Growth hormone status in morbidly obese subjects and correlation with body composition.
Morbidly obese subjects are characterized by multiple endocrine abnormalities and these are paralleled by unfavorable changes in body composition. In obese individuals, either 24-h spontaneous or stimulated GH secretion is impaired without an organic pituitary disease and the severity of the secretory defect is proportional to the degree of obesity. The GHRH+arginine (GHRH+ARG) test is likely to be the overall test of choice in clinical practice to differentiate GH deficiency (GHD) patients. Similarly to other provocative tests, GHRH+ARG is influenced by obesity per se. Therefore, a new cut-off limit of peak GH response of 4.2 microg/l in obese subjects has been recently assumed. The aim of the present study was to investigate the reciprocal influence between decreased GH secretion and body composition in a group of 110 morbidly obese subjects, using the new cut-off limit of peak GH response to GHRH+ARG test for these subjects. In our study, GHD was identified in 27.3% of the obese subjects, without gender difference. In GDH obese subjects body mass index (BMI), waist circumference, waist-to-hip ratio (WHR), fat mass (FM), and resistance (R) were higher while reactance (Xc), phase angle, body cell mass (BCM), IGF-I, or IGF-I z-scores were lower than in normal responders (p<0.001). In all obese subjects, GH peak levels showed a negative correlation with age, BMI, waist circumference and FM, and a positive correlation with IGF-I. In the stepwise multiple linear regression, waist circumference and FM were the major determinants of GH peak levels and IGF-I. In conclusion, using the new cut-off limit of peak GH response to GHRH+ARG test for obese subjects, about 1/3 morbidly obese subjects were GHD. GHD subjects showed a significantly different body composition compared with normal responders, and the secretory defect was correlated to different anthropometric variables with waist circumference and FM as the major determinants.


High incidence of severe neutropenia after gemcitabine-based chemotherapy in Chinese cancer patients with CDA 79A>C mutation.
Cytidine deaminase (CDA) is a crucial enzyme in gemcitabine inactivation. Mutations in CDA gene have been found to influence the activity of CDA enzyme, which might lead to altered pharmacokinetics profile and clinical outcome of gemcitabine. In this study, the screening for the presence of CDA 79A>C and CDA 208G>A was performed by allele-specific PCR and restriction fragment length polymorphism, respectively. No difference in CDA allele frequencies was found between Chinese cancer patients and healthy volunteers. The frequencies for CDA 79A>C and 208G>A in the studied population were 12.2% and 1.0%, respectively. While a high incidence of grade 3-4 neutropenia was noted as 5 out of 8 (62.5%) patients heterozygous or homozygous for CDA 79A>C mutation developed it, in patients homozygous for the wild-type allele, the incidence was only 17.2% (5 out of 29) (p=0.021). Our study suggests that CDA 79A>C mutation might be a potential risk factor of gemcitabine-induced neutropenia toxicity.


Alleviating suffering of individuals with multimorbidity and complex needs: A descriptive qualitative study.
Individuals living with multimorbidity and/or mental health issues, low education, socioeconomic status, and polypharmacy are often called complex patients. The complexity of their health and social care needs can make them prone to disease burden and suffering. Therefore, they frequently access health care services to seek guidance for managing their illness and suffering. The aim of this research was to describe the approaches used by nurses to alleviate the suffering of individuals with multimorbidity and complex needs in acute care settings. A qualitative descriptive approach. Semi-structured interviews were conducted with 19 nurses working in general, medical-surgical, specialized, and intensive care settings across five hospitals in Pakistan. Reflexive thematic analysis was used for analysis. Ethical approval was obtained from the Ethical Committee of Al-Nafees Medical College Islamabad, Pakistan. Four themes were generated: Deeper Exploration of Patients' Health-Illness Situation and Complexity, Prioritizing Patient Psychosocial and Emotional Needs, Instilling Hope and Encouragement in Patients, and Creating a Comforting Environment to Foster Sharing of felt needs. Nurses emphasized the need of deeper inquiry into patients illness situation and complexity to discern the impact of determinants on their well-being and develop care plans that are tailored to address psychosocial, emotional, and physical suffering of this patient population. Alleviation of patient suffering is integral to compassionate nursing care. Nurses use a multifaceted approach entailing sensitive understanding, recognizing sociocultural and structural determinants impact on patient situation, and individual and interdisciplinary altruistic actions to alleviate patient suffering.


Trabecular bone scores and lumbar spine bone mineral density of US adults: comparison of relationships with demographic and body size variables.
This study examines demographic patterns and body size relationships in trabecular bone score and lumbar spine BMD of US adults from NHANES 2005-2008. Limited data exist on demographic and body size relationships for trabecular bone score (TBS), a new variable derived from bone texture analysis of lumbar spine dual-energy X-ray absorptiometry (DXA) scans. This study compares demographic patterns and correlations with body size (body mass index (BMI), weight, waist circumference, total body fat, trunk fat, trunk lean) between TBS and lumbar spine bone mineral density (LSBMD) for adults age ≥20 years from the National Health and Nutrition Examination Survey (NHANES) 2005-2008 with BMI in the optimal range for TBS (15-37 kg/m(2)). LSBMD, TBS, body fat, and lean were obtained by DXA. Weight, height, and waist circumference were measured. BMI was calculated from height and weight. Sex differences in TBS varied by age and race/ethnicity (p sex X age interaction and p sex X race/ethnicity interaction < 0.001). In most of the nine demographic subgroups examined, TBS did not differ by sex (four subgroups) or was significantly higher in women (three subgroups). TBS differences by race/ethnicity were inconsistent in men; in women, non-Hispanic whites (NHWs) had higher TBS than non-Hispanic blacks (NHBs) or Mexican Americans (MAs) in all age groups. In contrast, LSBMD was either significantly higher in men (five subgroups) or did not differ by sex (four subgroups). Race/ethnic differences in LSBMD were consistent across age and sex (NHB > NHW > MA). All body size variables were negatively related to TBS but positively related to LSBMD. Demographic patterns and body size relationships differed between TBS and LSBMD.


Increased intracranial hemorrhage of mechanical thrombectomy in acute ischemic stroke patients with atrial fibrillation.
The impact of atrial fibrillation (AF) on outcomes of mechanical thrombectomy (MT) for acute ischemic stroke (AIS) is controversial, and with a paucity of evidence base. This study aimed to investigate the potential association between AF and outcomes after MT in AIS patients. A post-hoc analysis of a multi-center prospective clinical trial was conducted. Before and after propensity score matching (PSM), the clinical features were compared between patients with and without AF. Multivariable logistic regression and mediation analyses were performed to assess the relationship between AF and ICH. Of the total 245 patients, 123 patients were included in the AF group. After PSM, the AF group showed more retrieval attempts (P = 0.004), comparable favorable outcome (P = 0.493), and mortality (P = 0.362) at 90 days. Multivariate analysis revealed that AF was significantly associated with increased risk for ICH (OR 2.198; 95%CI 1.099-4.395; P = 0.026). INR and retrieval attempts were found to act as partial mediations. In the subgroup with lower INR, AF still had a significant association with ICH (OR 2.496; 95%CI 1.331-4.679; P = 0.004). In AIS patients undergoing MT, AF was associated with more retrieval attempts and higher risk of any ICH. Of note, the effect of AF on the increased risk of ICH was partly attributable to the adjusted anticoagulation status and more retrieval attempts. It is crucial to elaborately prevent ICH after thrombectomy for stroke patients with AF.


Inhibition of IgE binding to mast cells and basophils by monoclonal antibodies to murine IgE.
In an attempt to identify the site on IgE which binds with high affinity to the Fc epsilon receptor (Fc epsilon R) on mast cells, we established monoclonal anti-IgE antibodies (mAb) by fusion of myeloma cells with rat splenocytes immunized with purified murine IgE mAb. Six individual mAb were found to react with various IgE mAb of different specificities and not with immunoglobulins of other classes. Three different clusters of epitopes on the Fc epsilon portion could be detected by antibody competition studies. These antigenic determinants were expressed on the Fc epsilon portion and required the two heavy chains in their native conformation. Two groups of mAb and their Fab' fragments completely inhibited the binding of 125I-labeled IgE to rat basophilic leukemia cells (RBL), and one mAb inhibited the specific IgE binding only partially (55-65%). Likewise, the Fab' fragments of the purified mAb inhibited the antigen-mediated, IgE-dependent, serotonin release of RBL cells. These in vitro findings were confirmed by in vivo experiments, which demonstrated that the anti-IgE mAb could specifically block passive cutaneous anaphylaxis reaction when injected i.d., before challenging with the antigen. The differences in blocking reactivity of the various anti-IgE mAb are discussed in view of heterogeneity in the IgE-Fc epsilon R interaction.


