A reduced population of CD103(+)CD11b(+) dendritic cells has a limited impact on oral Salmonella infection.
CD103(+)CD11b(+) dendritic cells (DC) are the major migratory DC subset in the small intestine lamina propria (siLP) and their survival is dependent on the transcription factor interferon regulatory factor 4 (IRF4). Mice with a DC-specific deletion of irf4 (CD11c-cre.Irf4 mice) have reduced mucosal CD103(+)CD11b(+) DC and altered T cell differentiation to protein antigen. The influence of CD103(+)CD11b(+) DC on oral infection with the gastrointestinal pathogen Salmonella, however, is poorly understood and is investigated here. We show that, despite being infected with Salmonella, CD11c-cre.Irf4 mice (called Cre(+) mice) conserve the reduction in CD103(+)CD11b(+) DC observed in naive Cre(+) mice, particularly in the mesenteric lymph nodes (MLN) but also in the siLP at day 3 post infection. Moreover, Salmonella-infected Cre(+) mice have a similar bacterial burden in intestinal tissues (siLP, MLN and Peyer's patches) as well as the spleen compared to infected Cre(-) controls. The T cell compartment, including the frequency of IFN-γ and IL-17-producing T cells, is not altered in intestinal tissues of Salmonella-infected Cre(+) mice relative to infected Cre(-) controls. In addition, no difference between infected Cre(+) and Cre(-) mice was observed in either the concentration of IL-6 or IL-17 in whole tissue lysates of siLP, MLN or Peyer's patches or in the serum concentration of Salmonella-specific IgG and IgM. Overall the data suggest that the reduction of CD103(+)CD11b(+) DC in Cre(+) mice has little if any impact on Salmonella burden in infected tissues or eliciting effector functions important in host survival at later stages of the infection.


Increased invasion through basement membrane by CXCL7-transfected breast cells.
CXC chemokines may modify breast cancer cells and surrounding extracellular matrix to facilitate metastasis. CXCL7 is heparin binding, has heparanase activity, and is a ligand to CXCR2, a G-protein-linked receptor. Isogenic cell lines, malignant MCF10CA1a.cl1 cells, and premalignant MCF10AT cells were used. CXCR2 and CXCL7 expression levels were quantified by reverse transcriptionase-polymerase chain reaction and Western blot. MCF10AT cells were stably transfected with CXCL7, and matrigel invasion assays were performed. Antibody to CXCL7 was used to inhibit invasion. CXCL7 secretion by transfectants and heparanase activity were quantified by enzyme-linked immunosorbent assay. CXCL7 and CXCR2 expression were significantly higher in malignant MCF10CA1a.cl1 cells than in premalignant MCF10AT cells. Secreted CXCL7, secreted heparanase activity, and invasiveness were all increased in CXCL7-transfected MCF10AT cells. CXCL7 antibody inhibited invasion of CXCL7-transfected MCF10AT cells. Malignant MCF10CA1a.cl1 cells express more CXCL7 and CXCR2 than premalignant MCF10AT cells. CXCL7-transfected MCF10AT cells are as invasive as malignant breast cancer cells.


Integration of morphogen signalling within the growth regulatory network.
The need to coordinate patterning and growth has been appreciated for many years. The logic that enables seamless integration of the relevant inputs is beginning to be elucidated, particularly in wing imaginal discs of Drosophila. In this tissue, multiple regulatory layers involving the two morphogens Wingless and Dpp, the wing-specific determinant, Vestigial, and the Hippo pathway, converge to regulate growth. Intricate cross-regulation between these components may explain why, at the local level, there is no direct correlation between growth and the graded signalling activity of Wingless and Dpp, despite the requirement of these two pathways for growth.


Biomolecular Interactions of Tannin Isolated from Oenothera gigas with Liposomes.
We have examined the interaction between hydrolysable tannin 1-O-galloyl-4,6-hexahydroxydiphenoyl-β-D-glucose (OGβDG) with neutral liposomes as a model of cell membranes composed of three lipids: lecithin, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) at different mass ratios. OGβDG in the concentration range 0.5-15 µg/ml (0.4-12 µM) strongly interacts with liposomal membranes by changing their structure, surface charge and fluidity. Used OGβDG molecules decrease and increase the rigidity of hydrophilic surface and hydrophobic parts of liposomes, respectively. At higher concentrations of tannin (>15 µM), liposomes are aggregated. Fourier Transform Infra-Red (FTIR) analysis showed that mainly -OH groups from OGβDG and also PO(2-) groups from phospholipids are responsible for the interaction. Obtained data indicate the importance of membrane lipid composition in interactions between tannins and cells.


Dissecting genetic cross-talk between ADHD and other neurodevelopmental disorders: Evidence from behavioural, pharmacological and brain imaging investigations.
Several epidemiological and genetic studies have provided evidence of an overlap between neurodevelopmental disorders. However, the details of the etiological pathways remain to be elucidated. In this study, we garnered the findings of previous GWAS, conducted with schizophrenia and bipolar disorder. We conducted an exploratory study to examine the association between these SNPs and quantitative clinical/ behavioural/ cognitive/ structural brain parameters, as well as response to treatment with a fixed dose of methylphenidate, in a relatively large sample of children with ADHD. Family-based association tests were conducted with nine tag SNPs with 602 nuclear families. In addition, structural magnetic resonance imaging (sMRI) was conducted in a subset of children with ADHD (n = 76). Of the 9 tag SNPs examined, rs1602565 showed a significant association with ADHD, several dimensional measures and response to treatment. An association was also observed between rs1006737 (CACNA1C) and performance IQ. In addition, significant reductions in cortical thickness measurements were observed with the risk allele in rs1006737. These results provide preliminary evidence for putative shared genetic vulnerability between childhood ADHD and other neurodevelopmental disorders.


Intravenous versus intracoronary streptokinase in acute myocardial infarction.
One hundred sixty-four consecutive patients with acute myocardial infarction were enrolled in a prospective trial of coronary thrombolysis with streptokinase (STK). The first 98 patients received intracoronary (i.c.) STK after coronary angiography and the next 66 received a high-dose rapid infusion of STK (900,000 IU) intravenously (i.v.) before angiography. First-pass radionuclide ejection fraction (EF) was performed early (within 24 hours of admission) and late (10 to 14 days after admission) to evaluate left ventricular function. In the i.v. group, 42 of 66 (64%) of infarct-related arteries were patent at the initial angiogram and 6 (9%) opened with subsequent i.c. STK. In the i.c. group, 13 of 98 (13%) of infarct-related arteries were patent at the initial angiogram and 50 of 85 (59%) opened with the i.c. STK. The i.v. and i.c. groups did not differ in time from onset of chest pain to presentation, type of infarct or underlying severity of coronary artery disease. In the i.v. group, STK was begun 67 minutes earlier than in the i.c. group. In 62 patients in whom reperfusion was successful, mean EF increased from 39 +/- 11% early to 48 +/- 13% late. In 30 in whom it was not, the mean EF increased from 36 +/- 10% to 40 +/- 12%. The increase in EF was significantly greater in patients in the reperfused group (p less than 0.03). In 18 patients who underwent reperfusion by i.v. STK, the mean EF increased 11 +/- 12%, whereas in 44 patients who had reperfusion by i.c. STK, the mean EF increased 9 +/- 10% (difference not significant).(ABSTRACT TRUNCATED AT 250 WORDS)


Evaluation of antibody response after COVID-19 vaccination of healthcare workers.
The common goal of all vaccines developed against COVID-19, although they have been designed with different methods, is to develop an effective immunity and antibody response against SARS-CoV-2. However, the postvaccination immune response and antibody levels differ between individuals. This study examined the relationship between postvaccine seropositivity rates, age, gender, smoking, and body mass index (BMI), and antibody titers. A total of 314 healthcare workers (HCW) who were not previously infected with COVID-19 and who had received two doses of CoronaVac inactivated vaccine participated in the study. Seropositivity against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein was measured from the participants 4 weeks after the second dose of vaccine using the electrochemiluminescence (ECLIA) method. In addition, the antibody developed against the nucleocapsid protein (NCP) was evaluated and compared using Elecsys Anti-SARS-CoV-2 kit. One hundred and eighty-one of the participants were female (57.6%) with a median age of 39 (interquartile range [IQR], 10) and 133 (42.4%) were male with a median age of 41 (IQR, 11). 99.6% of the volunteers developed seropositivity 4 weeks after the second dose of vaccine. It was also observed that the rate of RBD protein antibody titer was >250 U/ml in smokers, which is quite low compared to nonsmokers (p = 0.032), and that high RBD antibody titers were proportionally lower in obese participants, according to BMI values, compared to those with normal BMI (49.5% and 9.9%). It was observed that seropositivity developed in almost all participants after the CoronaVac vaccine. However, it was determined that the antibody titer measured varied depending on factors such as smoking, BMI, and duration.


Persistence of Aβ seeds in APP null mouse brain.
Cerebral β-amyloidosis is induced by inoculation of Aβ seeds into APP transgenic mice, but not into App(-/-) (APP null) mice. We found that brain extracts from APP null mice that had been inoculated with Aβ seeds up to 6 months previously still induced β-amyloidosis in APP transgenic hosts following secondary transmission. Thus, Aβ seeds can persist in the brain for months, and they regain propagative and pathogenic activity in the presence of host Aβ.


How do family members perceive re-integration of male state patients into their families in South Africa? A qualitative analysis.
State patients are admitted to a psychiatric hospital after being declared as such by the magistrate courts as a result of not found fit to stand trial for the offence they had committed. After successful rehabilitation of state patients at the psychiatric hospital, they need to be re-integrated into their families. Family members' perceptions regarding re-integration of male state patients are not largely explored in the scientific body of knowledge. The aim of the study was to determine the perceptions of family members regarding reintegration of male state patients into their families. This study was conducted in Vhembe District of Limpopo province, South Africa. A qualitative approach using explorative, descriptive and contextual designs was adopted. In-depth interviews were conducted with 10 family members who were purposefully sampled, and data were thematically analysed using Tech Open Coding method. Three themes emerged, namely, family members understand re-integration; family members' expectations from a mental healthcare user; and threat to re-integration as perceived by family members. Data revealed that family members have varied perceptions regarding re-integration. These perceptions were based on the behaviour displayed or an offence committed by the mental healthcare user before admission and how participants experienced it. The study recommends that an investigation is to be conducted on the kind of support family members need regarding re-integration of state patients into their families.


