed treatment of repairable rotator cuff tears results in irreparable tears requiring more-complicated surgery and resulting in less-optimal outcomes. Delayed treatment of shoulder pathology is a problem. Solutions include education and research investigation.


MicroRNAs regulate and provide robustness to the myogenic transcriptional network.
The genetics of skeletal muscle lineage commitment are deceptively complicated. MyoD overexpression is sufficient to convert fibroblasts into skeletal muscle myotubes. In vivo, there are a number of different steps of differentiation that require a large network of transcription factors that control differentiation and homeostasis of skeletal muscle progenitors. Each transcription factor has been shown to have the ability to promote the next factor in the cascade, but the mechanisms regulating the transitions remain incomplete. Recently, microRNAs have been shown to be important for a large number of developmental and oncogenic processes. In this review, we will discuss recent advances in the understanding of how microRNA is critical for skeletal muscle development by interacting with protein-coding genes that had previously been shown to be important for myogenesis.


Cell biology and evolution: molecular modules link it all?
Classical studies comparing developing embryos have suggested the importance of modified cell biological processes in the evolution of new phenotypes. Here, I revisit this connection focusing on embryonic development, in particular nematode embryogenesis. I compare phenotypic differences in nematode embryogenesis in two basic cell biological processes, the cell cycle and the localization of the first division axis. The analysis of these and other processes shows that, at the cell biological level, exhaustive variation is found that does not necessarily translate into morphological differences. Modern molecular analyses have led to a view in which molecular complexes, made up of groups of proteins, or modules, that are working together, are responsible for the proper execution of cell biological programs. I discuss how this modular architecture could facilitate the phenotypic changes observed in cell biological processes. Ultimately, understanding the connection between cellular behavior and phenotypic outcome will further elucidate the mechanisms responsible for phenotypic evolution.


Basal body structure in Trichonympha.
Trichonympha is a symbiotic flagellate of many species of termites and of the wood-feeding cockroach. Remarkably, this unicellular organism harbors up to over ten thousand flagella on its surface, which serve to propel it through the viscous environment of the host hindgut. In the 1960s, analysis of resin-embedded Trichonympha samples by electron microscopy revealed that the basal bodies that give rise to these flagella are exceptionally long, with a proximal, cartwheel-bearing, region some 50 times longer than that of regular centrioles. In recent years, this salient feature has prompted the analysis of the 3D architecture of Trichonympha basal bodies in the native state using cryo-electron tomography. The resulting ~40 Å resolution map of the basal body proximal region revealed a number of novel features that may be conserved in centrioles of other systems. These include proximal-distal polarity of the pinhead structure that links the cartwheel to centriolar microtubules, as well as of the linker between the A and the C microtubules. Moreover, this work demonstrated that the cartwheel is made of stacked ring-like structures that likely each comprise 18 molecules of SAS-6 proteins.


The effect of grinding conditions on the toxicity of cobalt-chrome-molybdenum particles in vitro.
Powders of cobalt-chrome-molybdenum alloy were produced by grinding larger particles for 8 h in water, serum or joint fluid. They were administered, in low doses (0.05-0.5 mg/ml) for 1-6 d, to human dermal fibroblasts in vitro. Particles were ground in a biological fluid in order to simulate conditions in an artificial hip joint. Such particles adhered to, or were phagocytosed by, the cells far less than those ground in water. The toxicity of the alloy was linked with a failure of test cells to grow as quickly as the controls - particles ground in water were the most toxic.


Trajectories of college students' general self-efficacy, the related predictors, and depression: A piecewise growth mixture modeling approach.
General self-efficacy plays a critical role in the development of college students, and mastering the development of students' general self-efficacy is helpful to explain students' behavior and psychological performance. Based on the data from the same cohort of college students for four consecutive years, this study used the piecewise growth mixture model to identify the developmental trajectories of general self-efficacy, built a multinomial logistic regression model to analyze the related predictors on different trajectories, and further compared the differences in depression symptoms in general self-efficacy trajectories. Three trajectories of college students' general self-efficacy were identified: stable-rising (8.7%), stable-decreasing (2.4%), and moderate and stable (88.9%). With the moderate and stable class as the reference, gender and extraversion are the predictors of students in the stable-increasing class; gender, extraversion, mother's education level, and university tier significantly predict students who fall into the stable-decreasing class. With the stable-increasing class as the reference, gender also has a significant predictive effect on students who belong to the stable-decreasing class. However, age, ethnicity, siblings, hometown location, father's education level, BMI, sleep, and major were not related predictors. Furthermore, mean differences in depression between latent classes of general self-efficacy trajectories were significant, and the depression scores of the stable-decreasing class were beyond the normal range in the third and fourth years. To promote college students' mental health, we suggest that colleges provide more specific psychological interventions to students based on the classification.


Mapping of quantitative trait loci related to primary rice root growth as a response to inoculation with Azospirillum sp. strain B510.
Azospirillum sp. strain B510 has been known as the plant growth-promoting endophyte; however, the growth-promotion effect is dependent on the plant genotype. Here, we aimed to identify quantitative trait loci (QTL) related to primary root length in rice at the seedling stage as a response to inoculation with B510. The primary root length of "Nipponbare" was significantly reduced by inoculation with B510, whereas that of "Kasalath" was not affected. Thus, we examined 98 backcrossed inbred lines and four chromosome segment substitution lines (CSSL) derived from a cross between Nipponbare and Kasalath. The primary root length was measured as a response to inoculation with B510, and the relative root length (RRL) was calculated based on the response to non-inoculation. Three QTL alleles, qRLI-6 and qRLC-6 on Chromosome (Chr.) 6 and qRRL-7 on Chr. 7 derived from Kasalath increased primary root length with inoculation (RLI), without inoculation, (RLC) and RRL and explained 20.2%, 21.3%, and 11.9% of the phenotypic variation, respectively. CSSL33, in which substitution occurred in the vicinity region of qRRL-7, showed a completely different response to inoculation with B510 compared with Nipponbare. Therefore, we suggest that qRRL-7 might strongly control root growth in response to inoculation with Azospirillum sp. strain B510.


Disease Mechanisms of Multiple System Atrophy: What a Parallel Between the Form of Pasta and the Alpha-Synuclein Assemblies Involved in MSA and PD Tells Us.
Intracellular deposits rich in aggregated alpha-synuclein that appear within the central nervous system are intimately associated to Parkinson's disease and multiple system atrophy. While it is understandable that the aggregation of proteins, which share no primary structure identity, such as alpha-synuclein and tau protein, leads to different diseases, that of a given protein yielding distinct pathologies is counterintuitive. This short review relates molecular and mechanistic processes to the observed pathological diversity associated to alpha-synuclein aggregation.