Medical students' attitudes and perspectives regarding novel computer-based practical spot tests compared to traditional practical spot tests.
Most universities currently practice traditional practical spot tests to evaluate students. However, traditional methods have several disadvantages. Computer-based examination techniques are becoming more popular among medical educators worldwide. Therefore incorporating the computer interface in practical spot testing is a novel concept that may minimize the shortcomings of traditional methods. Assessing students' attitudes and perspectives is vital in understanding how students perceive the novel method. One hundred and sixty medical students were randomly allocated to either a computer-based spot test (n=80) or a traditional spot test (n=80). The students rated their attitudes and perspectives regarding the spot test method soon after the test. The results were described comparatively. Students had higher positive attitudes towards the computer-based practical spot test compared to the traditional spot test. Their recommendations to introduce the novel practical spot test method for future exams and to other universities were statistically significantly higher. The computer-based practical spot test is viewed as more acceptable to students than the traditional spot test.


Programmed death ligand 1 expression in diffuse large B cell lymphoma: correlation with clinicopathological prognostic factors.
The prognostic value of the level of programmed death ligand 1 (PD-L1) expression in non-Hodgkin lymphoma (NHL) is still debatable. This study examined the effect of the level of PD-L1 expression on the clinicopathological characteristics and prognosis of diffuse large B cell lymphoma (DLBCL). A retrospective study was conducted on formalin-fixed paraffin-embedded tissue blocks of one hundred de novo DLBCL patients diagnosed from 2013 to 2016. PD-L1 expression was defined by a modified Combined-Positive Score (CPS) and their medical records were reviewed to collect their clinical, laboratory and radiological data, treatment, and outcome. The included patients were aged from 23 to 85 years and treated by rituximab- cyclophosphamide, doxorubicin, oncovin, prednisone (R-CHOP); 49% were males; 85% of the cases were presented at Ann Arbor stages III, IV; 33% of patients were seropositive for HCV and 87% of cases were presented with intermediate and high IPI. All included cases expressed PD-L1 using modified CPS. 27% of patients showed low PD-L1 expression (≥ 5% to < 50% of total tumor cellularity) while 73% of patients showed high PD-L1expression (≥ 50% of total tumor cellularity). High PD-L1 expression is statistically correlated with advanced stage (p 0.01), high IPI score (p 0.017), high incidence of stationary and progressive disease (p 0.002) and high incidence of relapse (p value 0.01). Five-year disease-free survival (DFS) was 29% for patients with high PD-L1 expression compared with 84.8% for patients with low PD-L1 expression (p 0.001). This study suggests that high PD-L1 expression in DLBCL is associated with aggressive clinicopathological features and a decreased response to R-CHOP. The level of PD-L1 expression could be an independent predictor of DFS of DLBCL. More research is mandatory to standardize the cutoff value and scoring methods.


[Breech Presentation: CNGOF Guidelines for Clinical Practice - Labour and Induction].
To issue guidelines on management of labour induction and breech vaginal delivery. Bibliographic search restricted to French and English languages using Medline database®, Cochrane Library and international guidelines of medical societies. Breech delivery must take place in a maternity ward, in the presence of an obstetrician and gynaecologist and with the immediate availability of an anesthesiologist and a pediatrician during active second stage (Professional consensus). Term breech is not a contraindication to labour induction when the criteria for acceptance of vaginal delivery are met (Grade C). In this case, oxytocin or prostaglandins can be used (Grade C). Epidural analgesia with low concentrations of local anesthetics should be encouraged in case of vaginal delivery attempt (Professional consensus). It is recommended to use continuous monitoring of the CTG (Professional consensus). The use of second-line fetal monitoring is not recommended (Professional consensus). The administration of oxytocin is possible for labour augmentation (Professional consensus). It is better to start the expulsive efforts when the presentation is engaged as low as possible in the pelvic excavation (Professional consensus). Breech presentation is not an indication of episiotomy (Professional consensus). Due to insufficient data, it was not possible to make recommendations on specificities of preterm breech delivery. In case of planned vaginal delivery, labour induction is possible for term breech fetuses, even with unfarable cervix. Guidelines for labour and vaginal delivery management have a low level of evidence.


Molecular pathways of regeneration and repair after liver transplantation.
Injury to liver grafts due to cold ischemia, preservation, and reperfusion continues to be an important factor in patient outcome after liver transplantation. The development of therapeutic interventions that can limit ischemic injury, enhance recovery, and improve early graft function can have a major impact on patient morbidity. The mechanisms of hepatic preservation and reperfusion injury, the molecular pathways of graft recovery, and the cells involved remain poorly understood. With significant damage to parenchymal tissue following cold ischemic injury comes the need for replacement or repair of injured cells. In a rat liver transplant model, expression of cytokines and activation of transcription factors associated with the cell cycle resulting in cellular replication correlates with the length of cold ischemia and the degree of damage. The resident liver macrophage, the Kupffer cell, has been implicated as the primary source of inflammatory factors but may also be the source of important growth factors and cytokines that initiate cellular recovery and regeneration. Determining the source of the initiating signal is important, as manipulation of this signal can be used for therapeutic interventions in such fields as transplantation, tumor immunology, and inflammatory disease. These studies demonstrate the critical interrelation between parenchymal cells and cells of the immune system during signaling and recovery from preservation and reperfusion injury in the liver. Further defining the role of these immune cells and their products during the initiation of cellular recovery is essential for developing strategies to improve hepatocellular function after injury.


An endoscopic silastic keel for anterior glottic webs.
The use of a specially designed silastic keel endoscopically inserted into the larynx to prevent restenosis after division of anterior commisure webs of the larynx is described. The treatment of such webs is discussed.


Modelling bioclogging in variably saturated porous media and the interactions between surface/subsurface flows: Application to Constructed Wetlands.
Horizontal subsurface Flow Constructed Wetlands (HF CWs) are biofilters planted with aquatic macrophytes within which wastewater is treated mostly through contact with bacterial biofilms. The high concentrations of organic carbon and nutrients being transported leads to high bacterial biomass production, which decreases the flow capacity of the porous material (bioclogging). In severe bioclogging scenarios, overland flow may take place, reducing overall treatment performance. In this work we developed a mathematical model using COMSOL Multiphysics™ and MATLAB(®) to simulate bioclogging effects in HF CWs. Variably saturated subsurface flow and overland flow were described using the Richards equation. To simplify the inherent complexity of the processes involved in bioclogging development, only one bacterial group was considered, and its growth was described using a Monod equation. Bioclogging effects on the hydrodynamics were taken into account by using a conceptual model that affects the value of Mualem's unsaturated relative permeability. Simulation results with and without bioclogging were compared to showcase the impact of this process on the overall functioning of CWs. The two scenarios rendered visually different bacteria distributions, flow and transport patterns, showing the necessity of including bioclogging effects on CWs models. This work represents one of the few studies available on bioclogging in variably saturated conditions, and the presented model allows simulating the interaction between overland and subsurface flow occurring in most HF CWs. Hence, this work gets us a step closer to being able to describe CWs functioning in an integrated way using mathematical models.


Comparison of 1% lignocaine with 0.5% bupivacaine in digital ring blocks.
In a randomised double-blind trial comparing 1% lignocaine with 0.5% bupivacaine in digital ring block, the mean time of onset of complete anaesthesia was 5.8 minutes (range 5 to 10 minutes) for lignocaine and 11.2 minutes (range 8 to 20 minutes) for bupivacaine. The duration of action was 59.6 minutes (S.D. +/- 28.7 minutes) for lignocaine and 476 minutes (S.D. +/- 277 minutes) for bupivacaine. We describe how these differences can be exploited in clinical practice.


Two-hole trephination (Muntarbhorn) technique for a large frontal sinus osteoma: a case report.
To present an alternative surgical option for frontal sinus osteoma. A woman presented with a symptomatic large osteoma in right frontal sinus. Two-hole trephination was planned to remove the osteoma using nasal endoscope and a drill in each hole. The osteoma was drilled and removed transnasally. Two months later, two small fragments of osteoma were detected remaining in the lateral aspect of the sinus. The fragments were removed successfully with the same technique. The patient was asymptomatic six months postoperatively. Two-hole trephination technique or Muntarbhorn technique is an attractive option for frontal sinus osteoma.


Serology for Plasmodium vivax surveillance: A novel approach to accelerate towards elimination.
Plasmodium vivax is the most widespread causative agent of human malaria in the world. Despite the ongoing implementation of malaria control programs, the rate of case reduction has declined over the last 5 years. Hence, surveillance of malaria transmission should be in place to identify and monitor areas that require intensified malaria control interventions. Serological tools may offer additional insights into transmission intensity over parasite and entomological measures, especially as transmission levels decline. Antibodies can be detected in the host system for months to even years after parasite infections have been cleared from the blood, enabling malaria exposure history to be captured. Because the Plasmodium parasite expresses more than 5000 proteins, it is important to a) understand antibody longevity following infection and b) measure antibodies to more than one antigen in order to accurately inform on the exposure and/or immune status of populations. This review summarises current practices for surveillance of P. vivax malaria, the current state of research into serological exposure markers and their potential role for accelerating malaria elimination, and discusses further studies that need to be undertaken to see such technology implemented in malaria-endemic areas.