Dynamics of monocyte chemoattractant protein type one (MCP-1) and HIV viral load in human cerebrospinal fluid and plasma.
Increased expression of monocyte chemoattractant protein type 1 (MCP-1) is associated with HIV CNS disease. This study evaluated the temporal relationships between MCP-1 expression and HIV replication in the CNS. MCP-1 and HIV viral load (VL) were measured in serially obtained samples of plasma and cerebrospinal fluid (CSF) in subjects either interrupting (TI) or starting (TS) antiretroviral therapy. Following TI, plasma VL rebounded first, followed by increases in CSF MCP-1, which immediately preceded or coincided with a rebound of CSF VL. The close temporal relationship of the increase of MCP-1 and CSF VL suggests that they are co-regulated, or that one is a stimulus for the other.


Plasmodium falciparum serine-repeat antigen (SERA) forms a homodimer through disulfide bond.
Plasmodium falciparum serine-repeat antigen (SERA) is one potential blood-stage vaccine candidate and is expressed as a protomer that is subsequently processed into four fragments (P47, P50, P6, and P17). Although recent evidence shows that P50 exhibits chymotrypsin-like protease activity, the function of SERA is still largely unknown. Here, we found that apart from cathepsin L-like cysteine protease, P50 showed significant homology to silicatein-alpha and testin which were shown to bind to cellular components, suggesting that SERA may have similar function. Immunoprecipitation of schizont lysate and molecular assignment of its precipitate by mass spectrometry provided evidence that SERA forms a homodimer through disulfide bond. Moreover, analysis of the fate of SERA using cell-free system revealed that the kinetics of conversion of SERA dimer into monomer is faster than that of processing of SERA monomer into various fragments. These findings may contribute to elucidate a possible function of SERA other than a protease.


Enhanced thermotolerance of E. coli by expressed OsHsp90 from rice (Oryza sativa L.).
A gene encoding the rice (Oryza sativa L.) 90-kDa heat shock protein (OsHsp90) was introduced into Escherichia coli using the pGEX-6p-3 expression vector with a glutathione-S-transferase (GST) tag to analyze the possible function of this protein under heat stress for the first time. We compared the survivability of E. coli (BL21) cells transformed with a recombinant plasmid containing GST-OsHsp90 fusion protein with control E. coli cells transformed with the plasmid containing GST and the wild type BL21 under heat shock after isopropyl beta-D: -thiogalactopyranoside induction. Cells expressing GST-OsHsp90 demonstrated thermotolerance at 42, 50, and 70 degrees C, treatments that were more harmful to cells expressing GST and the wild type. Further studies were carried out to analyze the heat-induced characteristics of OsHsp90 at 42, 50, and 70 degrees C in vitro. When cell lysates from E. coli transformants were heated at these heat stresses, expressed GST-OsHsp90 prevented the denaturation of bacterial proteins treated with 42 degrees C heat shocks, and partially prevented that of proteins treated at 50 and 70 degrees C; meanwhile, cells expressing GST-OsHsp90 withstood the duration at 50 degrees C. These results indicate that OsHsp90 functioned as a chaperone, binding to a subset of substrates, and maintained E. coli growth well at high temperatures.


Bone age in 116 untreated patients with Turner's syndrome rated by a computer-assisted method (CASAS).
Bone age maturation in 116 untreated patients with Turner's syndrome was evaluated in a cross-sectional and longitudinal analysis. A total of 265 radiographs were rated using the TW2-RUS method on the computer-assisted skeletal age score (CASAS) system. Bone age was found to be retarded from the chronological age of 3 to 6y. Between the ages of 7 and 12 y bone age almost equalled chronological age and progressed normally at a rate of 1 y y(-1). Bone maturation slowed down thereafter and epiphyseal closure was not reached before the age of 17 y. Reference data are presented on bone age and a bone age maturation curve for untreated patients with Turner's syndrome to be used in clinical practice. In the assessment of bone age and bone age velocity in Turner's syndrome the CASAS system produced reliable and valid results. The absolute difference between repeated bone age ratings was 0.26 "y" (median) with a range of 0.00-0.56 "y". Future studies evaluating the effect of growth-promoting treatment in Turner's syndrome should use a computerized method for the determination of bone age.


The Utility of Metal Ion Trends in Predicting Revision in Metal-on-Metal Total Hip Arthroplasty.
There is a paucity of data examining metal ion levels over time. We retrospectively reviewed 59 patients (69 hips) with an articular surface replacement total hip arthroplasty. We reviewed prerevision cobalt and chromium concentrations over time. Seventy-one percent of patients who were revised and had multiple ion measurements (12/17) demonstrated increasing cobalt ion levels or elevated ion levels over time. There was a trend toward an elevated risk of revision for increasing cobalt and chromium levels starting at 12 and 4 ppb, respectively; this was significant for chromium levels above 7 ppb (hazard ratio 22.35, P = .001). Similarly, there was a trend toward an elevated risk of pseudotumor formation for increasing cobalt and chromium levels starting at 5 and 2.5 ppb, respectively; this was significant for cobalt levels above 7 ppb (hazard ratio 6.88, P = .027). In this paper, cobalt and chromium levels levels above 5 and 2.5 ppb started to demonstrate an increased risk of ARMD, and should be considered as a lower cutoff for discussion with patients about the potential for future revision.


Diagnosis and treatment of a newborn with homozygous protein C deficiency.
The case is reported of a seriously affected newborn with homozygous protein C deficiency who developed neonatal purpura fulminans. Foetal ultrasound at 33 wk of gestation revealed ventriculomegaly. The first lesions appeared on the scalp 48 h after birth. She was initially treated with fresh-frozen plasma and, after the diagnosis was confirmed, with purified protein C concentrate. After skin necrosis had healed, therapy was continued with oral warfarin. The infant was homozygous for protein C W380G mutation. Diagnosis at the DNA level gave the parents an option of reliable prenatal diagnosis in their subsequent pregnancy. Difficulties in reaching an accurate diagnosis are discussed since early diagnosis and urgent therapy with protein C replacement are crucial to avoid further damage after delivery.


Emergency general surgery specific frailty index: A validation study.
Assessment of operative risk in geriatric patients undergoing emergency general surgery (EGS) is challenging. Frailty is an established measure for risk assessment in surgical cases. The aim of our study was to validate a modified 15-variable EGS-specific frailty index (EGSFI). We prospectively collected geriatric (age older than 65 years) EGS patients for 2 years. Postoperative complications were collected. Frailty index was calculated for 200 patients based on their preadmission condition using 50-variable modified Rockwood frailty index. Emergency general surgery-specific frailty index was developed based on the regression model for complications and the most significant factors in the frailty index. Receiver operating characteristic curve analysis was performed to determine cutoff for frail status. We validated our results using 60 patients for predicting complications. A total of 260 patients (developing, 200; validation, 60) were enrolled in this study. Mean age was 71 ± 11 years, and 33% developed complications. Most common complications were pneumonia (12%), urinary tract infection (9%), and wound infection (7%). Univariate analysis identified 15 variables significantly associated with complications that were used to develop the EGSFI. A cutoff frailty score of 0.325 was identified using receiver operating characteristic curve analysis for frail status. Sixty patients (frail, 18; nonfrail, 42) were enrolled in the validation cohort. Frail patients were more likely to have postoperative complications (47% vs. 20%; p < 0.001) compared to nonfrail patients. Frail status based on EGSFI was a significant predictor of postoperative complications (odds ratio, 7.3; 95% confidence interval, 1.7-19.8; p = 0.006). Age was not associated with postoperative complications (odds ratio, 0.99; 95% confidence interval, 0.92-1.06; p = 0.86). The 15-variable validated EGSFI is a simple and reliable bedside tool to determine the frailty status of patients undergoing EGS. Frail status as determined by the EGSFI is an independent predictor of postoperative complications and mortality in geriatric EGS patients. Prognostic study, level II.


Organ abscission: exit strategies require signals and moving traffic.
Flowers are frequently programmed to release their outer organs after pollination. Managing the timing and extent of cell separation during abscission is crucial, as premature shedding could interfere with reproduction and the structural integrity of neighboring tissues would be affected by uninhibited loss of cellular adhesion. In Arabidopsis flowers, the framework of the cell signaling, membrane traffic and transcriptional networks responsible for organ abscission is now emerging. A proposed ligand-receptor system consisting of a secreted peptide and a pair of redundant receptor-like kinases switches on a mitogen-activated protein kinase cascade that leads to cell separation. A homeodomain transcription factor acting downstream of the ligand-receptor module may inhibit cell expansion and separation by restricting the expression of other closely related transcription factors. Three additional receptor-like kinases may inhibit abscission by reducing the pool of receptors at the cell surface available to be ligand-activated. A G-protein regulator is required to direct the movement of key molecules required for abscission. Expression of a polygalaturonase active during organ abscission is modulated by a zinc finger transcription factor.


Phosphorylation of PI3K/Akt and MAPK/ERK in an early entry step of enterovirus 71.
Viruses have been known to subvert the anti-apoptotic pathways of the host cell in order to delay apoptosis. However, the mechanisms utilized by enterovirus 71 (EV71) to mediate anti-apoptotic activity remained undetermined. We observed that EV71 infection induced an early activation of both phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK/ERK signaling pathways. The activity of GSK3beta, a downstream target of these pathways, was negatively regulated by the activation of both MAPK/ERK and PI3K/Akt. The phosphorylation of GSK3 could be inhibited by treatment with the specific inhibitors of MAPK/ERK and PI3K/Akt. Other Akt downstream targets, BAD, caspase-9 and the Forkhead transcription factor (FKHR), were not phosphorylated during the course of infection by EV71. We further demonstrated that infection by UV-irradiated, inactivated virus triggered early Akt activation but was insufficient to trigger late Akt activation. These data suggest that with the phosphorylation of MAPK/ERK and PI3K/Akt the subsequent inactivation of GSK3beta is utilized by EV71 as a potential mechanism to delay host cell apoptosis.


ILO activities in the area of chemical safety.
The ILO has been active in the area of safety in the use of chemicals at work since the year of its creation in 1919, including the development of international treaties and other technical instruments, the provision of technical assistance to its member States, and the development of chemical safety information systems. The two key ILO standards in this area are the Conventions on safety in the use of chemicals at work (No. 170, 1990), and the Prevention of Major Industrial Accidents (No. 174, 1993). The ILO Programme on occupational safety, health and environment (Safe Work) is currently responsible for ILO chemical safety activities. In the past two decades, most of ILO work in this area has been carried out within the context of inter-agency collaboration frameworks linking the ILO, WHO, UNEP, FAO, UNIDO, UNITAR, and the OECD, including the International Programme on Chemical Safety (IPCS), the Inter-Organisation Programme for the Sound Management of Chemicals (IOMC), and the Intergovernmental Forum on Chemical Safety (IFCS). Apart from the regular development, updating and dissemination of chemical safety information data bases such as the IPCS International Chemical Cards, the elaboration of a Globally harmonized system for the classification and labelling of Chemicals (GHS) has been the most outstanding achievement of this international collaboration on chemical safety.