Epidemiology of Hajj pilgrimage mortality: Analysis for potential intervention.
The Saudi Vision 2030 predicts the attendance of 30 million pilgrims each year by 2030. Cost-effective healthcare services during the Hajj are important to manage this increase in the number of pilgrims. Little is known about the impact of the existing chronic diseases on morbidity and mortality during the Hajj. Furthermore, the quality of services provided by Hajj hospitals warrants further study. This study aims to describe patterns of inpatient, all-cause mortality during the Hajj and the relationship between mortality and preexisting chronic diseases as well as the services provided in Hajj hospitals. The population included pilgrims who were admitted to Hajj hospitals in Makkah and sacred sites between 2012 and 2017, excluding 2015. A retrospective, matched, case-control study design was utilized. 2237 cases of mortality were matched to 4474 control cases based on age and gender. The data were extracted from hospital admissions offices and medical records. Hierarchical, logistic regression models were used to examine the medical services. The effect measure modification of the copresence of more than one chronic disease was also examined. The rate of inpatient all-cause mortality was higher in Makkah hospitals compared to sacred site hospitals. Inpatient, all-cause mortality was significantly associated with diabetes, hypertension, and cardiovascular diseases. Effect measure modification was present between diabetes and cardiovascular diseases, hypertension, and cardiovascular diseases, but not between diabetes and hypertension. Patients who received medical services were more likely to die during their hospital stay compared to patients not receiving services. The current focus on public health issues during the Hajj should be equally distributed between communicable and non-communicable diseases. Although advanced services are provided by Hajj hospitals, interventions to address the increased risks, including mortality, faced by pilgrims with preexisting, chronic diseases should be further investigated and considered.


Oral benzo[a]pyrene in Cyp1a1/1b1(-/-) double-knockout mice: Microarray analysis during squamous cell carcinoma formation in preputial gland duct.
Benzo[a]pyrene (BaP) is a prototypical polycyclic aromatic hydrocarbon (PAH) found in combustion processes. Cytochrome P450 1A1 and 1B1 enzymes (CYP1A1, CYP1B1) and other enzymes can activate PAHs to reactive oxygenated intermediates involved in mutagenesis and tumor initiation; also, CYP1 enzymes can detoxify PAHs. Cyp1(+/+) wild-type (WT) and Cyp1b1(-/-) knockout mice receiving oral BaP (12.5 mg/kg/day) remain healthy for >12 months. In contrast, we found that global knockout of the Cyp1a1 gene (1a1KO) results in proximal small intestine (PSI) adenocarcinoma within 8-12 weeks on this BaP regimen; striking compensatory increases in PSI CYP1B1 likely participate in initiation of adenocarcinoma in 1a1KO mice. Cyp1a1/1b1(-/-) double-knockout (DKO) mice on this BaP regimen show no PSI adenocarcinoma, but instead preputial gland duct (PGD) squamous cell carcinoma (SCC) occurs by 12 weeks. Herein, we compare microarray expression of PGD genes in WT, 1a1KO and DKO mice at 0, 4, 8, 12 and 16 weeks of oral BaP; about four dozen genes up- or down-regulated during most critical time-points were further verified by qRT-PCR. In DKO mice, CYP3A59 was unequivocally identified as the BaP-inducible and BaP-metabolizing best candidate responsible for initiation of BaP-induced SCC. Striking increases or decreases were found in 26 cancer-related genes plus eight Serpin genes in DKO, but not in 1a1KO or WT, mice on this BaP regimen; of the 26, 8 were RAS-related oncogenes. The mechanism by which cancer-related genes are responsible for SCC tumor progression in the PGD remains to be elucidated.


Comparison of response between food supplemented with powdered iron and iron in syrup form for iron deficiency anemia.
To evaluate and compare the response between food supplemented with iron in powdered and iron in syrup forms for the treatment of iron deficiency anemia in children aged 1-5 years. Quasi-experimental study. This study was conducted at Combined Military Hospital, Multan, from January 2000 to December 2000. Consecutive 200 cases of iron deficiency anemia, aged 1-5 years, were included in the study. Diagnosis was based on history, physical examination, complete blood counts (CBC) and serum ferritin levels. The patients were randomized to receive either iron in syrup form (Group A) or equivalent doses of iron powder sprinkled over food (Group B). The patients were followed up with hemoglobin estimation (Hb) and reticulocyte response at 2 weeks, 4 weeks and 6 weeks. CBC and serum ferritin were repeated at 6 weeks. Over half (51%) of the patients were between 1-2 years of age. One hundred thirty-two were males and 68 females. Most of the patients belonged to poor socioeconomic class. The iron in powder form was better tolerated than iron syrup as this group witnessed fewer episodes of gastrointestinal disturbances. The rise in mean Hb level after 6 weeks of treatment in group A and B was 1.6 g/dl and 1.9 g/dl respectively. Hemoglobin rise in group B was more than group A but this was statistically non-significant (p > 0.05). There was small but significant (p < 0.05) rise in serum ferritin in both the groups. There was no significant difference between the two groups for response to the two forms of iron administration. The powdered form of iron is a cost-effective and better tolerated method of iron administration in children and can be considered as an alternate option for the treatment of iron deficiency anemia in children.


Spatial attention-based residual network for human burn identification and classification.
Diagnosing burns in humans has become critical, as early identification can save lives. The manual process of burn diagnosis is time-consuming and complex, even for experienced doctors. Machine learning (ML) and deep convolutional neural network (CNN) models have emerged as the standard for medical image diagnosis. The ML-based approach typically requires handcrafted features for training, which may result in suboptimal performance. Conversely, DL-based methods automatically extract features, but designing a robust model is challenging. Additionally, shallow DL methods lack long-range feature dependency, decreasing efficiency in various applications. We implemented several deep CNN models, ResNeXt, VGG16, and AlexNet, for human burn diagnosis. The results obtained from these models were found to be less reliable since shallow deep CNN models need improved attention modules to preserve the feature dependencies. Therefore, in the proposed study, the feature map is divided into several categories, and the channel dependencies between any two channel mappings within a given class are highlighted. A spatial attention map is built by considering the links between features and their locations. Our attention-based model BuRnGANeXt50 kernel and convolutional layers are also optimized for human burn diagnosis. The earlier study classified the burn based on depth of graft and non-graft. We first classified the burn based on the degree. Subsequently, it is classified into graft and non-graft. Furthermore, the proposed model performance is evaluated on Burns_BIP_US_database. The sensitivity of the BuRnGANeXt50 is 97.22% and 99.14%, respectively, for classifying burns based on degree and depth. This model may be used for quick screening of burn patients and can be executed in the cloud or on a local machine. The code of the proposed method can be accessed at https://github.com/dhirujis02/Journal.git for the sake of reproducibility.