Establishment of a monoclonal antibody for human LXRalpha: Detection of LXRalpha protein expression in human macrophages.
Liver X activated receptor alpha (LXRalpha) forms a functional dimeric nuclear receptor with RXR that regulates the metabolism of several important lipids, including cholesterol and bile acids. As compared with RXR, the LXRalpha protein level in the cell is low and the LXRalpha protein itself is very hard to detect. We have previously reported that the mRNA for LXRalpha is highly expressed in human cultured macrophages. In order to confirm the presence of the LXRalpha protein in the human macrophage, we have established a monoclonal antibody against LXRalpha, K-8607. The binding of mAb K-8607 to the human LXRalpha protein was confirmed by a wide variety of different techniques, including immunoblotting, immunohistochemistry, and electrophoretic mobility shift assay (EMSA). By immunoblotting with this antibody, the presence of native LXR protein in primary cultured human macrophage was demonstrated, as was its absence in human monocytes. This monoclonal anti-LXRalpha antibody should prove to be a useful tool in the analysis of the human LXRalpha protein.


The role of depressive symptoms within the association of long-term exposure to indoor and outdoor traffic noise and cognitive function - Results from the Heinz Nixdorf Recall study.
Traffic noise is negatively associated with cognitive function, and its perception can differ between depressed and non-depressed people. We studied the role of depressive symptoms in the association between traffic noise and cognitive function. We studied the role of depressive symptoms in the association between traffic noise and cognitive function. During the first follow-up examination (2006-2008) of the German Heinz Nixdorf Recall study, cognitive function (five subtests and an additive global summary score, GCS) and depressive symptoms (CES-D score) were assessed in 2745 participants (aged 50-80, 49.8% women). Mild cognitive impairment (MCI) was diagnosed according to the Petersen criteria in 380 participants. Long-term exposure to traffic noise was modeled as weighted 24-h mean (LDEN) and night-time mean (LNIGHT) at the façade of the baseline addresses, and was corrected for indoors (LDEN_IN and LNIGHT_IN). We developed multiple linear and logistic regression models adjusted for individual-level characteristics to investigate cross-sectionally the role of depressive symptoms in the association of traffic noise with cognitive function. Overall, 8.6% participants had depressive symptoms. The median noise values were LDEN 52.1 dB(A) and LDEN_IN 34.7 dB(A). Associations were slightly stronger for cognitive subtests in those with severe depression (CES-D>21), i.e., per 10 dB(A) LDEN and verbal fluency: β = -0.04 [-0.11; 0.03] for CES-D≤21 and β = -0.09 [-0.24; -0.06] for CES-D>21. Additional adjustment of the main model for CES-D did not change the association between noise and cognitive outcomes. Estimates using indoor noise exposure were generally stronger and more precise. Depressed people may be more susceptible to adverse effects of noise than non-depressed. Modeled estimates of indoor noise exposure is possibly a more appropriate measure of exposure.


Adhesive resin and the hydrophilic monomer HEMA induce VEGF expression on dental pulp cells and macrophages.
Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis by inducing endothelial cell proliferation, migration and survival. Direct pulp capping with an adhesive resin system was shown to induce local increase in blood vessel density and lack of dentin bridging. However, the mechanisms involved in the increase in blood vessel density observed near the pulp exposures capped with an adhesive resin are largely unknown. OBJECTIVES.: To investigate the effect of an adhesive resin or one of its hydrophilic monomers (HEMA), in the expression of VEGF by pulp cells. METHODS.: Mouse odontoblast-like cells (MDPC-23), undifferentiated pulp cells (OD-21), gingival fibroblasts, and macrophages were exposed to SingleBond (3M) or to 0-1000nM HEMA. VEGF expression was evaluated by ELISA and semi-quantitative RT-PCR. RESULTS AND SIGNIFICANCE.: VEGF expression was upregulated in MDPC-23 cells exposed to HEMA (p<0.001) or to SingleBond (p<0.018), and in macrophages exposed to HEMA (p<0.001) or SingleBond (p=0.001). In contrast, VEGF expression remained unchanged in undifferentiated pulp cells (OD-21), or fibroblasts exposed to either HEMA or Single Bond (p>0.05). Treatment with SingleBond or HEMA did not affect VEGF expression at the mRNA level of any cell type evaluated here, suggesting that the induction of VEGF expression in these cells is regulated primarily at the post-transcriptional level. These findings suggest that VEGF is involved in the regulation of pulp neovascularization observed in response to the application of adhesive resins at site of pulp exposure.


Lamotrigine plus leukocyte filtration as a neuroprotective strategy in experimental hypothermic circulatory arrest.
Lamotrigine and leukocyte filtration seem to improve cerebral protection during experimental hypothermic circulatory arrest (HCA). This study was performed to evaluate whether their combined use may further improve cerebral protection. Twenty-four pigs undergoing 75-minute period of HCA at 20 degrees C were randomly assigned to receive saline; lamotrigine (20 mg/kg) before HCA (L); or lamotrigine (20 mg/kg) before HCA plus leukocyte filtration before and after HCA (L + LF). Seven animals (87%) in the L + LF group, 4 (50%) in the L group, and 3 (37%) in the control group were alive on the seventh postoperative day. The median electroencephalogram burst recovery was 94% in the L + LF group (p = 0.024 versus control group), 81% in the L group, and 64% in the control group. Among the surviving animals, the median behavioral scores were 9, 9, and 6 at the seventh day, respectively (p = 0.005 between the L + LF group and the control group). The median histopathologic score was 14 in the L + LF group (p = 0.046 versus control group), 14.5 in the L group (p = 0.062 versus control group), and 21 in the control group. Lamotrigine has neuroprotective effect during HCA. The combined use of lamotrigine and LF may further improve the survival outcome.


Ramosetron, dexamethasone, and their combination for the prevention of postoperative nausea and vomiting in women undergoing laparoscopic cholecystectomy.
In this randomized and controlled study, we evaluated the antiemetic efficacy of ramosetron combined with dexamethasone for postoperative nausea and vomiting (PONV) compared with that of dexamethasone or ramosetron alone in women who underwent laparoscopic cholecystectomy. One hundred twenty female patients were randomly assigned to one of three groups to receive antiemetics as follows: ramosetron 0.3 mg (group R), dexamethasone 8 mg (group D), or ramosetron 0.3 mg combined with dexamethasone 8 mg (group RD). PONV, postoperative pain intensity, rescue antiemetics requirement, and side effects were assessed at 0-6, 6-12, and 12-24 h after surgery. The ratio of complete response (no PONV and no rescue antiemetic) was higher at 6-12 h in groups R and RD than in group D (p < 0.05) and at 12-24 h in group RD than in group D (p < 0.05). The incidence of nausea was lower at 6-12 h in groups R (p = 0.043) and RD (p = 0.003) compared to group D and at 12-24 h in group RD (p = 0.01) compared to group D. The severity of nausea was also significantly reduced at 6-12 h in groups R and RD compared to group D (p < 0.05). There were no clinically serious adverse events related to the studied drugs. Antiemetic efficacy of the combination of ramosetron 0.3 mg and dexamethasone 8 mg for PONV was most superior, with 93% of the patients showing complete response at 12-24 h after surgery followed by ramosetron alone and dexamethasone alone.


Comparison of the effects of human recombinant insulin-like growth factor I and insulin on plasma amino acid concentrations and leucine kinetics in humans.
We examined the effects of recombinant human insulin-like growth factor I (IGF-I) and insulin on the plasma amino acid (AA) profile and leucine kinetics in eight normal subjects. IGF-I was infused at 52 pmol.kg-1.min-1, in combination with prime-continuous [1-14C] leucine infusion, to obtain steady-state plasma concentrations of total (54 +/- 3 nmol/l) and free (7.3 +/- 1 nmol/l) IGF-I (study 1). In response to IGF-I, plasma AA levels declined by 37 +/- 3% (1975 +/- 198 to 1368 +/- 120 mumol/l) and total branched chain amino acids (BCAA) declined by 34 +/- 3% (390 +/- 21 to 256 +/- 13 mumol/l). This hypoaminoacidaemic effect was associated with a decline in endogenous leucine flux of 17 +/- 2% (1.88 +/- 0.05 to 1.57 +/- 0.04 mumol.kg-1.min-1) and leucine oxidation of 17 +/- 1% (0.31 +/- 0.02 vs 0.26 +/- 0.02 mumol.kg-1.min-1) (both p < 0.01 vs basal). The same subjects underwent a second study (study 2) in which insulin was infused at 6.22 pmol.kg-1.min-1 to obtain a steady-state plasma insulin concentration of 530 +/- 25 pmol/l while maintaining euglycaemia. The infusion rate was designed to match the declines in plasma BCAA levels and leucine turnover observed during IGF-I infusion. The rates of glucose infusion necessary to maintain euglycaemia during IGF-I and insulin infusion were 4.9 +/- 1.0 and 7.8 +/- 0.6 mg.kg-1.min-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Interferon research BC (before cloning).
As we approach the 50th anniversary of the publications describing the discovery of interferon, it is appropriate to look back at some of the trials and tribulations marking the early days of interferon research. This brief chapter, drawn largely from the author's own experiences, relates how progress was achieved in some key areas of interferon research in the 1960s and 1970s despite the lack of analytical tools that had become available only after the successful cloning of interferon genes. One of the topics discussed concerns the evolution of the idea that interferon synthesis is controlled both at transcriptional and posttranscriptional levels. I also recount some of the early work that led to the identification of IFN-alpha and IFN-beta as the two major type I interferon species.