DZNep attenuates allergic airway inflammation in an ovalbumin-induced murine model.
Growing evidence shows that enhancer of zeste homolog 2 (EZH2) plays a role in various physiological functions and cancer pathogenesis. However, its contribution to allergic diseases remains controversial. We sought to investigate the role of EZH2 in the pathogenesis of allergic airway inflammation. 3-Deazaneplanocin A (DZNep), an indirect inhibitor of EZH2, was administered via intraperitoneal injection in an ovalbumin (OVA)-induced murine model of allergic airway inflammation. The expression of EZH2 in the allergic airway tissues was examined by immunohistochemistry (IHC) and western blot. The inflammatory cell infiltration and the goblet cell hyperplasia in the murine nose and lung were detected by hematoxylin and eosin (H&E) staining and periodic acid-Schiff (PAS) staining. Levels of cytokines, including IL-4, IFN-γ, IL-6, and IL-10, were evaluated in the bronchoalveolar lavage fluid (BALF) using Enzyme-linked immune sorbent assay (ELISA). EZH2 expression was inhibited by DZNep treatment (P < 0.05). The administration of DZNep significantly inhibited the inflammatory cell infiltration (P < 0.0001) and goblet cell hyperplasia (P < 0.001). Moreover, it suppressed the secretion of IL-4 (P < 0.0001) and IL-6 (P < 0.01) in the BALF. Our findings demonstrate that DZNep attenuates allergic airway inflammation and could be a new therapeutic option for allergic rhinitis and asthma.


Mental Stress-Induced Myocardial Ischemia.
To summarize recent evidence on mental stress-induced myocardial ischemia (MSIMI), its mechanisms, and clinical significance. MSIMI can occur in patients with normal cardiac stress testing, is only weakly related to severity of coronary artery disease (CAD), and it is often silent. Among patients with CAD, MSIMI is associated with a twofold increased risk of major adverse cardiovascular events compared to those who do not have MSIMI. Certain groups such as young women with myocardial infarction and those with psychological comorbidities are more susceptible to MSIMI. Abnormal microvascular vasoreactivity and inflammation are implicated mechanisms in MSIMI. Increased brain activity in regions that modulate autonomic reactivity to emotional stress and fear is associated with MSIMI. MSIMI has important prognostic implications in patients with CAD. Stress can no longer be ignored as a risk factor in cardiology care. Clinical trials testing effective strategies to target MSIMI are needed.


Differential modulation of primary afferent depolarization of segmental and ascending intraspinal collaterals of single muscle afferents in the cat spinal cord.
We examined primary afferent depolarization (PAD) in the anesthetized cat elicited in 109 pairs of intraspinal collaterals of single group I afferents from the gastrocnemius nerve, one of the pair ending in the L3 segment, around the Clarke's column nuclei, and the other in the L6 segment within the intermediate zone. Tests for refractoriness were made to assess whether the responses produced by intraspinal stimulation in the L3 and L6 segments were due to activation of collaterals of the same afferent fiber. PAD in each collateral was estimated by independent computer-controlled measurement of the intraspinal current required to maintain a constant probability of antidromic firing. In most fibers, stimulation of the ipsilateral posterior biceps and semitendinosus (PBSt) nerve with trains of pulses maximal for group I afferents had a qualitatively similar effect but produced a larger PAD in the L6 than in the L3 collaterals. Stimulation of cutaneous nerves (sural and superficial peroneus) with single pulses and of the posterior articular nerve, the ipsilateral reticular formation, nucleus raphe magnus and contralateral motor cortex with trains of pulses often had qualitatively different effects. They could produce PAD and/or facilitate the PBSt-induced PAD in one collateral, and produce PAH and/or inhibit the PAD in the other collateral. These patterns could be changed in a differential manner by sensory or supraspinal conditioning stimulation. In summary, the present investigation suggests that the segmental and ascending collaterals of individual afferents are not fixed routes for information transmission, but parts of dynamic systems in which information transmitted to segmental reflex pathways and to Clarke's column neurons by common sources can be decoupled by sensory and descending inputs and funneled to specific targets according to the motor tasks to be performed.


A 6-year retrospective clinical review of iatrogenic ureteric injuries repaired in a resource-deprived setting.
Seventy percent of ureteric injuries result from iatrogenic causes with about 75% of these diagnosed in the postoperative period. It may have fatal complications such as sepsis and or renal functional damage increasing morbidity and treatment cost. The study aimed to identify the risk factors for iatrogenic ureteric injuries from open surgical procedures and the intervention outcome in a resource-poor setting. This was a multi-centre study. The clinical records of patients with iatrogenic ureteric injuries seen between 2015-2021 who were managed at the urology units of the Margaret Marquart Catholic Hospital, and the Ho Teaching Hospital, in the Volta region of Ghana, were retrieved. The data extracted included patients' demographic factors, the clinical presentation, the primary surgery details, the time from surgery to presentation, the intervention offered, and the outcomes. The data were analysed using the Statistical Package for Social Scientists (SPSS) version 24.0. Twelve patients aged between 24-54 years with a total of 19 ureteric injuries were managed. The injuries resulted from a hysterectomy in 10 cases (83.3%), and one each from emergency caesarean section and inguinal hernia repair with traction and transection injuries respectively (16.7%). Seven out of 12 cases were diagnosed 48 h after surgery. Bilateral injuries occurred in 7 cases (14/19 injuries). Intraoperative recognition was common in unilateral injuries and surgeries performed by specialist surgeons. Ureteroneocystostomy (14/19), uretero-ureterostomy (1/19), and open suture release were the management procedures performed as in the intervention. Open hysterectomy (83.7%) was the most common procedure leading to iatrogenic ureteric injuries in this study. Intra-operative recognition occurred when trained specialist surgeons performed the surgery. Late presentation with more severe morbidity was found amongst non-specialist surgeons. Thus, improvement in training to allow intra-operative diagnosis should be encouraged in general practitioners to reduce morbidity and improve outcomes.


Malignancy-associated multicentric reticulohistiocytosis: a clinical, histological and immunophenotypic study.
The clinical, histopathological, and immunophenotypic characteristics of four cases of malignancy-associated multicentric reticulohistiocytosis (MMR) and one case each of diffuse cutaneous reticulohistiocytosis (DCR) and isolated reticulohistiocytoma (IR), are reviewed. In all four cases of MMR the cutaneous lesions and joint manifestations were judged to be concurrent with the diagnosis of malignancy. Malignancies observed included one case each of pancreatic adenocarcinoma, squamous cell carcinoma of the lung, metastatic melanoma and intraperitoneal grade 4 mucinous adenocarcinoma of uncertain origin. Histologically, all six cases demonstrated the typical changes of a diffuse histiocytic and multinucleated giant cell infiltrate with ground-glass cytoplasm, predominantly in the upper dermis. Immunohistochemical investigation revealed strong cytoplasmic staining with KP-1 (CD68) in all six cases. Prominent membrane staining was noted with leucocyte common antigen (CD45) in four cases (three MMR and one IR), and CD3 in four cases (three MMR and one IR). Weak membrane staining with Leu 22 (CD43) was noted in two MMR cases. UCHL-1 (CD45RO), L26 (CD20), S-100 and BerH2 stains were all uniformly negative. A prominent number of perilesional factor XIIIa-positive dermal dendrocytes were noted in the single case of IR, in contrast with the other five cases. We conclude that MMR, DCR and IR are histopathologically and immunohistochemically similar. The pattern of immunoreactivity observed is consistent with a monocyte-macrophage origin of the infiltrating tumour cells. We emphasize the paraneoplastic association of multicentric reticulohistiocytosis, which we have observed in four of 13 such cases (31%) evaluated at our institution.


Apical filling characteristics of carrier-based techniques vs. single cone technique in curved root canals.
In this in vitro study, we assessed filling characteristics (adaptation, homogeneity, sealer percentage, position of the carrier) of warm and cold obturation methods in curved root canals. A reciprocating method was used to prepare 90 curved roots (25 ° average curvature) to an apical size of 25.08. They were then obturated with either (A) Guttafusion (VDW, Munich, Germany), (B) Thermafil (Maillefer, Ballaigues, Switzerland) or (C) single cone technique using 25.08 gutta-percha (VDW) and sealer (2Seal easymix) (n = 30 each group). Five sections in 1-mm steps were obtained from each root, beginning 1 mm short of the apex. The percentage of voids in contact with root canal walls (PVO), the proportion of voids per area (PVA) and the percentage of sealer per area (PSA) were measured. Little to no differences between Guttafusion and Thermafil were seen in curved root canals with respect to adaptation and homogeneity in the apical region. Both methods showed significantly better adaptation and homogeneity than the single cone technique. The proportion of sealer was significantly greater when roots were obturated with Guttafusion than with Thermafil, but both warm obturation techniques had significantly smaller sealer areas than the single cone technique. Compared to the single cone technique, a more favourable root canal filling with less sealer could be expected from both warm obturation techniques in curved root canals. The easier-to-handle Guttafusion leads to comparable results as Thermafil in curved root canals.


Neuromagnetic motor fields accompanying self-paced rhythmic finger movement at different rates.
We have studied the effect of movement rate on MEG activity associated with self-paced finger movement in four subjects to determine whether the amplitude or latency of motor-evoked activity changes across a range of rates. Subjects performed a continuation paradigm at 21 distinct rates (range: 0.5-2.5 Hz) chosen because of their relevance for many types of sensorimotor coordination (e.g. musical performance). Results revealed a pair of field patterns whose topography and temporal dynamics were similar across all subjects. The strongest pattern was a movement-evoked field (MEF) that emerged during the response and exhibited one or two polarity reversals in time depending on the subject. The MEF complex was tightly coupled to the biphasic response profile but neither latency nor peak amplitude of each MEF component had significant dependence on the temporal duration between successive responses, i.e. movement rate. In contrast, the maximal amplitude of a second, weaker pattern decreased by over 50% when movement rates exceeded 1.1 Hz (inter-response interval <1 s). This pattern was characterized by a change in field line direction over the midline of the scalp and a gradual accumulation of amplitude prior to movement onset. Both characteristics are suggestive of a readiness field. The observed rate-dependent changes in this field may contribute to known transitions in sensorimotor coordination that emerge when the frequency of coordination is increased.