Experience and expectations of patients on weight loss: The Learning Health System Network Experience.
Weight perception and degree of confidence in achieving healthy lifestyle can be determinants of engagement in obesity interventions. This study explored patients' perceived need for weight loss and the degree of self-confidence in ability to lose weight and sought to identify factors associated with patients' self-confidence in ability to lose weight. The authors analysed data from a survey mailed to primary care patients within five sites of the Learning Health Systems Network that explored participants' prior experience with weight management. Among the 2,263 participants who completed the survey section on 'Patients' Experience with Weight Management', perceived need to lose 51 lb or more was statistically significant among those with class III obesity compared with other body mass index (BMI) groups (p value < 0.001). Reported desire to lose weight was also significantly higher among those with the highest BMI than those who were overweight (p value < 0.001). However, this same group had the lowest belief in ability to lose weight (p value < 0.001). In a multiple regression analysis, female gender, higher BMI and need to lose >10 lb were each independently associated with less belief in being able to lose weight. Patients had varying perceptions on weight loss; those with category III obesity had the highest desire to lose weight but had the least confidence in ability to lose weight. Higher BMI, female gender and need to lose >10 lb were associated with decreased self-confidence in ability to lose weight.


Carrier mediated action of platinum complexes on estrogen receptor positive tumors.
Three 1,2-diaminoethane-dichloro-platinum(II) complexes linked to 5-hydroxy-2-(4-hydroxyphenyl)-3-methylindole by spacer groups of varying length were evaluated for cytostatic activity in estrogen receptor (ER) positive and negative tumor cells. In vitro, only the growth of ER positive MCF-7 mammary tumor cells was inhibited whereas hormone independent MDA-MB 231 cells did not respond. In vivo, a strong inhibitory effect was only observed in ER positive MXT mammary tumors of the mouse. The complex with a hexyl group as spacer reduced the tumor weight by 89% after 6 weeks of treatment. The R 3327 Dunning prostatic tumor of the rat, which also contains ER was inhibited, too. Generally, the effect in ER negative tumors was weak. These findings can be rationalized by the high binding affinities of the complexes for ER. By the mouse uterine weight test it was shown that the endocrine activity of the complexes is very low. Therefore, a mode of action different from that exerted by estrogens or antiestrogens has to be assumed.


Sequential expression of mRNA-encoded keratin sets in neonatal mouse epidermis: basal cells with properties of terminally differentiating cells.
The keratin pattern of newborn mouse epidermis was investigated during terminal differentiation. In highly pure fractions of basal and suprabasal cells, obtained by Percoll density gradient centrifugation, we identified two sets of mRNA-encoded proteins: a basal set of 58.5, 52, and 47 kd subunits and a suprabasal set of 67 and 60 kd subunits. The large subunits of each set were alkaline to neutral, while the small subunits were acidic. Polyclonal antibodies against the suprabasal, acidic 60 kd protein and the basal, alkaline 58.5 kd protein selectively recognized their antigens in immunoblots of NEPHGE -resolved keratins and decorated the corresponding epidermal compartments in frozen sections. The antibody to the suprabasal 60 kd protein also recognized distinct cells in the basal cell layer. Quantification of this cell population revealed a 10% cell fraction, morphologically indistinguishable from the total cell population, that, in addition to expressing basal keratin proteins, was already synthesizing suprabasal keratin subunits.


The use of UV/H2O2 to facilitate removal of emerging contaminants in anaerobic membrane bioreactor effluents.
Effluent from anaerobic membrane bioreactor (AnMBR) contains ammonia and would require post-polishing treatment before it can be disinfected by chlorine. However, additional post-treatment steps to remove nutrients offset the energetic benefits derived from anaerobic fermentation. The use of chlorine or ozone also promotes concerns associated with disinfection byproducts. This study evaluates UV/H2O2 as a potential strategy suited for the removal of pharmaceutical compounds as well as antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs) from AnMBR effluent. Our findings indicate that 10 mg/L H2O2 and 61.5 mJ/cm2 of UV fluence are able to achieve a 4-log removal of both Escherichia coli PI7 and Klebsiella pneumoniae L7. However, a higher fluence of 311 mJ/cm2 with the same amount of H2O2 would be required to achieve >90% removal of atenolol, carbamazepine and estrone. The removal of the pharmaceutical compounds was driven by the hydroxyl radicals generated from H2O2, while UV exposure governed the inactivation of ARB and ARGs. UV/H2O2 increased overall mutagenicity of the treated wastewater matrix but did not result in any changes to the natural transformation rates. Instead, UV significantly reduced natural transformation rates by means of DNA damage. Overall, UV/H2O2 could be the ideal final disinfection strategy for AnMBR effluent without requiring additional post-treatment prior disinfection.


Optimisation of the foot-and-mouth disease virus 2A co-expression system for biomedical applications.
Many biomedical applications require the expression or production of therapeutic hetero-multimeric proteins/protein complexes: in most cases only accomplished by co-ordinated co-expression within the same cell. Foot-and-mouth disease virus 2A (F2A) and '2A-like' sequences are now widely used for this purpose. Since 2A mediates a co-translational 'cleavage' at its own C-terminus, sequences encoding multiple proteins (linked via 2As) can be concatenated into a single ORF: a single transgene. It has been shown that in some cases, however, the cleavage efficiency of shorter versions of F2A may be inhibited by the C-terminus of certain gene sequences immediately upstream of F2A. This paper describes further work to optimise F2A for co-expression strategies. We have inserted F2A of various lengths in between GFP and CherryFP 'reporter' proteins (in reciprocal or tandem arrangements). The co-expression of these proteins and cleavage efficiencies of F2As of various lengths were studied by in vitro coupled transcription and translation in rabbit reticulocyte lysates, western blotting of HeLa cell lysates and fluorescence microscopy. Optimal and suboptimal lengths of F2A sequences were identified as a result of detailed 'fine-tuning' of the F2A sequence. Based on our data and the model according to which 2A activity is a product of its interaction with the exit tunnel of the ribosome, we suggest the length of the F2A sequence which is not 'sensitive' to the C-terminus of the upstream protein that can be successfully used for co-expression of two proteins for biomedical applications.