Effect of Solanum trilobatum on the antioxidant status during diethyl nitrosamine induced and phenobarbital promoted hepatocarcinogenesis in rat.
The methanolic extract of Solanum trilobatum (ST) is cytotoxic and exerts an inhibitory effect on tumor growth and in the present study, its role on the antioxidant status of N-diethylnitrosamine (DEN) induced and phenobarbital (PB) promoted hepatocarcinogenesis was assessed. The protective role of ST on DEN induced and PB promoted hepatocarcinogenesis in Wistar rats was assessed from total nodular incidence, nodule multiplicity and volume of persistent nodules after an experimental period of 3 and 6 months following co-administration. The levels of thiobarbituric reactive substances (TBARS), glutathione (GSH) and activities of antioxidant enzymes were assessed in the haemolysate and liver of experimental animals to evaluate the antioxidant status. In DEN+PB+ST animals, the nodular incidence, multiplicity and volume reduced significantly compared to DEN+PB treated animals. In DEN+PB animals, the levels of TBARS increased significantly, whereas the levels of GSH and the activities of antioxidant enzymes-superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase and glucose 6 phosphate dehydrogenase showed significant alterations compared to control both in the haemolysate and liver. However, in DEN+PB+ST animals, the levels of TBARS decreased significantly and the levels of GSH increased with favorable alterations in the activities of antioxidant enzymes in both the haemolysate and liver. The present results suggest that ST exerts its chemopreventive effects by modulating the antioxidant status during DEN induced hepatocarcinogenesis.


Factors Associated with Requesting Magnetic Resonance Imaging during the Management of Glomus Tumors.
The characteristic clinical presentation of glomus tumors and the low negative predictive value of the magnetic resonance imaging (MRI) raise the question whether MRI improves their management. Therefore, this study aimed to investigate whether MRI improved the management of glomus tumors. In total, 87 patients with a histologically confirmed glomus tumor were treated over a 25-year period and analyzed retrospectively. Multivariable logistic regression analysis was used to evaluate the independent predictors of an MRI request during the management of glomus tumors. ccording to the results, the patients who were treated by orthopaedic surgeons were more likely to have an MRI during the management of a glomus tumor. The role of an MRI during the management of a glomus tumor is unclear. Orthopaedic surgeons are more likely to request an MRI. Furthermore, visible lesions with characteristic symptoms probably do not benefit from MRI. However, it may help to be sure that the highest-quality MRI is used with the best possible coil for the finger.


Price transparency implementation: Accessibility of hospital chargemasters and variation in hospital pricing after CMS mandate.
National regulations have increasingly focused on transparency in hospital billing and pricing practices. A January 2019 federal mandate required hospitals to publicize lists of billable procedures and items known as chargemasters. We identified the 500 top self-pay/uninsured revenue grossing hospitals nationally and searched each hospital's website for a chargemaster. Corresponding items were matched across chargemasters. Intrahospital and interhospital price variation were calculated. To investigate variation in item naming, a name variant and fuzzy matching search was conducted for fifteen common chargemaster items. Of 500 hospitals in this study, 69 (13.8%) had chargemasters that were inaccessible and 30 (6.0%) had chargemasters that did not meet mandated requirements. Among the remaining 431 hospitals, the mean interhospital and intrahospital variation in pricing for identical items was 18% (SD 28%) and 28% (SD 29%), respectively. 388 hospitals listed multiple prices for the same item, with a mean of 687.3 duplicated items (SD 1157.7). Among fifteen common chargemaster items, each item was associated with an average of 275 (SD 213) unique name variants. Interhospital price variation of these items ranged from 53% (transthoracic echocardiogram) to 243% (furosemide 40 mg). Many chargemasters have barriers to access, and item naming is inconsistent across chargemasters. There is significant interhospital price variation for similar items. Chargemasters are uninterpretable for the purpose of patient price comparison in their current form. Further regulatory efforts are necessary to increase price transparency and enhance the ability of patients to compare hospital prices.


Application of active breathing control in 3-dimensional conformal radiation therapy for hepatocellular carcinoma: the feasibility and benefit.
To investigate the feasibility and effectiveness of utilizing active breathing coordinator (ABC) in 3DCRT for HCC. A dosimetric comparison between the free-breathing (FB) plan and ABC plan in HCC 3DCRT was performed. Set-up errors and reproducibility of diaphragm position using ABC were measured, and patients' acceptance was also recorded. From April 2005 to February 2007, 28 HCC were irradiated with ABC and they tolerated ABC well. The mean dose to normal liver was reduced from 16.9Gy in FB plan to 14.3Gy in ABC plan. PTV for ABC and FB plans were 529cm(3) and 781cm(3), respectively, and V(23) were reduced from 45% to 30%. The predicted incidences of radiation-induced liver disease by Lyman model were 1% and 2.5%, respectively, in favor of ABC plan. The systematic and random errors for the ABC and FB plans were 1.2mm vs. 4.7mm, 1.6mm vs. 3.5mm, and 1.8mm vs. 2.7mm, respectively, in cranio-caudal, anterior-posterior, and left-right directions. The average intrafraction reproducibility of diaphragm position in cranio-caudal direction was 1.6mm, and the interfraction, 6.7mm. The utilization of ABC in HCC 3DCRT is feasible, and can reduce liver irradiation.


Molecular evolution of the N-formyl peptide and C5a receptors in non-human primates.
N-formyl peptides (FMLP) and complement fragment C5a are neutrophil chemoattractants. In humans, a single-copy gene was identified for the C5a receptor, and the receptor for FMLP (FPR1) is encoded by a single gene that shows 53% amino acid similarity to the C5aR. Two other human FPR1 homologues, FPR-like 1 (FPR2/FPRL1) and FPR-like 2 (FPRL2) have been cloned. The human C5aR, FPR1, FPRL1, and FPRL2 are physically linked. By direct sequencing or by sequencing plasmid clones we studied the C5aR and FPR genes from four non-human primates (chimpanzee, gorilla, orangutan, and macaque). The sequences showed 95% - 99% similarity to the human homologues, with the major divergences observed in macaque. In these genes, the transmembrane and the cytoplasmic domains are highly conserved, while the highest divergence corresponded to the extracellular loops involved in ligand binding. Additionally, we constructed a physical map of these genes in non-human primates. In all species the four genes were physically linked and we defined the relative orientation of the four genes in primates: C5aR>FPR1>FPR2 (FPRL1)>FPRL2.


The role of inflammation in the cardio-renal syndrome: a focus on cytokines and inflammatory mediators.
Cardiovascular and kidney diseases are highly prevalent and frequently are seen in the same patient. This overlap between cardiac and kidney diseases, in part, relates to common etiologies such as diabetes and hypertension. However, there are important dynamic and bidirectional interactions between the cardiovascular system and kidneys that may explain the occurrence of organ dysfunction. In this regard, it is clear that inflammation plays an important role in the pathogenesis of both cardiovascular and renal diseases. Given the circulating nature of many inflammatory mediators (cytokines, immune cells), it is tempting to speculate that the immune system can act as a mediator of organ cross-talk and may be involved in the reciprocal dysfunction that is encountered commonly in cardio-renal syndromes.


The zinc finger transcription factor Egr-1 is essential for and restricts differentiation along the macrophage lineage.
We have isolated cDNA clones of myeloid differentiation primary response (MyD) genes, activated in the absence of de novo protein synthesis following induction for differentiation along either the macrophage or granulocyte lineage in human myeloblastic leukemia HL-60 cells. One cDNA clone of a primary response gene, expressed upon macrophage differentiation, encoded for Egr-1, a zinc finger transcription factor. The Egr-1 gene was observed to be transcriptionally silent in HL-60 cells, but active in U-937 and M1 cells, the latter two being predetermined for macrophage differentiation. Egr-1 antisense oligomers in the culture media blocked macrophage differentiation in both myeloid leukemia cell lines and normal myeloblasts. HL-60 cells constitutively expressing an Egr-1 transgene (HL-60Egr-1) could be induced for macrophage, but not granulocyte, differentiation. These observations indicate that expression of Egr-1 is essential for and restricts differentiation of myeloblasts along the macrophage lineage.