Systematic review of perianal implants in the treatment of faecal incontinence.
Injectable bulking agents have been used with varying success for the treatment of faecal incontinence. This systematic review aimed to investigate the various injectable agents and techniques used for the treatment of faecal incontinence, and to assess their safety and efficacy. Thirty-nine publications were identified and studied. The following variables were pooled for univariable analysis: type, location, route of bulking agents, and the use of ultrasound guidance, antibiotics, laxatives and anaesthetics. Predictors of the development of complications and successful outcomes were identified by multivariable logistic regression analysis. A total of 1070 patients were included in the analysis. On multivariable analysis, the only significant predictor of the development of complications was the route of injection of bulking agents (odds ratio 3·40, 95 per cent confidence interval 1·62 to 7·12; P = 0·001). Two variables were significant predictors of a successful short-term outcome: the use of either PTQ(®) (OR 5·93, 2·21 to 16·12; P = 0·001) or Coaptite(®) (OR 10·74, 1·73 to 65·31; P = 0·001) was associated with a greater likelihood of success. Conversely, the use of local anaesthetic was associated with a lower likelihood of success (OR 0·18, 0·05 to 0·59; P = 0·005). Failure to use laxatives in the postoperative period resulted in a poorer medium- to longer-term outcome (OR 0·13, 0·06 to 0·25; P = 0·001). This systematic review has identified variations in the practice of injection of bulking agents that appear to influence the likelihood of complications and affect the outcomes after treatment.


Early and late management of the neuropathic bladder in spinal cord injury patients.
Early and late management of neuropathic bladders in 562 consecutive patients with spinal cord injuries is described. Indications for an operation to relieve outlet obstruction by transurethral resection and external sphincterotomy are outlined, and the management of urinary infection and incontinence is discussed. Approximately 30 per cent of all spinal cord injury patients had outlet obstruction for which either external sphincterotomy, transurethral resection or both procedures were necessary. Operations appeared to be required more frequently in patients with complete and thoracic lesions, and more than 1 operation may be necessary to achieve satisfactory bladder emptying.


Cross-sectional and longitudinal associations between radiographic features and measures of pain and physical function in hand osteoarthritis.
Previous longitudinal studies have shown no associations between increasing amount of radiographic hand osteoarthritis (OA) and levels of hand pain/disability. In this longitudinal study, we aimed to study whether radiographic hand OA was related to pain/disability in cross-sectional and longitudinal settings focusing on joint-specific analyses. We included 190 patients (173 women, mean (standard deviation, SD) age 61.5 (5.7) years) from the Oslo hand OA cohort, of whom 112 had 7-year follow-up data. Finger joints were scored for radiographic OA according to the Kellgren-Lawrence scale and Osteoarthritis Research Society International (OARSI) atlas. Pain and function were assessed by clinical examination (joint tenderness), grip strength and the Australian/Canadian (AUSCAN) questionnaire. Associations between radiographic hand OA and tenderness in the same joint were examined by logistic regression analyses with Generalized Estimating Equations, whereas associations between overall amount of radiographic OA and hand pain/disability were assessed by linear regression (adjusted for age and sex). A dose-dependent association was found between the severity of radiographic OA and tenderness in the same joint. Joints that progressed into severe radiographic OA during follow-up had the highest odds of developing tenderness (OR = 11, 95% confidence interval (CI) 4.0-33). Incident erosions seemed to be the most important individual feature associated with incident tenderness (OR = 6.2, 95% CI 3.2-12). Weak associations were found between the amount of radiographic hand OA and overall hand pain/disability. Radiographic hand OA is associated with tenderness in the same joint, and erosive development strongly predicts future joint tenderness independent of other radiographic features.


Comparison of analgesic and systemic effects of bupivacaine, methadone, or bupivacaine/methadone administered epidurally in conscious sheep.
The aim of this study was to evaluate the combination of bupivacaine and methadone administered epidurally in sheep. Six healthy female mixed-breed sheep weighing 35-46 kg and aged 12-18 months were included. Each sheep was assigned to receive three treatments: 0.5 mg/kg 0.25% bupivacaine (BP), 0.3 mg/kg 1% methadone (MT) or 0.25 mg/kg bupivacaine and 0.15 mg/kg methadone (BPMT). All drugs were injected into the lumbosacral space through an epidural catheter. Each animal received each treatment at random. Heart rate, arterial blood pressure (systolic, diastolic and mean), respiratory rate, rectal temperature, analgesia, sedation and motor block were determined before treatment and at predetermined intervals. The duration of analgesia was 240, 220, and 180 min for BP, MT and BPMT, respectively (P < 0.05). Motor block for all agents was mild to moderate. None or the treatments significantly altered the heart rate, blood pressure or respiratory rate. Our findings suggest that lumbosacral epidural administration of bupivacaine, methadone or a combination of the two drugs can provide perioperative analgesia in sheep as part of their management for surgical procedures in the flank and hindlimbs.


Author Correction: Detecting protein and post-translational modifications in single cells with iDentification and qUantification sEparaTion (DUET).
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


The Māori foot exhibits differences in plantar loading and midfoot morphology to the Caucasian foot.
The question being addressed in the current study was whether the diabetic Māori foot was more or less prone to ulceration than the diabetic New Zealand Caucasian (NZC) foot. Harris mat and pedobarographic analyses were employed to assess static and dynamic foot morphology and plantar loading in 40 Māori and NZC diabetic and non-diabetic participants. Significantly higher peak pressures were exhibited by the diabetic Māori participants compared to their NZC peers at the central forefoot. Significantly higher static and dynamic arch index values and significantly higher sub-arch angle values were exhibited by the non-diabetic Māori participants compared to their NZC peers. The latter findings suggest that healthy Māori may have a predisposition towards having a flatter foot than healthy NZC, which may have footwear design implications.


4-Chloro-N-(2,3-dimethyl-phen-yl)benzamide.
In the title compound, C(15)H(14)ClNO, the ortho- and meta-methyl substituents in the aniline ring are anti to the N-H bond. The dihedral angle between the benzoyl and aniline benzene rings is 95.0 (1)°. N-H⋯O hydrogen bonds and C-H⋯π inter-actions link the mol-ecules in the crystal structure.


The effect of 3D-printed Ti6Al4V scaffolds with various macropore structures on osteointegration and osteogenesis: A biomechanical evaluation.
A properly designed porous scaffold can accelerate the osseointegration process, and the use of computer-aided design (CAD) and additive manufacturing (AM) techniques has the potential to improve the traditional porous scaffold approach. In this study, we evaluate the effect of porous Ti6Al4V (Ti) with different pore structures on osteointegration and osteogenesis. Porous Ti scaffolds with different pore structures based on four commercially available implants were designed and manufactured by CAD and selective laser melting (SLM). Micro-CT showed that SLM was able to produce Ti scaffolds with different pore structures. The mechanical properties evaluated by finite element analysis and compression tests indicated that the four porous scaffolds in our study were mechanically adapted, despite their different mechanical properties. Then, we used 3D-printed porous discs to culture human bone marrow mesenchymal stem cells (hBMMSCs), the main seed cells of bone tissue engineering. The results showed no significant difference among the four groups in cell morphology, viability and proliferation. In addition, four groups showed a comparable mineralization ability even though Ti-g had a higher alkaline phosphatase activity (ALP). In vivo tests in a rabbit model showed that all four groups were suitable for new bone ingrowth and integration. These findings indicate that the four different pore structures in the Ti scaffolds provided good osteointegration and osteogenesis.


Percutaneous endoscopic gastrostomy and jejunostomy by a single pass of the endoscope.
A modified Gauderer-Ponsky technique of percutaneous endoscopic gastrostomy has been described. The major advantage is elimination of a second insertion of the endoscope, as well as unnecessary traversing of the esophagus by snares and strings. The result achieved is equal to what has been achieved with the original technique, but the single-pass technique is more expeditious and less uncomfortable for the patient. In addition, it can easily be modified to insert both draining gastrostomy and feeding jejunostomy tubes at the same time, using only one pass of the endoscope.


[Implementation of a Pilot Project Supporting Parents Suffering from Cancer with Underage Children].
Families with one parent suffering from cancer are exposed to extraordinary emotional and organizational burdens, affecting underaged children. To help coordinated access to social and logistic support options and thus reduce the stress on family members, the project Brückenschlag was founded. The aim of this paper was to evaluate the implementation of this pilot project following the healthcare utilization model by Andersen. A cross-sectional observational study was conducted using a mixed-method approach. Semi-structured written expert surveys (n=10) and secondary analysis of routine data of the care model (n=171 families) were combined. Quantitative secondary analysis: The participating families had 1-7 children (median (m) 2, range (s) 6). In 66% of the cases, the mother was affected by cancer, in 20% the diseased parent was in a single parent household. The communication structure in these families was rated "limited" to "rather open". Of the total of 171 contacts (study period 9/14 to 11/17), 133 families made use of Brückenschlag; 59.2% of the contacts were made by psycho-oncologists and the social services department of the hospital. If the contact was initiated by the patients themselves or by psycho-oncologists, a guidance was established significantly more frequently (significance of chi-squared test 0.047). Qualitative analysis: There was a lack of awareness and coordination of existing support services and a lack of family resources to use existing support offers. Both the desired and the established support fell primarily in the area of organizational support. Brückenschlag improved networking and took on a navigating function for the families. The data collected indicate that in families, matching the German average in their socio-demographic characteristics, a great need for organizational support develops as soon as one parent becomes sick with cancer. The model project Brückenschlag creates an access to support services for families with one parent suffering from cancer.


Current medical and surgical management of Raynaud's syndrome.
Raynaud's syndrome (RS) is characterized by episodic digital ischemia induced by cold or emotional stress. Pathophysiologic mechanisms include temporary vasospasm and fixed digital artery obstruction. A number of pharmacologic and invasive therapies have been studied to treat RS symptoms; however, there are no specific treatments that are currently approved by the U.S. Food and Drug Administration specifically for RS. Of the available pharmacologic agents, calcium-channel blockers remain the preferred initial treatment for vasospastic RS, although many vasodilators have been studied and found to be efficacious. Vasodilators are less effective in treating digital artery obstruction, and no treatments have been found to be universally beneficial, although the phosphodiesterase V inhibitors have been gaining in popularity. Invasive therapies may have a role in selective cases. In this review, the current evidence of treatment for RS is summarized.