Immediate facial reanimation in oncological parotid surgery with neurorrhaphy of the masseteric-thoracodorsal-facial nerve branch.
The extracranial facial nerve may be sacrificed together with the parotid gland during a radical parotidectomy, and immediate reconstruction of the facial nerve is essential to maintain at least part of its function. We report five patients who had had radical parotidectomy (two with postoperative radiotherapy) and immediate (n=3) or recent (n=2) reconstructions of the masseteric-thoracodorsal-facial nerve branch. The first mimetic musculature movements started 6.2 (range 4-8.5) months postoperatively. At 24 months postoperatively clinical evaluation (modified House-Brackmann classification) showed grade V (n=3), grade IV (n=1), and grade III (n=1) repairs. This first clinical series of masseteric-thoracodorsal-facial nerve neurorrhaphies has given encouraging results, and the technique should be considered as an option for immediate or recent reconstruction of branches of the facial nerve, particularly when its trunk is not available for proximal neurorrhaphy.


Effects of corn supplementation on serum and muscle microRNA profiles in horses.
Laminitis associated with equine metabolic syndrome causes significant economic losses in the equine industry. Diets high in non-structural carbohydrates (NSC) have been linked to insulin resistance and laminitis in horses. Nutrigenomic studies analyzing the interaction of diets high in NSCs and gene expression regulating endogenous microRNAs (miRNA) are rare. This study's objectives were to determine whether miRNAs from dietary corn can be detected in equine serum and muscle and its impacts on endogenous miRNA. Twelve mares were blocked by age, body condition score, and weight and assigned to a control (mixed legume grass hay diet) and a mixed legume hay diet supplemented with corn. Muscle biopsies and serum were collected on Days 0 and 28. Transcript abundances were analyzed using qRT-PCR for three plant-specific and 277 endogenous equine miRNAs. Plant miRNAs were found in serum and skeletal muscle samples with a treatment effect (p < .05) with corn-specific miRNA being higher than control in serum after feeding. Endogenous miRNAs showed 12 different (p < .05) miRNAs in equine serum after corn supplementation, six (eca-mir16, -4863p, -4865p, -126-3p, -296, and -192) previously linked to obesity or metabolic disease. The results of our study indicate that dietary plant miRNAs can appear in circulation and tissues and may regulate endogenous genes.


Early Enteral Nutrition Reduces Mortality and Improves Other Key Outcomes in Patients With Major Burn Injury: A Meta-Analysis of Randomized Controlled Trials.
To identify, appraise, and synthesize current evidence to determine whether early enteral nutrition alters patient outcomes from major burn injury. Medline, Embase, and the China National Knowledge Infrastructure were searched. The close out date was May 1, 2018. Early enteral nutrition was defined as a standard formula commenced within 24 hours of injury or admission to ICU or burn unit. Comparators included any form of nutrition support "except" early enteral nutrition. Only randomized controlled trials reporting patient-centered outcomes were eligible for inclusion. The primary outcome was mortality. Gastrointestinal hemorrhage, sepsis, pneumonia, renal failure, and hospital stay were evaluated as secondary outcomes. Nine-hundred fifty-eight full-text articles were retrieved and screened. Seven randomized controlled trials enrolling 527 participants with major burn injury were included. Compared with all other types of nutrition support, early enteral nutrition significantly reduced mortality (odds ratio, 0.36; 95% CI, 0.18-0.72; p = 0.003; I = 0%). Early enteral nutrition also significantly reduced gastrointestinal hemorrhage (odds ratio, 0.21; 95% CI, 0.09-0.51; p = 0.0005; I = 0%), sepsis (odds ratio, 0.23; 95% CI, 0.11-0.48; p < 0.0001; I = 0%), pneumonia (odds ratio, 0.41; 95% CI, 0.21-0.81; p = 0.01; I = 63%), renal failure (odds ratio, 0.27; 95% CI, 0.09-0.82; p = 0.02; I = 32%), and duration of hospital stay (-15.31 d; 95% CI, -20.43 to -10.20; p < 0.00001; I = 0%). The improvements in clinical outcomes demonstrated in this meta-analysis are consistent with the physiologic rationale cited to support clinical recommendations for early enteral nutrition made by major clinical practice guidelines: gut integrity is preserved leading to fewer gastrointestinal hemorrhages, less infectious complications, a reduction in consequent organ failures, and a reduction in the onset of sepsis. The cumulative benefit of these effects improves patient survival and reduces hospital length of stay.


Orexin-corticotropin-releasing factor receptor heteromers in the ventral tegmental area as targets for cocaine.
Release of the neuropeptides corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced cocaine-seeking behavior. We provide evidence for pharmacologically significant interactions between CRF and orexin-A that depend on oligomerization of CRF1 receptor (CRF1R) and orexin OX1 receptors (OX1R). CRF1R-OX1R heteromers are the conduits of a negative crosstalk between orexin-A and CRF as demonstrated in transfected cells and rat VTA, in which they significantly modulate dendritic dopamine release. The cocaine target σ1 receptor (σ1R) also associates with the CRF1R-OX1R heteromer. Cocaine binding to the σ1R-CRF1R-OX1R complex promotes a long-term disruption of the orexin-A-CRF negative crosstalk. Through this mechanism, cocaine sensitizes VTA cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces cocaine seeking.


Cyclic nucleotide concentrations in 1,2-dimethylhydrazine and x-ray induced rat small intestinal cancer.
The intracellular concentrations of adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) were determined in adult male Holtzman rat small intestinal tumors induced by subcutaneous administration of 1,2-dimethylhydrazine (DMH) or X-irradiation of only the hypoxic ileum and jejunum. The levels of cAMP and cGMP in the cancer cells from DMH-treated animals were 50% and 200%, respectively, of the values measured for intestinal tissue. The amounts of cGMP in the lesion of the X-irradiation induced rat small bowel adenocarcinoma determined in the present investigation and of cAMP measured previously were observed to be only 50% of the value for unirradiated intestine. It has thus been shown that in the DMH-induced colon and small intestinal tumors, the X-irradiation induced rat small bowel adenocarcinoma and the human colon adenocarcinoma, the cAMP concentrations are consistently about 50% of the levels measured in comparable normal tissues. These findings of diminished intracellular cAMP concentrations imply a serious cellular defect mechanism occurring in intestinal cancer. However, there appears to be no similar pattern of change for the intracellular concentrations of cGMP, which suggests that different biochemical pathways exist in these malignancies.


Morphometry of mitochondria in ovine forestomach epithelia: high densities of mitochondria correlate with specialised metabolic activity.
The volume density of mitochondria and the surface density of mitochondrial inner membranes were investigated in the stratified squamous epithelia of the oesophagus and forestomachs of sheep, and in the oesophagus and nonglandular part of the ventricle of rats. The higher values found for both parameters in all forestomach regions are thought to be correlated with the special metabolic activity known to take place in these epithelia.