Determinants of COVID-19 Vaccine Acceptability among Healthcare Workers in Kenya-A Mixed Methods Analysis.
Healthcare workers (HCWs) were a priority group for COVID-19 vaccination. Adopting the World Health Organization's 3C and the expanded 5C vaccine hesitancy models, we assessed the factors associated with COVID-19 vaccine acceptability among HCWs in Kenya. In a mixed methods study, respondents were from eight selected counties across the country. An online survey (n = 746), key informant interviews (n = 18) and focus group discussions (n = 3) were conducted. The data were analyzed concurrently. Quantitative data showed that all the 3C antecedents were strong predictors of vaccine acceptability. The association of vaccine acceptability was strongest with convenience (aOR 20.13, 95% CI 9.01-44.96), then complacency (aOR 10.15, 95% CI 4.63-22.21) and confidence (aOR 6.37, 95% CI 2.90-14.02). Marital status was a significant independent factor associated with vaccine acceptability (aOR 2.70, 95% CI 1.20-6.08). Qualitatively, convenience presented as the no-cost availability of vaccines at the health facilities, whereas non-complacency manifested from the first-hand observed experience of COVID cases, and the need to protect oneself and family members. Confidence was mainly attributed to increased knowledge, resulting from multiple training sessions and trust in regulatory authorities. Other social factors including workplace pressure, religion and misinformation had a role in influencing HCW vaccination decisions. In the background of a pandemic, the 3C model is a strong predictor of vaccine acceptability, and making the vaccines easily available and convenient to HCWs significantly impacts their uptake.


Coronavirus disease 2019 and laparoscopic surgery in resource-limited settings.
During the coronavirus disease 2019 (COVID-19) pandemic, the use of laparoscopy has been discouraged by the Intercollegiate General Surgery because of its potential for aerosol generation and infection. In contrast, the Society of American Gastrointestinal and Endoscopic Surgeons and the European Association of Endoscopic Surgery recommend continuing to use laparoscopy but with devices to filter released CO2 aerosol particles. However, commercially available systems are costly and may not be readily available. Herein, we describe a custom-made system to safely remove surgical smoke and CO2 , as well as a case of laparoscopic cholecystectomy in which we used it. The patient had had multiple episodes of biliary pancreatitis and required urgent cholecystectomy during the COVID-19 pandemic. Although India was in complete lockdown, it was decided to operate with precaution. A system was designed using underwater seal chest tube drainage and an electrostatic membrane filter with a viral retention function greater than 99.99%. The system was connected to an extra port for continuous controlled egression of CO2 pneumoperitoneum. A regular four-port cholecystectomy was performed at an intra-abdominal pressure of 12 mm Hg. The gas flow rate was 10 L/min. CO2 for pneumoperitoneum, surgical aerosol, and effluents passed through the system before collecting in the suction apparatus. The exchange of operating instruments through the ports was kept to a minimum. It was done after the abdomen was temporarily desufflated using this system. The system we designed appears safe and is cost-effective. In resource-limited settings, it will be handy in patients requiring laparoscopic surgery both during and after the COVID-19 pandemic.


The development and evaluation of a social media-based HIV knowledge dissemination platform in China.
This study aimed to introduce the development of a social media-based HIV knowledge dissemination platform and evaluate its dissemination effects, users' feedback, and preferences. A social media-based HIV knowledge dissemination platform ("Lihui Space") was developed as a WeChat Official Account (WOA) to disseminate HIV-related information and knowledge to the public and answer subscribers' questions. A cross-sectional study was conducted on 784 platform subscribers between July 2021 and September 2021 to evaluate users' experiences with and preferences for the platform. This platform included three content levels about HIV-related information and knowledge: individual level (health self-management), community level (social function), and society level (news and policy), and dissemination information through texts, pictures, videos, and websites. A descriptive analysis was conducted to estimate the dissemination effects of the platform and evaluation scores. As of September 16, 2021, this platform's WeChat Communication Index (WCI) score was 923.60, the total number of users was 100,008, and the total views in one month was more than 724,000. Participants reported a high level of satisfaction with this platform in terms of overall evaluation (23.36 ± 3.06), readability (18.46 ± 2.63), function evaluation (13.93 ± 1.92), design and structure (22.96 ± 3.36), and interactivity (12.56 ± 2.69). This social media-based platform is currently available in the WeChat application. It is a promising tool for HIV knowledge dissemination and addressing disparities in accessing health care resources.


[Microbiological investigations into soil in a fertilizer trial with spruce in the fume-damaged zone of the Erzgebirge (author's transl)].
In the heavily fume-damaged spruce stands on crest sites in the eastern parts of Erzgebirge the composition of microbe population and organic matter conversion in the A0 horizon can be positively changed with a lasting effect by fertilization using CaNP. Ammonification, nitrification, urea transformation, and decomposition of cellulose are enhanced by the increased occurrence of bacteria and actinomycetes. As a result of fertilization acidity was reduced from pH (KCl) 3.0 to 3.6 as a maximum. The influence of the nutrient status is clearly manifest in the humus form (raw humus in the case of quartz porphyry, mull-resembling moder in the case of basalt), but scarcely in the chemical and microbiological properties of the Of subhorizon. No pronounced effect of the SO2 fallout on the microbiological conditions in the A0 horizon was observed. The increased soil fertility after application of Ca and P can lead to an increased and a more stable yield of wood only under certain conditions.


Reduction in anisotropic response of corrosion properties of selective laser melted Co-Cr-Mo alloys by post-heat treatment.
The application of selective laser melting (SLM) to dentistry has been rapidly expanding; however, SLM-processed parts possess orientation-dependent properties (i.e., anisotropy) that can affect the long-term reliability of the dental prostheses. This study aimed to evaluate the anisotropic corrosion response of SLM-processed Co-Cr-Mo alloys under various heat treatments. Samples fabricated via SLM along the horizontal plane (x-y plane) and vertical plane (x-z plane), with respect to the build direction, were subjected to various heat treatments. The resulting microstructures of the samples were characterized, and their corrosion properties were evaluated using anodic polarization and immersion tests. All samples showed similar transpassive behavior of the polarization curves. However, the immersion tests showed that the as-built x-z plane samples released significantly more metal ions than those fabricated on the x-y plane because of the larger area of preferentially corroded molten pool boundaries (MPBs) in the x-z plane samples. Our results further demonstrated that the heat treatments eliminated the MPBs, resulting in isotropic corrosion properties. However, excessive heat treatment at high temperatures induces the formation of coarse precipitates, resulting in a less-protective passive film. The post-build heat treatments at temperatures that eliminate the MPBs are effective in reducing anisotropic corrosion behavior, and the lowest possible temperature is suitable for reducing the amount of released metal ions. These findings are expected to facilitate the application of SLM in dentistry to allow fast and precise production of prosthetic devices.


Risk behaviour and sexually transmitted diseases are on the rise in gay men, but what is happening with HIV?
Increases in sexually transmitted diseases and sexual risk behaviour among men who have sex with men in the Western world have raised concern with regard to the HIV/AIDS epidemic in this group. The aim of this review is to give an overview of possible explanations for these alarming increases and to indicate what impact they might have on this epidemic.


Percutaneous balloon valvuloplasty for mitral stenosis complicated by fatal pericardial tamponade in a patient with extreme pulmonary hypertension.
A case of left ventricular perforation by straight-tipped balloon catheter during double-balloon mitral valvuloplasty with fatal outcome is presented. Technical considerations to prevent this complication are discussed.


Changes in brain levels of cyclic nucleotides and gamma-aminobutyric acid in barbiturate dependence and withdrawal.
Rats exposed to chronic intake of sodium barbital maintained high circulating levels of barbital in blood and brain and exhibited increased sensitivity ot audiogenic convulsions during the withdrawal period. Levels of gamma-aminobutyric acid (GABA), glutamate, guanosine 3',5'-monophosphate (cyclic GMP) and adenosine 3',5'-monophosphate (cyclic AMP) were measured in selected brain regions after sacrifice with high power microwave inactivation. Cyclic GMP during chronic barbital administration was significantly lower than controls in most brain regions, especially the hindbrain. During the withdrawal period cyclic GMP in the cerebellum was significantly increased, while returning at least to control levels in all other regions. GABA throughout the brain tended to be reduced during barbital dependence, while cyclic AMP and glutamate levels remained unchanged in all groups. These results indicate a possible role for cyclic GMP in the mediation of the central nervous system response during barbiturate dependence and withdrawal.


Skeletal Muscle Dystrophy mutant of lamin A alters the structure and dynamics of the Ig fold domain.
Mutations in the different domains of A-type lamin proteins cause a diverse plethora of diseases collectively termed as laminopathies which can affect multiple organs. Ig fold is one such domain of lamin A which is implicated in numerous nuclear interactions wherein the mutations lead to different laminopathies. W514R is one such mutation in the Ig fold which leads to severe phenotypes in Skeletal Muscle Dystrophy (SMD) which is a class of laminopathies. In this report, we elucidated gross alterations in structure and dynamics at the level of individual amino acids. These studies indicate altered conformational features of residues in the close vicinity of W514. Imaging of mammalian cells transfected with the mutant have shown distinct perturbation of the nuclear meshwork with concomitant alteration in nuclear interactions as a result of increased oligomerization of Ig W514R. Hence, this novel approach of amalgamating theoretical and experimental procedures to predict the severity of a mutant in the context of laminopathies could be extended for numerous lamin A mutants.