In Search of the Optimal Antithrombotic Regimen for Intracerebral Hemorrhage Survivors with Atrial Fibrillation.
Spontaneous intracerebral hemorrhage (ICH) constitutes 10-15% of all strokes, and is a significant cause of mortality and morbidity. Survivors of ICH, especially those with atrial fibrillation (AF), are at risk for both recurrent hemorrhagic and ischemic cerebrovascular events. A conundrum in the field of vascular neurology, neurosurgery, and cardiology has been the decision to initiate or resume versus withhold anticoagulation in survivors of ICH with AF. To initiate anticoagulation would decrease the risk of ischemic stroke but may increase the risk of hemorrhage. To withhold anticoagulation maintains a lower risk of hemorrhage but does not decrease the risk of ischemic stroke. In this narrative review, we discuss the evidence for and against the use of antithrombotics in ICH survivors with AF, focusing on recently completed and ongoing clinical trials.


Impact of creatinine values on MELD scores in male and female candidates for liver transplantation.
A systematic bias against women, resulting from the use of creatinine as a measure of renal function, has been identified in Model for End-stage Liver Disease (MELD)-based liver allocation. Correction of this bias by calculation of female creatinine levels using the Modification of Diet in Renal Disease (MDRD) formula has been suggested. A cohort of 639 cirrhotic candidates for first-time liver transplantation was studied. Creatinine levels were corrected for gender using the MDRD formula. The accuracy of MELD, with or without creatinine correction, to predict 3-and 6-month mortality after inclusion in a transplant waiting list was estimated. Women exhibited significantly lower creatinine levels, glomerular filtration rate, and MELD scores than men. After creatinine correction, female MELD scores had a mean increase of 1.1 points. Creatinine correction yielded an increase of 3 points in the MELD score in 15.2% of patients, 2 points in 22.4%, and 1 point in 17.6% of patients. The likelihood of death at 3 and 6 months after enrollment in the transplant waiting list was similar in males and females and the likelihood of receiving a transplant, as assessed by Kaplan-Meier survival curves, was also similar in males and females. The survival or the likelihood of receiving a transplant while on the waiting list were similar in men and women in both pre- and post-MELD eras and creatinine correction did not increase the accuracy of the MELD score in estimating 3- and 6-month mortality in female candidates for liver transplantation.


Attributable Length of Stay, Mortality Risk, and Costs of Bacterial Health Care-Associated Infections in Australia: A Retrospective Case-cohort Study.
Unbiased estimates of the health and economic impacts of health care-associated infections (HAIs) are scarce and focus largely on patients with bloodstream infections (BSIs). We sought to estimate the hospital length of stay (LOS), mortality rate, and costs of HAIs and the differential effects on patients with an antimicrobial-resistant infection. We conducted a multisite, retrospective case-cohort of all acute-care hospital admissions with a positive culture of 1 of the 5 organisms of interest (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, or Enterococcus faecium) from 1 January 2012 through 30 December 2016. Data linkage was used to generate a data set of statewide hospital admissions and pathology data. Patients with bloodstream, urinary, or respiratory tract infections were included in the analysis and matched to a sample of uninfected patients. We used multistate survival models to generate LOS, and logistic regression to derive mortality estimates. We matched 20 390 cases to 75 635 uninfected control patients. The overall incidence of infections due to the 5 studied organisms was 116.9 cases per 100 000 patient days, with E. coli urinary tract infections (UTIs) contributing the largest proportion (51 cases per 100 000 patient days). The impact of a UTI on LOS was moderate across the 5 studied pathogens. Resistance significantly increased LOS for patients with third-generation cephalosporin-resistant K. pneumoniae BSIs (extra 4.6 days) and methicillin-resistant S. aureus BSIs (extra 2.9 days). Consequently, the health-care costs of these infections were higher, compared to corresponding drug-sensitive strains. The health burden remains highest for BSIs; however, UTIs and respiratory tract infections contributed most to the health-care system expenditure.


Bacteria-based biochar as a persulfate activator to degrade organic pollutants.
Carbon-based catalysts for activating persulfate to drive advanced oxidation processes (AOPs) are widely used in wastewater treatment. In this study, Shewanella oneidensis MR-1, a typical ferric reducing electroactive microorganism, was utilized as the raw material of biochar (BC) to prepare a novel green catalyst (MBC). The effect of MBC on activating persulfate (PS) to degrade rhodamine B (RhB) was evaluated. Experimental results showed that MBC could effectively activate PS to degrade RhB to reach 91.70% within 270 min, which was 47.4% higher than that of pure strain MR-1. The increasing dosage of PS and MBC could improve the removal of RhB. Meanwhile, MBC/PS can well perform in a wide pH range, and MBC showed good stability, achieving 72.07% removal of RhB with MBC/PS after 5 cycles. Furthermore, the free radical quenching test and EPR experiments confirmed the presence of both free radical and non-free radical mechanisms in the MBC/PS system, with •OH, SO4•- and 1O2 contributing to the effective degradation of RhB. This study successfully provided a new application for bacteria to be used in the biochar field.


Semiautomated enzyme immunoassay of thyrotropin as a mass screening test for neonatal hypothyroidism.
A sensitive, simple, and rapid semiautomated sandwich enzyme immunoassay (EIA) was developed for measuring thyrotropin in dried blood samples on filter paper for use in screening for neonatal hypothyroidism. Good correlation was found between values for thyrotropin determined by this method and those determined by radioimmunoassay (RIA) (r=0.94). In pilot tests on 17,160 newborn infants in the general population, five cases of primary hypothyroidism were detected by both EIA and RIA. The recall rate was slightly highter in EIA than in RIA.


Hypothalamic pro-opiomelanocortin gene delivery ameliorates obesity and glucose intolerance in aged rats.
Age-related obesity is associated with impaired hypothalamic pro-opiomelanocortin (Pomc) gene expression. We assessed whether overproduction of POMC in the hypothalamus ameliorates age-related obesity in rats. Recombinant adeno-associated virus (rAAV) encoding Pomc (rAAV-Pomc) or control vector was delivered bilaterally into the basomedial hypothalamus of aged obese rats with coordinates targeting the arcuate nucleus. Energy balance, glucose metabolism, brown adipose tissue thermogenesis and mRNA levels of hypothalamic neuropeptides and melanocortin receptors were assessed. Forty-two days after Pomc gene delivery, hypothalamic Pomc expression increased 12-fold while agouti-related protein and neuropeptide Y mRNA levels remained unchanged. Using a punch technique, we detected the highest Pomc RNA level in the arcuate nucleus. Pomc overexpression reduced food consumption from day 10 after vector injection, but this anorexic effect abated by day 30. In contrast, there was a steady decrease in body weight without apparent attenuation. Pomc gene delivery decreased visceral adiposity and induced uncoupling protein 1 in brown adipose tissue in aged rats. Serum NEFA and triglyceride levels were also diminished by rAAV-Pomc treatment. Improved glucose metabolism and insulin sensitivity were observed on day 36 but not day 20 after Pomc gene delivery. The expression of hypothalamic melanocortin 3 and 4 receptor decreased by 17% and 25%, respectively in rAAV-Pomc rats. This study demonstrates that targeted Pomc gene therapy in the hypothalamus reduces body weight and visceral adiposity, and improves glucose and fat metabolism in aged obese rats. Thus long-term activation of the central melanocortin system may be a viable strategy to combat age-related obesity and diabetes.


A "CALL" for community-focused palliative care.
Providing interdisciplinary coordinated health and social services has a profound positive impact on patients and families facing life-threatening illness. CALL Care is a demonstration project designed to provide this type of care and bridge gaps in the existing palliative care system. The program seeks to provide care that is comprehensive, adaptable, life-affirming, and longitudinal. Hallmarks of the approach include identification and offer of assistance to those facing terminal illness as close to diagnosis as possible, periodic comprehensive assessments of the patient and family situation, coordination of health and social care services made possible by an active interdisciplinary team process with a single care coordinator, and links to community resources. This article describes the CALL Care experience, presents several case studies illustrative of the interventions and their impact, and provides recommendations for those seeking to make a similar commitment to integrated palliative care services.


Measurement of carotid plaque burden: A tool for predicting and preventing dementia?
Carotid plaque burden is a strong predictor of stroke risk, and preventing stroke reduces the risk of dementia. Treating carotid plaque burden markedly reduces the risk of stroke. Among patients age 65-80 years attending a stroke prevention clinic, we identified those with a carotid plaque burden in the top 20% of Total Plaque Area (High TPA) and the bottom 20% (Low TPA) and performed cognitive tests: The Montreal Cognitive Assessment test (MoCA), the WAIS-III Digit Symbol-Coding Test (DSST) and Trail-Making Test (TMT) part A and B. There were 31 patients recruited; 11 Low TPA (5 men) and 20 High TPA (17 men), p = 0.04. TPA was 35 ± 25 mm2 in the Low TPA vs.392 ± 169 mm2 in the High TPA group (0.0001). Patients with a high plaque burden had significantly worse performance on all the cognitive tests, all p< 0.05. A high carotid plaque burden identifies patients at risk of cognitive impairment. Because carotid plaque burden is treatable, and treating it markedly reduces the risk of stroke, we suggest that measurement of plaque burden is a useful tool for both prediction of cognitive impairment, and prevention of dementia.


Bronchodilator action of an agonist for histamine H3-receptors in guinea pig perfused bronchioles and lung parenchymal strips.
Isolated guinea pig perfused bronchioles and lung parenchymal strips were examined as an in vitro model for assessment of the direct effect of pharmacologic agents on the airway smooth muscle. The experiments were performed with a perfusion technique in bronchioles, the input pressure being measured as an index of the state of dilation, while changes in tension of the lung parenchymal strips were measured with an isometric force transducer. In both preparations, histamine and acetylcholine elicited dose-related contractile responses whereas fenoterol induced a concentration-dependent relaxation. After the 3 agonists' activities were compared in these 2 preparations, we tested the intrinsic effects of a specific H3 agonist, (R) alpha-methylhistamine ([R] alpha-MeHA). Statistical analysis was by Student's t test on the Emax (expressed as a percentage of 10(-4) M papaverine relaxation), EC50, and slopes of regression lines calculated from the concentration-response curves plotted for (R) alpha-MeHA alone or in presence of antagonists. Our results showed that (R) alpha-MeHA induced a concentration-dependent relaxation of perfused bronchioles and lung parenchymal strips competitively inhibited by 10(-7) M thioperamide (H3-antagonist), whereas 10(-5) M cimetidine (H2-antagonist) failed to prevent this effect. These results suggest the presence of H3-histaminergic dilatory receptors in the guinea pig airway.