Dental caries experience in primary school-age children following "Students' Oral Health Promotion Program," Iran.
This study aimed at determining the changes in dental caries experience in elementary school-age children following 5 years of the Students' Oral Health Promotion Program implementation. In the present study, totally 2920 elementary school students participated and were selected by multistage cluster sampling. Based on the WHO Oral Health Survey Methods manual (4th edition), dental caries indices in primary and permanent teeth were assessed by clinical examination in schools. Data on socio-demographic characteristics and dental factors were collected through interviews based on questionnaire. The logistic and linear regression was used for data analysis. The mean (SD) age of the elementary school children was 9.45 (1.71) years, and 1481 (50.7%) were boys. There was a significant difference between genders, age, dental pain experience and student's parent supervision with dmft, DMFT and their caries status. For 1-year increase in age, 1.67 times increase in DMFT and 0.33 decrease in dmft were predicted. Girls had higher odds of DMFT. In contrast, the odds of dmft for girls were significantly lower compared with boys. Students with dental pain experience had significantly higher odds of DMFT and dmft. The Significant Caries Index (SiC) score for permanent dentition in 12-year-old children was 5.47. Sex was significantly correlated with SiC index. The odds of developing Sic was 0.98 times lower in girls than in boys. Dental caries was identified as a major public health problem among the elementary school students despite the implementation of the national project for oral health promotion.


Development of an indoor air purification system to improve ventilation and air quality.
Novel types of an air purification system for improving indoor air quality (IAQ) and ventilation by reducing carbon dioxide (CO2) concentration were assessed in office buildings in India. This study provides an evaluation of a control system that reduces toxic gases in indoor spaces using the synthesized filter media. The reduction potential of CO2 levels of the control system, for different air handling unit (AHU) capacities, were compared. Experimental studies and in-situ evaluation has been done using the air purification system. Ventilation rates and CO2 concentration are monitored before and after the installation of the purification system. The results of the investigation indicated CO2 concentrations were reduced by more than 40% with the purification system. Fresh air intake to maintain the desired ventilation rates has been reduced to more than 50%, further reduce heat load. Ventilation flow rates were achieved with this air purification system. This system has the potential aspiration in controlling the CO2 levels in mechanically ventilated buildings. CO2 concentrations were brought down to permissible limits and maintained further without introducing fresh air into the system. Based on the results, assessment of the air purification system is a crucial and wide range of applicability in indoor environments to reduce cooling costs.


VY bipedicle flap for resurfacing the nasal supratip region.
A procedure for the coverage of surgically created supratip defects up to 1.5 cm in diameter is described utilizing a VY bipedicle flap of nasal skin.


Investigation of MTHFR C677T gene polymorphism, biochemical and clinical parameters in Turkish migraine patients: association with allodynia and fatigue.
We investigated whether there is any relationship between biochemical and clinical parameters of migraine and methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism, associated with the migraine subtypes, symptoms, and gender. A total of 150 migraine patients with and without aura (MA and MO) and 107 non-sufferers were included in the study. Biochemical and clinical parameters were measured and genetic analysis was performed. The MTFHR C677T genotype was significantly higher in the migraine group (p = 0.000). The CT genotype frequency of individuals with a family history of migraine was significantly higher (p = 0.025). This genotype frequency was higher in patients who suffer from compression, allodynia, fatigue, and sleeplessness (p = 0.027, 0.023, 0.006, and 0.05, respectively). Homocysteine and total cholesterol levels were significantly higher in the migraine group than the control group (p = 0.007 and 0.010, respectively). However, the other biochemical and clinical parameters did not differ from each other (p > 0.05), with only attack frequency being significantly higher in the MO group (p = 0.005). While the folate and HDL levels were significantly higher in females (p = 0.001 and 0.000, respectively), the homocysteine and triglyceride levels were significantly higher in males (p = 0.000 for each one). BMIs were significantly lower in the control than the migraine group (p = 0.021); however, an association between the C677T variant and BMI was not found (p = 0.787) in the migraine group. An association between the MTHFR C667T polymorphism and migraine susceptibility was found. Additional studies including genetic, clinic, and biochemical parameters should be conducted to better understand the disease.


The new pharmaceutical regulatory procedures for Europe.
Since the late 1980s there has been considerable debate and discussion over the so called 'future system proposals' for the regulation of additional products throughout the European Union. On 1 January 1995 the future system became the new system with the coming into force of the Council and the associated Commission directives. These proposals are complex and have evolved from the present procedures that originated in 1965. David Jefferys gives an overview of the new procedures and considers how they will affect both the regulation of medicines and the development of new products over the rest of this decade.


Cation channels, cell volume and the death of an erythrocyte.
Similar to a variety of nucleated cells, human erythrocytes activate a non-selective cation channel upon osmotic cell shrinkage. Further stimuli of channel activation include oxidative stress, energy depletion and extracellular removal of Cl-. The channel is permeable to Ca2+ and opening of the channel increases cytosolic [Ca2+]. Intriguing evidence points to a role of this channel in the elimination of erythrocytes by apoptosis. Ca2+ entering through the cation channel stimulates a scramblase, leading to breakdown of cell membrane phosphatidylserine asymmetry, and stimulates Ca(2+)-sensitive K+ channels, thus leading to KCl loss and (further) cell shrinkage. The breakdown of phosphatidylserine asymmetry is evidenced by annexin binding, a typical feature of apoptotic cells. The effects of osmotic shock, oxidative stress and energy depletion on annexin binding are mimicked by the Ca2+ ionophore ionomycin (1 microM) and blunted in the nominal absence of extracellular Ca2+. Nevertheless, the residual annexin binding points to additional mechanisms involved in the triggering of the scramblase. The exposure of phosphatidylserine at the extracellular face of the cell membrane stimulates phagocytes to engulf the apoptotic erythrocytes. Thus, sustained activation of the cation channels eventually leads to clearance of affected erythrocytes from peripheral blood. Susceptibility to annexin binding is enhanced in several genetic disorders affecting erythrocyte function, such as thalassaemia, sickle-cell disease and glucose-6-phosphate dehydrogenase deficiency. The enhanced vulnerability presumably contributes to the shortened life span of the affected erythrocytes. Beyond their role in the limitation of erythrocyte survival, cation channels may contribute to the triggering of apoptosis in nucleated cells exposed to osmotic shock and/or oxidative stress.


Critical roles of protein disulfide isomerases in balancing proteostasis in the nervous system.
Protein disulfide isomerases (PDIs) constitute a family of oxidoreductases promoting redox protein folding and quality control in the endoplasmic reticulum. PDIs catalyze disulfide bond formation, isomerization, and reduction, operating in concert with molecular chaperones to fold secretory cargoes in addition to directing misfolded proteins to be refolded or degraded. Importantly, PDIs are emerging as key components of the proteostasis network, integrating protein folding status with central surveillance mechanisms to balance proteome stability according to cellular needs. Recent advances in the field driven by the generation of new mouse models, human genetic studies, and omics methodologies, in addition to interventions using small molecules and gene therapy, have revealed the significance of PDIs to the physiology of the nervous system. PDIs are also implicated in diverse pathologies, ranging from neurodevelopmental conditions to neurodegenerative diseases and traumatic injuries. Here, we review the principles of redox protein folding in the ER with a focus on current evidence linking genetic mutations and biochemical alterations to PDIs in the etiology of neurological conditions.