Protein metabolism and requirements in the critically ill patient.
The metabolic alterations of the critically ill patient greatly affect the processes of both protein synthesis and degradation as well as the nitrogen balance. It is important to understand these affects so that protein and nitrogen balance may be accounted for in parenteral nutritional support.


Methyl α-l-sorboside monohydrate.
Methyl l-sorboside monohydrate, C7H14O6·H2O, was prepared from the rare sugar l-sorbose, C6H12O6, and crystallized. It was confirmed that methyl l-sorboside formed α-pyran-ose with a 2 C 5 conformation and crystallized with one water molecule of crystallization. In the crystal, mol-ecules are linked by O-H⋯O hydrogen bonds, forming a three-dimensional network. The unit-cell volume of the title compound, methyl l-sorboside monohydrate, is 481.13 (2) Å3 (Z = 2), which is about 108.16 Å3 (29.0%) greater than that of half the amount of the chemical α-l-sorbose [745.94 (2) Å3 (Z = 4)].


The earliest most complete skeleton of Theropithecus.
The middle Pliocene site of Woranso-Mille in the Afar Region of Ethiopia has yielded numerous significant early hominin fossils representing multiple, coexisting taxa. Here we report on another significant discovery, the oldest partial skeleton of the papionin, Theropithecus. The specimen was recovered from the Aralee Issie collection area over multiple field seasons from 2004 through 2019. The specimen was unearthed in situ from the fluvial facies of the Mesgid Dora Tuff dated to 3.66-3.57 Ma. The partial skeleton, ARI-VP-1/26, is that of a subadult male lacking a skull. In the absence of unambiguously associated craniodental remains, the male status of the specimen was established from the dimensions of the long bones in comparison to those of other Theropithecus from Woranso-Mille. ARI-VP-1/26 is noteworthy because it preserves partial hand and foot skeletons, including a complete set of metacarpals from the left side. The theropith status of ARI-VP-1/26 was established based on the detailed anatomy of the postcranial skeleton, especially the proximal and distal humerus, proximal radius, and proximal femur. The morphology of the postcranium of ARI-VP-1/26 is consistent with that of recognized Theropithecus from Woranso-Mille and, specifically, with specimens recognized as Theropithecus oswaldi cf. darti from other sites. The ratio of the lengths of the first metacarpal to metacarpals 2-5 in ARI-VP-1/26 is intermediate between that seen in extant Papio and Theropithecus. In Theropithecus gelada and Theropithecus brumpti, the pairing of pollical and indical metacarpals of near equal length contributes to the species' high opposability index and is associated with a 'manual grazing' feeding habit. Cercopithecids constitute 43% of the identified vertebrates at Aralee Issie, and T. oswaldi cf. darti is the most common mammalian species. The monkeys of Aralee Issie lived in an open shrubland habitat, but the specific reasons for their high prevalence at the site are unclear.


Split-Sided Chest Study of Skin Rejuvenation Comparing Low-Energy, 1,927-nm Thulium Fractional Laser Treatment Prior to Photodynamic Therapy Versus Photodynamic Therapy Alone.
Treatment of photoaging and intrinsic aging of the chest, with the associated concerns of skin roughness, uneven pigmentation, laxity, atrophy, and telangiectasias, can be problematic because of the potential for worsened esthetic outcomes with existing treatments. This study assessed the efficacy and safety of using nonablative fractional laser therapy (FLT) pretreatment with photodynamic therapy (PDT) versus PDT alone for chest rejuvenation. In a randomized, evaluator-blinded, split-sided study, adult female patients with photodamage to the chest received three treatment courses over an 8-week period with follow-up visits at Weeks 12 and 20. FLT was applied to one side of the chest, randomly assigned at baseline, followed by aminolevulinic acid-based PDT, delivered using a thermal, short incubation, broad area technique, to both sides of the chest. In-person and photographic assessments were conducted using five-point scales to evaluate outcomes including rhytides, pigmentation, skin texture, and telangiectasias. Eleven adults completed the study, of whom 11 had improved scores for rhytides and 10 had improved scores for skin texture at Week 20. There was no significant difference in any efficacy outcome between FLT and PDT and standard PDT alone. The severity of adverse events was rated significantly greater with the combined FLT-PDT treatment vs PDT alone. Significant improvements were observed vs baseline for both sides of the chest treated with FLT-PDT or standard PDT following three treatment sessions. No significant difference in efficacy was observed between treatment approaches, although adverse events were more severe on the FLT-pretreated side. This study was not registered as it qualified as a nonsignificant risk study. Lasers Surg. Med. © 2019 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.


Substance P antagonists active in vitro and in vivo.
[Pro4, Trp7,9]SP-(4-11) and a newly developed compound, [Pro4, Trp7,9,10]SP-(4-11) were shown to be potent antagonists of substance P (SP). They inhibited the hypotensive effect of SP in the anesthetised rats, the vasodilator effect in the rabbit perfused heart and the relaxation induced by SP in dog carotid arteries contracted with noradrenaline. Stimulatory actions of SP in the guinea pig ileum and the guinea pig trachea were also inhibited by the two antagonists, which were shown to be specific for substance P and related peptides in all the pharmacological preparations utilised in the present study.


Towards patient-specific modeling of brain tumor growth and formation of secondary nodes guided by DTI-MRI.
Previous studies to simulate brain tumor progression, often investigate either temporal changes in cancer cell density or the overall tissue-level growth of the tumor mass. Here, we developed a computational model to bridge these two approaches. The model incorporates the tumor biomechanical response at the tissue level and accounts for cellular events by modeling cancer cell proliferation, infiltration to surrounding tissues, and invasion to distant locations. Moreover, acquisition of high resolution human data from anatomical magnetic resonance imaging, diffusion tensor imaging and perfusion imaging was employed within the simulations towards a realistic and patient specific model. The model predicted the intratumoral mechanical stresses to range from 20 to 34 kPa, which caused an up to 4.5 mm displacement to the adjacent healthy tissue. Furthermore, the model predicted plausible cancer cell invasion patterns within the brain along the white matter fiber tracts. Finally, by varying the tumor vascular density and its invasive outer ring thickness, our model showed the potential of these parameters for guiding the timing (83-90 days) of cancer cell distant invasion as well as the number (0-2 sites) and location (temportal and/or parietal lobe) of the invasion sites.


Traumatic incidents and emotional health.
The role of the occupational health nurse in recognizing the potential for posttraumatic stress disorder is discussed.


DNA-PKcs promotes sepsis-induced multiple organ failure by triggering mitochondrial dysfunction.
Multiple organ failure is the commonest cause of death in septic patients. This study was undertaken in an attempt to elucidate the functional importance of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) on mitochondrial dysfunction associated with the development and progression of sepsis-related multiple organ dysfunction syndrome (MODS). Cardiomyocyte-specific DNA-PKcs knockout (DNA-PKcsCKO) mice, liver-specific DNA-PKcs knockout (DNA-PKcsLKO) mice, and kidney tubular cell-specific DNA-PKcs knockout (DNA-PKcsTKO) mice were used to generate an LPS-induced sepsis model. Echocardiography, serum biochemistry, and tissue microscopy were used to analyze organ damage and morphological changes induced by sepsis. Mitochondrial function and dynamics were determined by qPCR, western blotting, ELISA, and mt-Keima and immunofluorescence assays following siRNA-mediated DNA-PKCs knockdown in cardiomyocytes, hepatocytes, and kidney tubular cells. DNA-PKcs deletion attenuated sepsis-mediated myocardial damage through improving mitochondrial metabolism. Loss of DNA-PKcs protected the liver against sepsis through inhibition of mitochondrial oxidative damage and apoptosis. DNA-PKcs deficiency sustained kidney function upon LPS stress through normalization of mitochondrial fission/fusion events, mitophagy, and biogenesis. We conclude that strategies targeting DNA-PKcs expression or activity may be valuable therapeutic options to prevent or reduce mitochondrial dysfunction and organ damage associated with sepsis-induced MODS.


Subperiosteal hemorrhage: A rare complication in neurofibromatosis which may mimic malignant peripheral nerve sheath tumor.
Currently, there is little in the medical literature on subperiosteal hematomas in neurofibromatosis patients, particularly in those who have subperiosteal neurofibromas. Initial imaging and clinical presentation can be very worrisome and to the unaware may lead to early surgical intervention and/or anxiety in the patient and parents. This report presents the case of a 9-year-old child with neurofibromatosis type-1 and progressively increasing calf pain and swelling about a known plexiform neurofibroma. Imaging at initial presentation and at 1 month demonstrated evolving subperiosteal hemorrhage. This report adds to the small body of literature on subperiosteal hemorrhage as a complication of neurofibromatosis. Additionally, this report demonstrates an approach to noninvasive management of these lesions with the utility of initial and 1 month follow-up radiographs helpful in demonstrating hemorrhage evolution and possibly negating the need for biopsy.