What is the significance of the circumferential margin in locally advanced rectal cancer after neoadjuvant chemoradiotherapy?
The circumferential resection margin (CRM) is highly prognostic for local recurrence in rectal cancer surgery without neoadjuvant treatment. However, its significance in the setting of long-course neoadjuvant chemoradiotherapy (nCRT) is not well defined. Review of a single institution's prospectively maintained database from 1998 to 2007 identified 563 patients with locally advanced rectal cancer (T3/T4 and/or N1) receiving nCRT, followed after 6 weeks by total mesorectal excision (TME). Kaplan-Meier, Cox regression, and competing risk analysis were performed. The authors noted that 75 % of all patients had stage III disease as determined by endorectal ultrasound (ERUS) and/or magnetic resonance imaging (MRI). With median follow-up of 39 months after resection, local and distant relapse were noted in 12 (2.1 %) and 98 (17.4 %) patients, respectively. On competing risk analysis, the optimal cutoff point of CRM was 1 mm for local recurrence and 2 mm for distant metastasis. Factors independently associated with local recurrence included CRM ≤1 mm, and high-grade tumor (p = 0.012 and 0.007, respectively). CRM ≤2 mm, as well as pathological, nodal, and overall tumor stage are also significant independent risk factors for distant metastasis (p = 0.025, 0.010, and <0.001, respectively). In this dataset of locally advanced rectal cancer treated with nCRT followed by TME, CRM ≤1 mm is an independent risk factor for local recurrence and is considered a positive margin. CRM ≤2 mm was associated with distant recurrence, independent of pathological tumor and nodal stage.


Substitution treatment in the era of "recovery": An analysis of stakeholder roles and policy windows in Britain.
Based on documentary analyses and interviews with twenty key informants in 2012, this paper analyses the shift in British drugs policy towards "recovery" from the perspectives of major stakeholders. The processes involved in reopening the debate surrounding the role of substitution treatment and its re-emergence on to the policy agenda are examined. Drawing on Kingdon's work on agenda-setting, the ways in which methadone maintenance was challenged and defended by key stakeholders in the initial phase of policy development and the negotiation of a "recovery" focus as the organizing concept for British drugs policy are explored. Study limitations are noted.


The Impact of Bariatric Surgery on the Incidence of Colorectal Cancer in Patients with Obesity-a Systematic Review and Meta-analysis of Registry Data.
Cancer and obesity represent two of the most significant global health concerns. The risk of malignancy, including colorectal cancer (CRC), increases with obesity. The aim of this study was to perform a systematic review and meta-analysis to determine the value of bariatric surgery in reducing CRC risk in patients with obesity using registry data. A systematic review and meta-analysis were performed as per PRISMA guidelines. The risk of CRC was expressed as a dichotomous variable and reported as odds ratios (OR) with 95% confidence intervals (CIs) using the Mantel-Haenszel method. A multi-treatment comparison was performed, examining the risk reduction associated with existing bariatric surgery techniques. Analysis was performed using RevMan, R packages, and Shiny. Data from 11 registries including 6,214,682 patients with obesity were analyzed. Of these, 14.0% underwent bariatric surgery (872,499/6,214,682), and 86.0% did not undergo surgery (5,432,183/6,214,682). The mean age was 49.8 years, and mean follow-up was 5.1 years. In total, 0.6% of patients who underwent bariatric surgery developed CRC (4,843/872,499), as did 1.0% of unoperated patients with obesity (54,721/5,432,183). Patients with obesity who underwent bariatric surgery were less likely to develop CRC (OR: 0.53, 95% CI: 0.36-0.77, P < 0.001, I2 = 99%). Patients with obesity undergoing gastric bypass surgery (GB) (OR: 0.513, 95% CI: 0.336-0.818) and sleeve gastrectomy (SG) (OR: 0.484, 95% CI: 0.307-0.763) were less likely to develop CRC than unoperated patients. At a population level, bariatric surgery is associated with reduced CRC risk in patients with obesity. GB and SG are associated with the most significant reduction in CRC risk. CRD42022313280.


Genotoxic studies in hypertensive and normotensive rats treated with amiodarone.
Amiodarone, a benzofuran derivative, is a very effective antiarrhythmic medication, but has potential to cause side effects. Although its cytotoxicity potential is very well-known, there are few reports about its genotoxicity effects. Since amiodarone has not been investigated in genotoxicity studies, and the spontaneously hypertensive rat (SHR) is a well-characterized model for hypertension, the aim of the present study was to perform cytogenetic analysis on chromosome aberrations in bone marrow cells of SHRs and normotensive Wistar-Kyoto rats (WKYs) that received oral amiodarone treatment for 4 weeks. Amiodarone activity was also monitored using electrocardiograms. The presence of bradycardia in amiodarone-treated rats confirmed that this drug was really active. Metaphase analysis on bone marrow cells showed that there were significant differences in total chromosomal damage and percentage abnormal metaphase between WKY and SHR negative controls. In the SHR negative control, the frequencies of basal chromosomal aberrations and abnormal metaphases were significantly higher (p<0.05). There were high numbers of chromosomal aberrations in all amiodarone-treated groups, compared with negative controls. In amiodarone-treated groups, the most frequent chromosomal aberration was chromatid breaks. More chromosomal aberrations were found in WKYs that received amiodarone, with a statistically significant difference in comparison with negative controls (p<0.05). However, in SHR rats there was no significant difference between the amiodarone and negative groups regarding chromosomal damage induction. These results showed that treatment with amiodarone was genotoxic in WKYs, but not in SHRs. Further studies are needed to confirm whether amiodarone is genotoxic or efficient and harmless, among humans undergoing therapy.


Worms, wisdom, and wealth: why deworming can make economic sense.
For those of us who have had worms, getting rid of them seems a good idea, and multiple studies demonstrate the simplicity and benefit of deworming children. In the past decade or so, there has been a dramatic increase in efforts to provide inexpensive deworming medications, but at the same time there have been calls to re-evaluate the impact of deworming programs. In this review, we examine the history of deworming and explore the evidence for effects of deworming on health, on child development, and on economic returns. Important policy conclusions include that a paucity of randomized trial data suggesting benefit does not equate to a lack of benefit and that a greater emphasis on documenting such benefit should be pursued.


[Anatomical double-bundle reconstruction of the medial patellofemoral ligament with a gracilis autograft].
Elimination of patellofemoral instability by reconstruction of the medial patellofemoral ligament (MPFL) with a gracilis autograft. Recurring lateral luxation and subluxation of the patella, tibial tuberosity-trochlear groove distance (TTTG) < 20 mm, persistent positive apprehension test in up to 45° of flexion, low grade trochlear dysplasia. Traumatic luxation of the patella without anatomical risk factors, isolated treatment if TTTG > 20 mm, and isolated treatment for high-grade trochlear dysplasia (type B, C, D). Supine postion. Stripping of the gracilis tendon. Drilling of two tunnels into the medial margin of the patella. Insertion of both tendon ends into the tunnels and fixation with resorbable screwlocks. Undermining of the fascia of the medial oblique vastus muscle and insertion of the tendon loop into the femoral point of insertion located at the medial epicondyle. Preparation of the femoral point of insertion and drilling of the femoral tunnel. Insertion of the graft into the femoral tunnel. Positioning of the knee in 30° of flexion. Positioning of the patella and fixation of the graft with a resorbable screw. Two weeks of partial weight bearing. Knee orthesis for 6 weeks. Passive motion up to 60° of flexion for the first 2 weeks. Three weeks postoperatively unrestricted motion exercises, strengthening of the quadriceps muscle. Unlimited activity is possible 3 months postoperatively. The method presented in this manuscript was performed on 32 patients with recurring patellar luxation; 27 patients were available for clinical assessment at 1 year postoperatively. There were no recorded events of reluxation; the Kujala score increased on average from 61 points preoperatively to 93 points postoperatively.


Prolonged exposure to tyrosine kinase inhibitors or early use of everolimus in metastatic renal cell carcinoma: are the two options alike?
We retrospectively analyzed metastatic renal cell carcinoma (RCC) patients treated with 3 targeted agents. Patients started the sequence with a tyrosine kinase inhibitor (TKI), sunitinib or sorafenib, and were divided into 2 groups based on the order in which they received the other reciprocal TKI and everolimus (EVE): TKI-TKI-EVE group (n = 19) and TKI-EVE-TKI group (n = 14). Median progression-free survival (PFS) with first TKI was 13 months in the TKI-TKI-EVE group and 10 months in the TKI-EVE-TKI group. PFS with the second agent showed a trend in favor of the TKI-TKI-EVE sequence, with a median of 11 versus 6.5 months, whereas median PFS with the third agent was 6 months in both groups. Total PFS also showed a trend in favor of the TKI-TKI-EVE sequence with a median of 31 versus 23 months. Median overall survival (OS) was 38 months in both groups, with more patients receiving subsequent treatment in the TKI-EVE-TKI group. The subgroup of patients no long-term responders (≤9 months) to first TKI showed similar outcomes irrespective of the sequence. The subgroup of long-term responders to first TKI (>9 months) who received the other TKI instead of EVE had better outcomes in terms of median PFS with the second agent (13 vs. 5.5 months; p = 0.0271), median total PFS (39.5 vs. 23.5 months; p = 0.0415), and median OS (46 vs. 38 months). In conclusion, no apparent advantage was observed with early use of EVE in advanced RCC, even in those patients who did not benefit long from first-line TKI, whereas long-term duration of first-line TKI seems to be predictor of second-line TKI efficacy.


Traffic police officers' use of first aid skills at work: a qualitative content analysis of focus group discussions in Dar Es Salaam, Tanzania.
The World Health Organisation (WHO) recommends involving lay people in prehospital care. Several training programmes have been implemented to build lay responder first aid skills. Findings show that most programmes significantly improved participants' first aid skills. However, there is a gap in knowledge of what factors influence the use of these skills in real situations. The current study aimed to describe police officers' views on and experiences of factors that facilitate or hinder their use of trained first aid skills at work. Thirty-four police officers participated in five focus group discussions. A structured interview guide was used to collect data. Interviews were audio-recorded and transcribed verbatim. Data were analysed using qualitative content analysis. We identified five categories of facilitators or hindrances. Training exposure was considered a facilitator; work situation and hospital atmosphere were considered hindrances; and the physical and social environments and the resources available for providing first aid could be either facilitators or hindrances. Practical exposure during training is perceived to improve police officers' confidence in applying their first aid skills at work. However, contextual factors related to the working environment need to be addressed to promote this transfer of skills.