Long Covid as an Indication for Heart Transplantation and Its Characteristics.
The post-acute cardiovascular manifestations of COVID-19, known as long COVID, have yet to be comprehensively characterized. There is also an increased risk of heart failure in individuals without cardiovascular disease before SARS-CoV-2 infection. The literature lacks information regarding the characteristics of patients with long COVID who developed advanced heart failure refractory to guideline-directed medical therapy. We describe the characteristics of patients with long COVID (LC) who were listed for heart transplantation. The study population comprised 45 patients listed for heart transplantation, divided into 2 groups: patients with etiologies other than LC (n = 41) and patients with LC (n = 4) between January 2020 and March 2022. The endpoint of this study was the description of the characteristics of each group. The average duration of hospitalization after the acute infectious episode with SARS-CoV-2 was 150 ± 113 days, and all patients were hospitalized in New York Heart Association class IV. All LC patients were oligosymptomatic in the initial infection, did not require hospitalization in the acute phase, had a lower ejection fraction, used more intra-aortic balloon pumps, had lower pulmonary vascular resistance, and fewer comorbidities compared with other etiologies, suggesting a clinical feature compatible with low cardiac output rather than congestion. This study is an early investigation of patients listed for heart transplantation due to a complex syndrome of COVID-19. These preliminary findings warrant further large-scale investigation.


Tissue plasminogen activator mediated blood-brain barrier damage in transient focal cerebral ischemia in rats: relevance of interactions between thrombotic material and thrombolytic agent.
Thrombolysis with tPA for acute ischemic stroke is associated with an increased risk of intracerebral hemorrhage. We investigated the impact of thrombolysis with tPA on the blood-brain barrier in a suture occlusion model in rats. Cerebral ischemia was performed for 2 h followed by 22 h of reperfusion. Treatment groups received either saline (A), 10 mg/kg bw rtPA (B) or "activated" rtPA (ArtPA, C, rtPA with in vitro clot contact). Blood-brain-barrier damage assessed by Evans blue extravasation as a permeability marker was significantly enhanced in basal ganglia of group C compared to groups A or B. Likewise was the upregulation of MMP-9. Interestingly, results of the rtPA and saline group showed only minor and not statistically significant differences. The results of the present study indicate a major role for thrombus-thrombolytic interaction in focal cerebral ischemia with subsequent increased BBB permeability.


Foot loading patterns can be changed by deliberately walking with in-toeing or out-toeing gait modifications.
The present study shows how foot loading patterns may be deliberately altered by either in-toeing or out-toeing gait during barefoot walking. The results indicate that in-toeing increasingly loads the lateral aspects of the midfoot and forefoot by as much as 61% and 49%, respectively, whereas out-toeing intensifies the load on the medial aspect, i.e. predominantly the medial midfoot and medial forefoot by as much as 72% and 52%. These findings are being discussed with respect to the potential benefits of consciously altering the gait pattern in order to off-load certain plantar regions.


Breakthrough venous thromboembolic events in five patients with COVID-19 on direct oral anticoagulants.
Coronavirus disease 2019 (COVID-19) is associated with increased risk of venous thromboembolism (VTE). Guidance for VTE prophylaxis continues to evolve, including addressing direct oral anticoagulants (DOACs) continued upon hospitalization. We present 5 patients hospitalized for COVID-19 while on DOACs. Four patients had atrial fibrillation and had a previous VTE. Four patients developed acute VTE and one developed stroke-like symptoms. Monitoring D-dimer assisted with the detection of VTE. Three patients died, and two were discharged alive. Therapeutic failure with DOACs appears to be commonplace in COVID-19. Further research is needed to determine whether there is an underlying cause to this association.


High levels of transcription factor RpoS (sigma S) in mviA mutants negatively affect 1,2-propanediol-dependent transcription of the cob/pdu regulon of Salmonella typhimurium LT2.
Expression of the cobalamin biosynthetic (cob) and 1,2-propanediol utilization (cob/pdu) regulon of Salmonella typhimurium LT2 is controlled at the transcriptional level by global and specific regulatory proteins. In this paper we show that mutations in the mviA gene negatively affect cob/pdu transcription in response to 1,2-propanediol in the environment. The effects of mviA mutations were consistent with its role in the regulation of RpoS levels in the cell. Null mutations in rpoS eliminated the negative effect of mviA mutations on cob/pdu transcription, and restored growth on succinate, propionate and 1,2-propanediol. In addition, mviA mutants were deficient in the utilization of succinate, propionate and 1,2-propanediol as carbon and energy sources.


Metabolic characteristics of bacterial cells entrapped in beaded calcium alginate and/or pectate gels.
A mixture of heterotrophic bacteria and collection strains of Escherichia coli and Pseudomonas fluorescens were immobilized in calcium alginate or pectate gels. Comparison of respiratory activity, substrate uptake and biosynthetic capacity of immobilized cells showed that both types of carriers permit a prolonged preservation of metabolic activity but the transfer of substances through the gel is faster in the pectate. Morphological changes include some intracellular structures, partial shrinkage of the plasma membrane of immobilized cells, and transformation of a rod-like cell shape to an oval one.


Parathyroid hormone intermittent administration promotes delay on rat incisor eruption.
This study evaluated the influence of parathyroid hormone (PTH) (1-34) intermittent administration on rat eruption rates of lower incisors under normo, hyper and hypofunctional conditions, Sharpey fibers insertion, and alveolar bone formation. Wistar male rats received PTH (1-34) three times a week during the entire experimental period, 31days. Control animals received the same concentration of the vehicle solution during the same period. Three injections of alizarin were also performed. The experiment evaluated the eruptive rate, the alveolar bone formation and also the morphology, and the area density of Sharpey fibers. After the sacrifice, the mandibles were dissected and samples were prepared for fluorescence and scanning electron microscopy observations. PTH-treated animals showed significantly reduced eruption rates in all different functional conditions. Analysis evidenced that PTH-treated rats present an increase in bone formation and area density of the Sharpey fibers. We concluded that the PTH (1-34) intermittent administration reduced the eruptive process rates, through bone formation enhancement and increase in the area density of Sharpey fibers.