Use of statistics when examining lifetime studies in rodents to detect carcinogenicity.
The lifetime assay for carcinogenicity that subjects groups of 50 animals per sex per dose to three doses and a control is examined for its statistical properties. Using the standard formulation of tests of hypothesis, it is shown that there is a 20-50% chance of having a false positive and that it is possible to define a "weak carcinogen" in terms of the degree of effect that would produce a false negative less than 5% of the time. Whether hypothesis testing is a proper use of statistics in this context is questioned, and alternatives are proposed.


Utility of phrenic nerve conduction studies for identification of patients with neuromuscular diseases requiring invasive mechanical ventilation.
Predicting when a patient will require invasive mechanical ventilation (IMV) is a major challenge in routine care for some neuromuscular diseases. In this study, we prospectively investigated whether phrenic nerve conduction studies (PNCS) can predict when IMV will be required in patients with amyotrophic lateral sclerosis (ALS), Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and myotonic dystrophy (DM). PNCS amplitude (avAMP) and latency (avLAT) were compared between patients who required IMV (IMV group) and those who did not (non-IMV group). PNCS were performed in 62 healthy controls and in patients with four different diseases that may require IMV: ALS (n = 56), GBS (n = 72), CIDP (n = 38), and DM (n = 24). The IMV group consisted of 12 patients with ALS, 14 with GBS, 2 with CIDP, and 4 with DM. avAMP was significantly lower in the IMV group with ALS than in the non-IMV group (P < .05), but no significant difference was observed in avLAT. avAMP was significantly lower and avLAT was significantly longer in the IMV group with GBS than in the non-IMV group (both P < .05). Receiver operating characteristic analysis showed that the avAMP cutoff between the IMV and non-IMV groups was 184.3 μV (area under the curve = 0.921; sensitivity, 84.6%; specificity, 88.2%) for ALS and GBS. PNCSs may aid in determining whether a patient with ALS or GBS requires IMV.


[Common variable immune deficiency complicated by amyloidosis: a case report].
Common variable immune deficiency (CVID) is the most common symptomatic immunodeficiency in adults, but it remains rare. It is characterized by its extremely heterogeneous phenotypic spectrum. We here report the case of a 39-year-old patient presenting with chronic diarrhoea with anal fistula. Laboratory tests showed inflammatory syndrome and malabsorption syndrome, hypogammaglobulinemia on serum protein electrophoresis, global hypogammaglobulinemia in weight-based assignments for immunoglobulin and a low level of lymphocytes in the analysis of lymphocyte subpopulations, thus confirming the diagnosis of common variable immune deficiency (CVID) complicated by systemic AA amyloidosis identified by amyloid deposits in the biopsies. This study highlights the importance of paying attention to common gastrointestinal symptoms of immune deficiency and to suspect it in patients with treatment-resistant symptoms.


Timing reproduction in teleost fish: cues and mechanisms.
Fish comprise half of extant vertebrate species and use a rich variety of reproductive strategies that have yielded insights into the basic mechanisms that evolved for sex. To maximize the chances of fertilization and survival of offspring, fish species time reproduction to occur at optimal times. For years, ethologists have performed painstaking experiments to identify sensory inputs and behavioral outputs of the brain during mating. Here we review known mechanisms that generate sexual behavior, focusing on the factors that govern the timing of these displays. The development of new technologies, including high-throughput sequencing and genome engineering, has the potential to provide novel insights into how the vertebrate brain consummates mating at the appropriate time.


Can Samba and Forró Brazilian rhythmic dance be more effective than walking in improving functional mobility and spatiotemporal gait parameters in patients with Parkinson's disease?
Parkinson's disease (PD) causes motor and nonmotor disorders in patients. Unlike aerobic training, potential adaptations from the practice of dance are less understood in PD, particularly compared with better known exercise modes. This study aimed to verify and compare the effects of a Brazilian dance program, inspired by Samba and Forrró rhythms, and a walking program on functional mobility and spatiotemporal gait parameters in patients with PD. Eighteen participants with PD were divided into a dance group (DG) and a walking group (WG) and were assessed before and after an intervention period of 24 1-h sessions, performed twice per week for 12 weeks. The timed-up-and-go test (TUG) and walking kinematics at self-selected speed (SSS) and fast speed (FS) were determined. The generalized estimating equation method was used to compare the DG and WG pre- and post-intervention and to evaluate the group*time interaction (α < 0.05). Both groups demonstrated a significant improvement in TUG test at SSS (p = 0.02; effect size [ES] = 0.42) and FS (p = 0.02; ES = 0.24). In general, spatiotemporal parameters remained unchanged, except at SSS, in which the DG increased the stride frequency (p = 0.011; ES = 0.72). At FS, the swing time demonstrated a significant group*time interaction (p < 0.001; ES = 1.10), in which the two groups exhibited different behaviors: DG decreased (p = 0.015) and WG increased (p = 0.012). Functional mobility improved similarly in both groups. The results suggest that a 12-week program of Brazilian dance was sufficient to produce improvements in functional mobility and gait in individuals with PD. This study is registered with the International Clinical Trial Registry under number NCT03370315 . Registered December 28, 2017 - Retrospectively registered.


Genomic taxonomy of the genus prochlorococcus.
The genus Prochlorococcus is globally abundant and dominates the total phytoplankton biomass and production in the oligotrophic ocean. The single species, Prochlorococcus marinus, comprises six named ecotypes. Our aim was to analyze the taxonomic structure of the genus Prochlorococcus. We analyzed the complete genomes of 13 cultured P. marinus type and reference strains by means of several genomic taxonomy tools (i.e., multilocus sequence analysis, amino acid identity, Karlin genomic signature, and genome to genome distance). In addition, we estimated the diversity of Prochlorococcus species in over 100 marine metagenomes from all the major oceanic provinces. According to our careful taxonomic analysis, the 13 strains corresponded, in fact, to ten different Prochlorococcus species. This analysis establishes a new taxonomic framework for the genus Prochlorococcus. Further, the analysis of the metagenomic data suggests that, in total, there may only be 35 Prochlorococcus species in the world's oceans. We propose that the dearth of species observed in this study is driven by high selective pressures that limit diversification in the global ocean.


Cognitive and medical features of chromosomal aneuploidy.
This chapter describes the physical characteristics, medical complications, and cognitive and psychological profiles that are associated with chromosomal aneuploidy conditions, a group of conditions in which individuals are born with one or more additional chromosome. Overall, chromosomal aneuploidy conditions occur in approximately 1 in 250 children. Information regarding autosomal disorders including trisomy 21 (Down syndrome), trisomy 13 (Patau syndrome), and trisomy 18 (Edward syndrome) are presented. Sex chromosome aneuploidy conditions such as Klinefelter syndrome (47,XXY), XYY, trisomy X, and Turner syndrome (45,X), in addition to less frequently occurring tetrasomy and pentasomy conditions are also covered. Treatment recommendations and suggestions for future research directions are discussed.


Machine Learning and Neurosurgical Outcome Prediction: A Systematic Review.
Accurate measurement of surgical outcomes is highly desirable to optimize surgical decision-making. An important element of surgical decision making is identification of the patient cohort that will benefit from surgery before the intervention. Machine learning (ML) enables computers to learn from previous data to make accurate predictions on new data. In this systematic review, we evaluate the potential of ML for neurosurgical outcome prediction. A systematic search in the PubMed and Embase databases was performed to identify all potential relevant studies up to January 1, 2017. Thirty studies were identified that evaluated ML algorithms used as prediction models for survival, recurrence, symptom improvement, and adverse events in patients undergoing surgery for epilepsy, brain tumor, spinal lesions, neurovascular disease, movement disorders, traumatic brain injury, and hydrocephalus. Depending on the specific prediction task evaluated and the type of input features included, ML models predicted outcomes after neurosurgery with a median accuracy and area under the receiver operating curve of 94.5% and 0.83, respectively. Compared with logistic regression, ML models performed significantly better and showed a median absolute improvement in accuracy and area under the receiver operating curve of 15% and 0.06, respectively. Some studies also demonstrated a better performance in ML models compared with established prognostic indices and clinical experts. In the research setting, ML has been studied extensively, demonstrating an excellent performance in outcome prediction for a wide range of neurosurgical conditions. However, future studies should investigate how ML can be implemented as a practical tool supporting neurosurgical care.