Uptake, transport and accumulation of micro- and nano-plastics in terrestrial plants and health risk associated with their transfer to food chain - A mini review.
Waste plastics enter the environment (water, soil, and atmosphere) and degrade into micro- and nano-plastics (MNPs) through physical, chemical, or biological processes. MNPs are ubiquitous in the environment and inevitably interact with terrestrial plants. Terrestrial plants have become important potential sinks, and subsequently, the sources of MNPs. At present, many studies have reported the effects of MNPs on plant physiology, biochemistry, and their phototoxicity. However, the source, detection method, and the absorption process of MNPs in terrestrial plants have not been systematically studied. In order to better understand the continuous process of MNPs entering terrestrial plants, this review introduces the sources and analysis methods of MNPs in terrestrial plants. The uptake pathways of MNPs in terrestrial plants and their influencing factors were systematically summarized. Meanwhile, the transport pathways and the accumulation of MNPs in different plant organs (roots, stems, leaves, calyxes, and fruits) were explored. Finally, the transfer of MNPs through food chains to humans and their health risks were discussed. The aim of this work is to provide significant theoretical knowledge to understand the uptake, transport, and accumulation of MNPs in terrestrial plants and the potential health risks associated with their transfer to humans through food chain.


A unique VP4 gene allele carried by an unusual bovine rotavirus strain, 993/83.
The VP4 protein of an unusual group A calf rotavirus strain, 993/83 (serotype G7 and subgroup non-I and non-II), was determined to contain 770 amino acids, shorter than any other VP4 proteins sequenced to date. The 993/83 VP4 exhibited only 55-62% amino acid identity to the VP4s of the representatives of 12 distinct P serotypes, suggesting that 993/83 VP4 represents a new P serotype.


Enhancement of the spectral broadening efficiency for circular polarization states in the high absorption regime for Gaussian and doughnut-shaped beams in fused silica.
We experimentally investigate the spectral broadening in fused silica in the multiphoton absorption regime. Under standard conditions of laser irradiation, linear polarization of laser pulses is more advantageous for supercontinuum generation. However, with high non-linear absorption, we observe more efficient spectral broadening for circular polarizations for both Gaussian and doughnut-shaped beams. The multiphoton absorption in fused silica is studied by measuring the total transmission of laser pulses and by the intensity dependence of the self-trapped exciton luminescence observation. The strong polarization dependence of multiphoton transitions fundamentally affects the broadening of the spectrum in solids.


Weight development from age 13 to 30 years and adolescent socioeconomic status: The Norwegian Longitudinal Health Behaviour study.
To describe the weight development and model change in body mass index (BMI), and to examine the association of adolescent socioeconomic status (SES) with change in BMI distribution in a cohort followed from adolescence through adulthood. Participants (n = 924) from western Norway were surveyed seven times from age 13 to 30 (1990-2007). BMI was based on self-reported height and weight. Quantile regression analyses were used to model change in weight development and to investigate associations between SES (measured by parental education) and change in BMI distribution. The analyses were adjusted for curvilinearity in BMI development, gender and relevant health behaviours. Body mass index increased over time with the greatest increase in the 90th percentile. No significant associations between change in BMI and SES were observed at any of the percentiles (10th, 25th, 50th, 75th or 90th). Those in the upper BMI percentile gained more weight than those in the lower percentiles indicating that these might need targeted interventions. Further investigation of the association of change in BMI and SES with better quality data might be warranted.


Repeated in vitro fertilization cycle attempts in patients undergoing controlled ovarian hyperstimulation with use of gonadotropin-releasing hormone antagonists.
To examine pregnancy rate in patients undergoing controlled ovarian hyperstimulation (COH) with use of multidose GnRH antagonists in multiple repeated IVF cycle attempts, we conducted a survey in 785 consecutive IVF cycles in our unit. Although pregnancy rate significantly decreased beyond the second IVF cycle attempt, no significant decrease was noted between cycle attempts 3 and 4 and 5 to 8.


Optic Nerve Enhancement and Restricted Diffusion in Postoperative Visual Loss.
Postoperative visual loss is rare and most often due to posterior ischemic optic neuropathy. We describe optic nerve MR imaging of a 37-year-old man with postoperative visual loss due to posterior ischemic optic neuropathy after complicated aortic aneurysm surgery. MR demonstrated restricted diffusion and focal enhancement of both optic nerves. Combined restricted diffusion and focal enhancement is a unique MR imaging feature with postoperative vision loss.


The MOVE study: a study protocol for a randomised controlled trial assessing interventions to maximise attendance at physical activity facilities.
Physical activity is associated with a host of health benefits, yet many individuals do not perform sufficient physical activity to realise these benefits. One approach to rectifying this situation is through modifying the built environment to make it more conducive to physical activity, such as by building walking tracks or recreational physical activity facilities. Often, however, modifications to the built environment are not connected to efforts aimed at encouraging their use. The purpose of the Monitoring and Observing the Value of Exercise (MOVE) study is to evaluate the effectiveness of two interventions designed to encourage the ongoing use of a new, multi-purpose, community-based physical activity facility. A two-year, randomised controlled trial with yearly survey points (baseline, 12 months follow-up, 24 months follow-up) will be conducted among 1,300 physically inactive adult participants aged 18-70 years. Participants will be randomly assigned to one of three groups: control, intervention 1 (attendance incentives), or intervention 2 (attendance incentives and tailored support following a model based on customer relationship management). Primary outcome measures will include facility usage, physical activity participation, mental and physical wellbeing, community connectedness, social capital, friendship, and social support. Secondary outcome measures will include stages of change for facility usage and social cognitive decision-making variables. This study will assess whether customer relationship management systems, a tool commonly used in commercial marketing settings, can encourage the ongoing use of a physical activity facility. Findings may also indicate the population segments among which the use of such systems are most effective, as well as their cost-effectiveness. Australian New Zealand Clinical Trials Registry: ACTRN12615000012572 (registered 9 January 2015).


Dorsally recumbent male equine urogenital endoscopic surgery.
Possibly no other development has revolutionized general surgery more dramatically than laparoscopic surgery in human patients. The development of instrumentation suitable for use in horses has allowed the veterinary surgeon to begin to introduce minimally invasive procedures. Clearly, in people, one of the greatest benefits is reduced patient morbidity and earlier return to function. The author's experience with laparoscopic procedures in the horse would tend to reinforce those observations. The most significant obstacle to widespread acceptance of minimally invasive surgery in the horse is possibly the veterinarian's reluctance to expend the funds necessary to purchase the necessary equipment as well as a hesitancy to abandon time-honored approaches to common surgical conditions. As a profession, veterinarians have been criticized for undervaluing their own services. Clearly, these new minimally invasive procedures can be successfully marketed if the advantages of the approaches in terms of patient well-being are impressed on the client.


p53 gene mutations in early colorectal carcinoma. De novo vs. adenoma-carcinoma sequence.
p53 gene mutations in early and advanced colorectal cancer were detected by PCR-SSCP analysis. Early colorectal cancer was classified into de novo cancer and polyp-forming cancer, respectively, according to morphology and presence of adenomatous components. A total of 94 paraffin-embedded tissue specimens from patients with colorectal cancer were analysed. p53 gene mutations were detected in 40.0% (12/30) of de novo cancer, 36.7% (11/30) of polyp-forming cancer, and 44% (15/34) of advanced cancer. p53 mutations were detected at a high frequency in both types of early colorectal cancer as well as in advanced cancer. No correlations were found between p53 mutations and clinicopathological data. Our data suggest that the p53 gene mutations occurred in the early colorectal cancer stage of carcinogenesis regardless of the pathway.


Vitamin E reverses multidrug resistance in vitro and in vivo.
Multidrug resistance (MDR) is a major obstacle to successful and effective chemotherapeutic treatments of cancers. This study explored the reversal effects of vitamin E on MDR tumor cells in vitro and in vivo, elucidating the potential mechanism of this reversal. VE at a concentration of 50 μM exhibited a significant reversal of the MDR effect (compared to only PTX in DMSO, p<0.05) in two human MDR cell lines (H460/taxR and KB-8-5). The MDR cell xenograft model was established to investigate the effect of VE on reversing MDR in vivo. Mice intravenously injected with Taxol (10 mg/kg) with VE (500 mg/kg, IP) showed an ability to overcome the MDR. VE and its derivatives can significantly increase intracellular accumulation of rhodamine 123 and doxorubicin (P-gp substrate), but not alter the levels of P-gp expression. These treatments also did not decrease the levels of intracellular ATP, but were still able to inhibit the verapamil-induced ATPase activity of P-gp. The new application of VE as an MDR sensitizer will be attractive due to the safety of this treatment.


Germline-specific H1 variants: the "sexy" linker histones.
The eukaryotic genome is packed into chromatin, a nucleoprotein complex mainly formed by the interaction of DNA with the abundant basic histone proteins. The fundamental structural and functional subunit of chromatin is the nucleosome core particle, which is composed by 146 bp of DNA wrapped around an octameric protein complex formed by two copies of each core histone H2A, H2B, H3, and H4. In addition, although not an intrinsic component of the nucleosome core particle, linker histone H1 directly interacts with it in a monomeric form. Histone H1 binds nucleosomes near the exit/entry sites of linker DNA, determines nucleosome repeat length and stabilizes higher-order organization of nucleosomes into the ∼30 nm chromatin fiber. In comparison to core histones, histone H1 is less well conserved through evolution. Furthermore, histone H1 composition in metazoans is generally complex with most species containing multiple variants that play redundant as well as specific functions. In this regard, a characteristic feature is the presence of specific H1 variants that replace somatic H1s in the germline and during early embryogenesis. In this review, we summarize our current knowledge about their structural and functional properties.


Evolutionary dynamics of collective action when individual fitness derives from group decisions taken in the past.
Many actions take some time to have an impact - their effects only appear at some point in the future. Such time lags turn out to be ubiquitous among living organisms. Here we study the impact of time lags in the evolutionary dynamics of cooperative collective action. We consider a population in which individuals interact via a N-Person Stag Hunt dilemma and must opt to cooperate or defect. In the absence of any delay, the replicator dynamics reveals the existence of regimes in which two internal fixed points appear simultaneously. We show that the presence of time delay in the fitness of individuals leads to a delayed replicator equation exhibiting new evolutionary profiles, each profile being separated by critical values of the delay that we determine explicitly. When we break the symmetry in the time lags, we show that, generally, defectors take more advantage from delay than cooperators. Finally, when we take into consideration, approximately, effects associated with the finite population size, we find that counter-intuitive evolutionary outcomes may occur, resulting from the interplay between delay and the basins of attraction in the neighborhood of the internal fixed-points, and which may lead to full cooperation in conditions under which the outcome would be Full Defection in infinite populations.