GPR43 regulates sodium butyrate-induced angiogenesis and matrix remodeling.
Butyrate is a short-chain fatty acid (SCFA) derived from microbiota and is involved in a range of cell processes in a concentration-dependent manner. Low concentrations of sodium butyrate (NaBu) were shown to be proangiogenic. However, the mechanisms associated with these effects are not yet fully known. Here, we investigated the contribution of the SCFA receptor GPR43 in the proangiogenic effects of local treatment with NaBu and its effects on matrix remodeling using the sponge-induced fibrovascular tissue model in mice lacking the Gpr43 gene (Gpr43-KO) and the wild-type (WT) mice. We demonstrated that NaBu (0.2 mM intraimplant) treatment enhanced the neovascularization process, blood flow, and VEGF levels in a GPR43-dependent manner in the implants. Moreover, NaBu was able to modulate matrix remodeling aspects of the granulation tissue such as proteoglycan production, collagen deposition, and α-smooth muscle actin (α-SMA) expression in vivo, besides increasing transforming growth factor (TGF)-β1 levels in the fibrovascular tissue, in a GPR43-dependent manner. Interestingly, NaBu directly stimulated L929 murine fibroblast migration and TGF-β1 and collagen production in vitro. GPR43 was found to be expressed in human dermal fibroblasts, myofibroblasts, and endothelial cells. Overall, our findings evidence that the metabolite-sensing receptor GPR43 contributes to the effects of low dose of NaBu in inducing angiogenesis and matrix remodeling during granulation tissue formation. These data provide important insights for the proposition of new therapeutic approaches based on NaBu, beyond the highly explored intestinal, anti-inflammatory, and anticancer purposes, as a local treatment to improve tissue repair, particularly, by modulating granulation tissue components.NEW & NOTEWORTHY Our data show the contribution of the metabolite-sensing receptor GPR43 in the effects of low dose of sodium butyrate (NaBu) on stimulating angiogenesis and extracellular matrix remodeling in a model of granulation tissue formation in mice. We also show that human dermal fibroblasts, myofibroblasts, and endothelial cells express the receptor GPR43. These data provide important insights for the use of NaBu in local therapeutic approaches applicable to tissue repair in sites other than the intestine.


Variability in protein quality used for embryo culture: embryotoxicity of the stabilizer octanoic acid.
To screen human serum albumin (HSA) preparations for toxicity and investigate causes of variation. Experimental laboratory study. University-based laboratory. FVB and CF1 mice crossed to create embryos used in experiments. Mouse embryo assay performed with 5% or 15% HSA (100 mg/mL albumin) from three samples from three separate manufacturers (A, B, C). Blastocyst rates calculated at 96 hours of culture (experiments repeated in triplicate). The HSA preparations were desalted to remove stabilizers added during HSA processing, then mass spectrometry was used to determine the relative variation in stabilizer concentrations; the effect of the stabilizer octanoic acid on embryo development was tested. At 5% HSA, all samples had blastocyst rates ≥ 70%; at 15% HSA, the blastocyst rates for samples B and C were <50%. Desalting did not affect sample B but did improve the blastocyst rates of sample C. Mass spectrometry revealed high levels of octanoic acid in sample C compared with sample A. The addition of octanoic acid to sample A produced toxicity similar to sample C. The stabilizer octanoic acid varies by lot and inhibits embryo development. Because octanoic acid is known to cause disruptions in mitochondrial bioenergetics, reduce intracellular pH, and induce oxidative damage in peripheral tissues, its use in embryo culture should be monitored and limited.


Transiliac Endoscopic-Assisted L5S1 Intraforaminal Lumbar Interbody Fusion: Technical Considerations and Potential Complications.
We sought to determine the clinical outcomes, complications, and fusion rates in transiliac endoscopic-assisted L5S1 intraforaminal lumbar interbody fusion (iLIF). Between September 2020 and September 2021, patients with L5S1 degenerative disk disease were enrolled in a prospective study on transiliac L5S1 iLIF and followed for a minimum of 12 months. Conflict of the preoperative planned approach with the ilium was mandatory. The primary outcome measures were the Oswestry Disability Index, the visual analog scale (VAS) score for low back pain (VAS back) and leg pain (VAS leg), and the modified MacNab criteria. The secondary outcomes were complications and fusion rates. Five consecutive patients were enrolled: 2 males and 3 females with a mean age of 50 ± 12.9. All had 12 months' follow-up. The mean improvement in the Oswestry Disability Index, VAS back, and VAS leg (44 ± 11.75, 6.6 ± 1.7, and 4.7 ± 4.2, respectively) was more than 3 times the minimum clinically important difference. The modified MacNab criteria were good or excellent in 80% of cases at all endpoints. Three patients had ipsilateral lower limb dysesthesia. One patient had revision surgery for foraminal bone fragment removal. All patients achieved fusion. The transiliac iLIF is a feasible but demanding surgical technique that allows overcoming cases in which the ilium prevents endoscopic transforaminal access to L5S1. Our preliminary results had good clinical outcomes and high fusion rates. The main complication was late-onset dysesthesia of the ipsilateral lower limb, 10 to 14 days after surgery. Special care must be taken to prevent L5 dorsal root ganglion injury.


Explaining racial differences in prostate cancer mortality.
In the United States, black males have an annual death rate from prostate cancer that is 2.4 times that of white males. The reasons for this are poorly understood. Using the Surveillance, Epidemiology, and End Results-Medicare database, 77,038 black and white males aged >65 years were identified with a first primary diagnosis of prostate cancer between 1995 and 2005, as well as 49,769 controls. The racial gap in mortality was decomposed to differential incidence and stage-specific prostate cancer mortality. The importance of various clinical and socioeconomic factors to each of these components was then examined. The estimated mortality gap for prostate cancer-specific mortality was 1320 more cases per 100,000 males among black than white men. This gap was due to higher prostate cancer incidence among black males (76%) and higher stage-specific mortality once diagnosed (24%). Differences in prostate-specific antigen testing, comorbidities, and income explained 29% of the difference in metastatic cancer incidence but none of the racial gap for local/regional incidence. Conditional on diagnosis, tumor characteristics explained 50% of the racial gap, comorbidities an additional 4%, choice of treatment and physician 17%, and socioeconomic factors 15%. Overall, approximately 25% of the racial gap in mortality and 86% of the gap in mortality conditional on diagnosis could be explained. More frequent prostate-specific antigen testing for black and low-income males could potentially reduce the prostate cancer mortality gap through earlier diagnosis of tumors that otherwise may become metastatic. More aggressive treatment of prostate cancer, especially in poor communities, might also reduce the gap.