Visual complications after stent-assisted endovascular embolization of paraophthalmic and suprasellar variant superior hypophyseal aneurysms: the Duke Cerebrovascular Center experience in 57 patients.
To review retrospectively experience with stent-assisted coiling of ophthalmic segment internal carotid artery (ICA) aneurysms to report outcome data and identify the rate of associated visual complications. The Duke endovascular database was retrospectively reviewed to identify all ICA aneurysms treated with stent-assisted embolization between November 2002 and October 2009. Only aneurysms arising from the ophthalmic segment of the ICA and originating from the paraophthalmic or suprasellar variant superior hypophyseal artery were included. These aneurysms have the potential to create visual disturbances related to mass effect on the optic nerve or chiasm or to disrupt the ophthalmic artery. Chart review was performed to obtain clinical information, immediate incidence, and follow-up of aneurysm remnants and any visual complications. There were 63 aneurysms (48 paraophthalmic and 15 suprasellar variant superior hypophyseal) identified in 57 patients. The ophthalmic artery was preserved in all but two (3.5%) cases, neither of which resulted in visual deficits. One (1.8%) patient experienced transient acute visual disturbances, and two (3.5%) patients had delayed, persistent deficits. Stent-assisted embolization of ophthalmic segment ICA aneurysms is technically achievable and in our series did not appear to result in increased visual complications compared with coil embolization alone or surgical treatment.


Structure-function relationships in rat brainstem subnucleus interpolaris: IV. Projection neurons.
In a companion paper (Jacquin et al., '89), the structure and function of local circuit (LC) neurons in spinal trigeminal (V) subnucleus interpolaris (Sp Vi) were described. The present report provides similar data for 44 projection neurons in Sp Vi. Of these, 25 thalamic, 16 cerebellar, 2 superior collicular, and 1 inferior olivary projecting neurons were studied. The majority responded to vibrissa(e) deflection, and all except 4 of these had multivibrissae receptive fields. The remainder were responsive to either guard hair deflection or indentation of glabrous skin. Latencies to V ganglion shocks were suggestive of monosynaptic activation from the periphery. Sp Vi projection neurons were topographically organized in a manner consistent with that of their primary afferent inputs. Nonvibrissa sensitive cells had diverse morphologies. Morphometric analyses of the more heavily sampled thalamic and cerebellar projecting, vibrissa(e)-sensitive cells indicated the following. (1) As compared to LC neurons, projection neurons had bigger receptive fields, cell bodies, dendritic trees, and axons; less circular dendritic trees; a greater preponderance of spiny dendrites and fewer axon collaterals in Sp Vi. (2) Dendritic tree extent correlated significantly with receptive field size, thus suggesting that dendritic tree size is one mechanism contributing to receptive field size in vibrissae-sensitive projection neurons. (3) V thalamic cells had significantly bigger receptive fields and dendritic trees, and also give off more local axon collaterals, than V cerebellar neurons. Collicular and inferior olivary projecting neurons shared structural and functional attributes with other Sp Vi long-range projecting cells. Structure-function relationships exist for vibrissa-sensitive projection neurons in Sp Vi. The relevant parameters correlating with projection neuron morphology are receptive field size and projection status, whereas for Sp Vi LC neurons the relevant correlative parameter is peripheral receptor association.


[Clinical aspects of patients with macrofocal myocardial infarction with a complicated or uncomplicated course].
The clinical manifestations and parameters of the laboratory and biochemical diagnosis of uncomplicated and the healing course of complicated myocardial infarction were studied. Substantiation has been provided for recognition of patients with hypo- and hyper-reactive myocardial infarction.


Structural features in the NH2-terminal region of a model eukaryotic signal peptide influence the site of its cleavage by signal peptidase.
The 20-amino acid signal peptide of human pre (delta pro)apolipoprotein A-II contains the tripartite domain structure typical of eukaryotic prepeptides, i.e. a positively charged NH2-terminal (n) region, a hydrophobic core (h) region, and a COOH-terminal polar domain (c region). This signal sequence has multiple potential sites for cotranslational processing making it an attractive model for assessing the consequences of systematic structural alterations on the site selected for signal peptidase cleavage. We previously analyzed 40 mutant derivatives of this model preprotein using an in vitro translation/canine microsome processing assay. The results showed that the position of the boundary between the h and c regions and properties of the -1 residue are critical in defining the site of cotranslational cleavage. To investigate whether structural features in the NH2-terminal region of signal peptides play a role in cleavage specificity, we have now inserted various amino acids between the positively charged n region (NH2-Met-Lys) and the h region of a "parental" pre(delta pro)apoA-II mutant that has roughly equal cleavage between Gly18 decreases and Gly20 decreases. Movement of the n/h boundary toward the NH2 terminus results in a dramatic shift in cleavage to Gly18 decreases. Replacement of the Lys2 residue with hydrophilic, negatively charged residues preserves the original sites of cleavage. Replacement with a hydrophobic residue causes cleavage to shift "upstream." Simultaneous alteration of the position of n/h and h/c boundaries has an additive effect on the site of signal peptidase cleavage. None of these mutations produced a marked decrease in the efficiency of in vitro cotranslational translocation or cleavage. However, in sequence contexts having poor signal function, introduction of hydrophobic residues between the n and h regions markedly improved the efficiency of translocation/processing. We conclude that the position of the n/h boundary as well as positioning of the h/c boundary affects the site of cleavage chosen by signal peptidase.


[Control of postoperative hemorrhage in isolated coronary bypass surgery: comparison of tranexamic acid effects in off-pump surgery with aprotinin effects in conventional surgery].
In spite of the strong criticism elicited thereafter, the results of a multicentric study on the consequences of several perioperative anti-hemorrhagic strategies in cardiac surgery, published five years ago, led to the aprotinin (Aprot) withdrawal from the market and its progressive replacement by tranexamic acid (TrAc) in many surgical departments. To evaluate the hemostatic effects and clinical consequences of TrAc use or non-use in off-pump coronary bypass surgery (CABG) and compare them with those of Aprot use or non-use in conventional (conv) CABG. Retrospective analysis of 2 groups (Gr) of patients (pts): GrA - 252 pts undergoing isolated conv CABG (GrA1 - 185 pts submitted to an intra-operative full-dose Aprot protocol; GrA2 - 67 pts operated without Aprot); GrB - 383 pts undergoing isolated off-pump CABG (GrB1 - 136 pts submitted to an intra-operative low-dose TrAc protocol; GrB2 - 247 pts operated in absence of TrAc). Pre-operative clinical characteristics (GrA1 vs GrA2, GrB1 vs GrB2): mean age (years) - 65 vs 64 (NS), 64 vs 64; female gender - 20% vs 21% (NS), 23% vs 20% (NS); logistic Euroscore - 5.1% vs 6.2% (NS), 6.3% vs 5.5% (NS); chronic renal failure - 21% vs 27% (NS), 27% vs 25% (NS); diffuse coronary artery disease - 34% vs 42% (NS), 36% vs 30% (NS); pre-operative betablocker treatment - 64% vs 55% (NS), 74% vs 71% (NS); statin therapy for > 3 months - 78% vs 82% (NS), 81% vs 85% (NS). Pts have been operated by 4 surgeons largely experienced in both CABG modalities. Antiplatelet therapy was stopped => 4 days prior to surgery (but aspirin was maintained in high-risk pts). Results (GrA1 vs GrA2, GrB1 vs GrB2): 1) Bleeding (mL/pt - mean): 783 vs 1375 (p < 0.001), 1061 vs 1368 (p < 0.001); blood loss > 1500 mL (%pts) - 5.4% vs 34% (p < 0.0001), 12% vs 28% (p < 0.001); surgical re-exploration for bleeding - 1.1% vs 3.0% (NS), 2.2% vs 2.0% (NS). 2) Transfusion of blood products (U/pt - mean): plasma - 0.56 vs 2.19 (p < 0.001), 1.45 vs 1.03 (p < 0.05); platelets - 0.09 vs 0.22 (p < 0.02), 0.24 vs 0.15 (NS). 3) Renal function (%pts): increased serum cre- atinine - 56% vs 56%, 55% vs 38% (p < 0.001); hemofiltration use - 1.1% vs 1.5% (NS), 1.5% vs 0.4% (NS). 4) Perioperative myocardial infarction - 21.6% vs 17.9% (NS), 17.6% vs 14.6% (NS); other ischemic events - 3.2% vs 3.0% (NS), 1.5% vs 1.2% (NS). 5) Hospital mortality: 4.8% vs 4.5% (NS), 4.4% vs 1.6% (NS). 1) TrAc does not reduce the risk of surgical re-exploration for bleeding. 2) Taking into account the differences between conv CABG and off-pump CABG, TrAc hemostatic effect seems to be inferior to that of Aprot, without offering a better safety profile in terms of lesser renal or ischemic risk as a counterpart.


Protist.guru: A Comparative Transcriptomics Database for Protists.
During the last few decades, the study of microbial ecology has been enabled by molecular and genomic data. DNA sequencing has revealed the surprising extent of microbial diversity and how microbial processes run global ecosystems. However, significant gaps in our understanding of the microbial world remain, and one example is that microbial eukaryotes, or protists, are still largely neglected. To address this gap, we used gene expression data from 17 protist species to create protist.guru: an online database equipped with tools for identifying co-expressed genes, gene families, and co-expression clusters enriched for specific biological functions. Here, we show how our database can be used to reveal genes involved in essential pathways, such as the synthesis of secondary carotenoids in Haematococcus lacustris. We expect protist.guru to serve as a valuable resource for protistologists, as well as a catalyst for discoveries and new insights into the biological processes of microbial eukaryotes. AVAILABILITY: The database and co-expression networks are freely available from http://protist.guru/. The expression matrices and sample annotations are found in the supplementary data.


Profiles of motor and cognitive impairment in the transgenic rat model of Huntington's disease.
The transgenic Huntington's disease (tgHD) rat strain provides a well regarded transgenic animal model of Huntington's disease, offering the prospect for a more detailed functional analysis in rats, along with neurological and therapeutic interventions, than is possible in the more widely available mouse models. In the present experiments, we compare the performance of heterozygous and homozygous tgHD rats against wildtype littermates on a range of motor and cognitive assessments in five separate cohorts of rats between 8 and 22 months of age. Male but not female heterozygous tgHD rats exhibit modest motor deficits in rotarod and staircase reaching tests, whereas most cognitive tests (including object recognition, exploration of novelty, delayed alternation, choice reaction time, and serial implicit learning tasks) revealed at best small or inconsistent deficits, in homozygous as well as heterozygous animals, up to 22 months of age. Thus, although we have observed modest but clear-cut deficits in motor phenotype, with a sex difference in line with previous reports, we have not established a robust cognitive impairment in this strain on a range of tasks sensitive to frontostriatal function, as required for testing novel (symptomatic, protective or reparative) therapeutics in a robust, valid, animal model of human Huntington's disease.