TNFAIP8 protein functions as a tumor suppressor in inflammation-associated colorectal tumorigenesis.
Tumor necrosis factor-α-induced protein 8 (TNFAIP8 or TIPE) is a member of the TNFAIP8 family. While TIPE was broadly considered to be pro-cancerous, its precise roles in carcinogenesis especially those of the intestinal tract are not clear. Here, we show that genetic deletion of TIPE in mice exacerbated chemical-induced colitis and colitis-associated colon cancer. Loss of TIPE exacerbated inflammatory responses and inflammation-associated dysbiosis, leading to the activation of NF-κB and STAT3, and it also accelerated dysplasia, DNA damage and proliferation of intestinal epithelial cells. We further show that colon microbiota were essential for increased tumor growth and progression in Tipe-/- mice. The tumor suppressive function of TIPE originated primarily from the non-hematopoietic compartment. Importantly, TIPE was downregulated in human colorectal cancers, and patients with low levels of Tipe mRNA were associated with reduced survival. These results indicate that TIPE serves as an important modulator of colitis and colitis-associated colon cancer.


Effectiveness of a self-management program for joint protection and physical activity in patients with rheumatoid arthritis: A randomized controlled trial.
Rheumatoid arthritis is a chronic, systemic disease, which results in progressive destruction of the joints and a reduction in quality of life. Joint protection can minimize injuries that worsen arthritis and pain and certain activities can help patients control or reduce the symptoms of this chronic disease. To determine the effectiveness of a self-management program for joint protection and physical activity for patients with rheumatoid arthritis based on self-efficacy theory. A two-arm (experimental vs control) randomized trial. Adult patients with rheumatoid arthritis were recruited from rheumatology departments of a medical center in Northern Taiwan. A total of 224 patients met the inclusion criteria and agreed to participate in the study. Eligible participants with rheumatoid arthritis were randomly assigned to either an 8-week program in self-management of joint protection and physical activity with nursing support (intervention group, n = 112) or standard care for rheumatology (control group, n = 112). Outcome variables were assessed at baseline and 2-, 3-, and 6-months after commencement of the intervention, which included measures of disease activity, and self-assessments for self-efficacy, quality of life, and self-management behaviors. Differences in outcome variables over time between the groups were analyzed with generalized estimating equations; the level of significance was set at p < 05. The mean age of participants was 58.8 years, duration of the rheumatoid arthritis was 10 years, and most participants (86%) were female. Characteristics and assessment variables did not differ between the two groups at baseline. When compared with the control group at 6 months following initiation of the self-management program, participants in the intervention group demonstrated significantly greater improvement in physical functioning (B = 4.08, p < 05), self-efficacy of pain (B = 4.89, p < .05), and self-management behaviors (B = 4.65, p < 05). A self-management program based on self-efficacy theory that focused on joint protection and physical activities resulted in significant improvements in physical functioning, self-efficacy, and self-management behaviors 6 months following commencement of the intervention. Nurses provided individualized evaluations and support, which may have made it easier for participants to learn and perform the activities. After commencement of participation in the intervention, no improvements were seen until 6 months of participation. This delay may suggest patients with chronic disease may need a longer duration of self-management training and increased follow-up time to incorporate lifestyle changes. Future studies measuring long-term outcomes are suggested.


Long acting methadone formulation. Part 3: Preparation and in vivo evaluation of tablets containing methadone salts and methadone-naloxone combinations.
The preparation and in vivo evaluation of the methadone salts, methadone-o-benzoylbenzoate and methadone-alpha-naphthalenesulfonate, and a number of methadone-naloxone formulations, in the form of three layered slowly eroding tablets, were examined. Male albino rats of the Wistar strain were used as experimental animals and the results indicated that a prolongation of the resistance to pain threshold was attained, though severe side-effects were observed. A number of animals died during these experimental procedures.


Synaptic vesicle distribution by conveyor belt.
The equal distribution of synaptic vesicles among synapses along the axon is critical for robust neurotransmission. Wong et al. show that the continuous circulation of synaptic vesicles throughout the axon driven by molecular motors ultimately yields this even distribution.


Successful medical management of multifocal psoas abscess following cesarean section: report of a case and review of the literature.
The psoas abscess is a rare complication in obstetric and gynaecology. Two types of psoas abscess are recognized. The primary psoas abscess is generally following haematogenous dissemination of an infectious agent and the source is usually occult. The most frequently isolated pathogen is Staphylococcus aureus. On the other hand, the secondary abscess is the result of local extension of an infectious process near the psoas muscle. We report the case of a patient who develops a bacteremia from an infected cesarean section wound. The complications were thigh and psoas abscesses with left sacroiliitis. Medical management with prolonged antibiotherapy permit clinical, biological and radiological improvement. Although it required a long hospital stay, medical treatment alone was effective. More experience is required to determine which therapeutic option: medical treatment and/or surgery, is the best choice for this type of complication.


Stent-Save a Life international survey on the practice of primary percutaneous coronary intervention during the COVID-19 pandemic.
To assess the impact of the COVID-19 pandemic on admissions of patients with acute coronary syndromes (ACS) and primary percutaneous coronary intervention (PPCI) in countries participating in the Stent-Save a Life (SSL) global initiative. We conducted a multicenter observational survey to collect data on patient admissions for ACS, ST-elevation myocardial infarction (STEMI) and PPCI in participating SSL member countries through a period during the COVID-19 outbreak (March and April 2020) compared with the equivalent period in 2019. Of the 32 member countries of the SSL global initiative, 17 agreed to participate in the survey (three in Africa, five in Asia, six in Europe and three in Latin America). Overall reductions of 27.5% and 20.0% were observed in admissions for ACS and STEMI, respectively. The decrease in PPCI was 26.7%. This trend was observed in all except two countries. In these two, the pandemic peaked later than in the other countries. This survey shows that the COVID-19 outbreak was associated with a significant reduction in hospital admissions for ACS and STEMI as well as a reduction in PPCI, which can be explained by both patient- and system-related factors.


Positional candidate cloning of a QTL in dairy cattle: identification of a missense mutation in the bovine DGAT1 gene with major effect on milk yield and composition.
We recently mapped a quantitative trait locus (QTL) with a major effect on milk composition--particularly fat content--to the centromeric end of bovine chromosome 14. We subsequently exploited linkage disequilibrium to refine the map position of this QTL to a 3-cM chromosome interval bounded by microsatellite markers BULGE13 and BULGE09. We herein report the positional candidate cloning of this QTL, involving (1) the construction of a BAC contig spanning the corresponding marker interval, (2) the demonstration that a very strong candidate gene, acylCoA:diacylglycerol acyltransferase (DGAT1), maps to that contig, and (3) the identification of a nonconservative K232A substitution in the DGAT1 gene with a major effect on milk fat content and other milk characteristics.