Clinical utility of negative methicillin-resistant Staphylococcus aureus (MRSA) nasal surveillance swabs in skin and skin structure infections.
Negative methicillin-resistant Staphylococcus aureus (MRSA) nasal swabs have a high negative predictive value of approximately 99% in respiratory infections. There is, however, a lack of data evaluating its use beyond respiratory infections. We conducted a retrospective analysis to determine the clinical utility of MRSA swabs for identifying MRSA-associated skin and skin structure infections (SSSIs) and the potential effects on antimicrobial stewardship efforts. Baseline characteristics, culture data, and antibiotic data were collected to determine the difference in duration of vancomycin therapy. Positive predictive value, negative predictive value, sensitivity, and specificity were secondary outcomes. A total of 473 patients were included, of which 156 patients had a positive MRSA nasal swab and 317 patients had a negative swab. The median duration of vancomycin was 4 days in the positive group and 3 days in the negative group (P = .01). The positive predictive value and negative predictive value were 22.4% and 97.5%. The sensitivity and specificity were 81.4% and 71.9%. Patients with a negative MRSA nasal swab received approximately 1 day less of vancomycin, which represented a decrease in drug administered. The negative predictive value for SSSIs is promising, showing potential for the role of MRSA nasal swabs in de-escalating therapy.


Development and evaluation of febuxostat solid dispersion through screening method.
Febuxostat (Febux) is a BCS II drug and has a very low solubility. In order to overcome this shortcoming, the purpose of study is to increase the in vitro dissolution (%) and drug release (%) of Febux by using a screening method. The Febux-SD formulation was prepared by screening solubilizers, pH agents, and carriers using with a solvent evaporation method. The novel Febux SD formulation was successfully developed. The dissolution (%) of Febux of optimal formulation (SD3) was higher than that of Feburic® tab in pH 1.2, distilled water (DW), and pH 6.8 buffer by 6.3-, 2.6-, and 1.1-fold, respectively, at 60 min. The in vitro drug release (%) and permeability (μg/cm2) of SD3 formulation were improved compared to those of Feburic® tab in the pH shifting method and PBS (7.4), respectively. The SD3 formulation was well maintained the stability for 6 months, and that of physicochemical properties were altered. In conclusion, the Febux solubilization study with meglumine was first attempted and successfully performed. Through the improved dissolution (%) of Febux, high bioavailability of SD3 formulation is expected in animal and human studies.


Involvement of heme regulatory motif in heme-mediated ubiquitination and degradation of IRP2.
Iron regulatory protein 2 (IRP2), a regulator of iron metabolism, is modulated by ubiquitination and degradation. We have shown that IRP2 degradation is triggered by heme-mediated oxidation. We report here that not only Cys201, an invariant residue in the heme regulatory motif (HRM), but also His204 is critical for IRP2 degradation. Spectroscopic studies revealed that Cys201 binds ferric heme, whereas His204 is a ferrous heme binding site, indicating the involvement of these residues in sensing the redox state of the heme iron and in generating the oxidative modification. Moreover, the HRM in IRP2 has been suggested to play a critical role in its recognition by the HOIL-1 ubiquitin ligase. Although HRMs are known to sense heme concentration by simply binding to heme, the HRM in IRP2 specifically contributes to its oxidative modification, its recognition by the ligase, and its sensing of iron concentration after iron is integrated into heme.


Comparison of Etest, agar dilution, broth microdilution and disk diffusion methods for testing in vitro activity of levofloxacin against Staphylococcus spp. isolated from neutropenic cancer patients.
The susceptibility to levofloxacin of 194 consecutive staphylococcal (45 Staphylococcus aureus and 149 coagulase-negative staphylococci) isolates from neutropenic patients was determined by Etest and the results compared with those obtained using NCCLS-methods (broth microdilution, agar dilution and disk diffusion). Overall agreement at +/- 1log(2) dilution for Etest compared with broth microdilution and agar dilution was 99.0 and 83.5%, respectively. The Etest category agreement with broth microdilution and disk diffusion was 95.9 and 89.7%, respectively. Comparison of categories with Etest and agar dilution method gave only 67.0% absolute categorical agreement, with 29.9% minor errors and 10.7% major errors. No very major errors occurred by the four methods tested. Our results show that Etest is a valid alternative to the reference NCCLS-methods for monitoring the clinical usefulness of levofloxacin against staphylococci isolates from neutropenic patients.


Identification of critical amino acids in the proximal C-terminal of TREK-2 K+ channel for activation by acidic pHi and ATP-dependent inhibition.
TWIK-related two-pore domain K+ channels (TREKs) are regulated by intracellular pH (pHi) and Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). Previously, Glu306 in proximal C-terminal (pCt) of mouse TREK-1 was identified as the pHi-sensing residue. The direction of PI(4,5)P2 sensitivity is controversial, and we have recently shown that TREKs are inhibited by intracellular ATP via endogenous PI(4,5)P2 formation. Here we investigate the anionic and cationic residues of pCt for the pHi and ATP-sensitivity in human TREK-2 (hTREK-2). In inside-out patch clamp recordings (ITREK-2,i-o), acidic pHi-induced activation was absent in E332A and was partly attenuated in E335A. Neutralization of cationic Lys (K330A) also eliminated the acidic pHi sensitivity of ITREK-2,i-o. Unlike the inhibition of wild-type (WT) ITREK-2,i-o by intracellular ATP, neither E332A nor K330A was sensitive to ATP. Nevertheless, exogenous PI(4,5)P2 (10 μM) abolished ITREK-2 i-o in all the above mutants as well as in WT, indicating unspecific inhibition by exogenous PI(4,5)P2. In whole-cell recordings of TREK-2 (ITREK-2,w-c), K330A and E332A showed higher or fully active basal activity, showing attenuated or insignificant activation by 2-APB, arachidonic acid, or acidic pHe 6.9. ITREK-1,w-c of WT is largely suppressed by pHe 6.9, and the inhibition is slightly attenuated in K312A and E315A. The results show concerted roles of the oppositely charged Lys and Glu in pCt for the ATP-dependent low basal activity and pHi sensitivity.


Practice patterns among pediatric urologists in the use of Deflux® for vesicoureteral reflux: a survey.
This study aims to assess pediatric urology practice patterns and factors which influence the use of Deflux(®) in the management of vesicoureteral reflux among pediatric urologists. A 11-question survey was sent out to 476 pediatric urologists who are members of the Society for Pediatric Urology. 23.7% of pediatric urologists use Deflux(®) as first line therapy for Grade III reflux or higher. The presence of renal scarring is not a deterrent to the use of Deflux(®). 17.7% would use Deflux(®) before a trial of observation with or without chemoprophylaxis. In children who are on observation, 20.3% would perform Deflux(®) when they are at an age considered appropriate for surgery as opposed to continued observation. The majority of pediatric urologists cite Deflux(®) success rates of >70% to >80% for Grades II-III and >50% to >60% for Grades IV-V. 23.3% of respondents indicated that new evidence citing low long-term success rates at one year decreased their use of Deflux(®). 59.8% of respondents indicated they would perform a second injection after an initial failure. Ultrasound and VCUG are used as follow-up in 86.9% and 65.4% respectively after Deflux(®); the majority are performed within the first 3 months, rarely at one year. The use of Deflux(®) is growing and whether it surpasses open reimplantation and chemoprophylaxis as first-line therapy remains to be seen. With new literature showing lower success rates, long-term follow-up with repeat imaging may be required.


Aberrant populations of circulating T follicular helper cells and regulatory B cells underlying idiopathic pulmonary fibrosis.
T follicular helper (Tfh) cells have been identified as a new category of helper T cells, which express CXCR5 on their surface and induce the production of antigen-specific antibodies. Many investigations have found morbid proliferation and/or activation of Tfh cells in systemic autoimmune and allergic diseases. It is also known that Tfh cells are regulated by regulatory B (Breg) cells in the deteriorating such diseases. Recently, CXCL13, a ligand of CXCR5, has been reported to increase in the peripheral blood and lungs of patients with idiopathic pulmonary fibrosis (IPF). This study aimed to investigate the involvement of Tfh cells and Breg cells in IPF. Peripheral blood samples were obtained from 18 patients with IPF. We isolated heparinized peripheral blood mononuclear cells and investigated the proportions of Breg cells, Tfh cells, PD-1+ICOS+ Tfh cells (activated form of Tfh cells), and the Tfh-cell subsets by flow cytometry. These cell profiles were compared with those of 21 healthy controls. Furthermore, we investigated the correlations between profiles of lymphocytes and lung physiology. The median proportions of Tfh cells per total CD4+ T cells and of PD-1+ICOS+ proportion of Tfh cells per total Tfh cells was significantly more in the IPF patients (20.4 and 5.2%, respectively) compared with healthy controls (15.4 and 2.1%, respectively; p = 0.042 and p = 0.004, respectively). The proportion of Tfh2 cells per total Tfh cells was significantly higher and the proportion of Tfh17 was smaller in the IPF patients than healthy controls. The percentage of Breg cells to total B cells was significantly decreased in the IPF patients (median, 8.5%) compared with that in the controls (median, 19.7%; p < 0.001). The proportion of Breg cells was positively correlated with the annual relative change in diffusing capacity of the lungs for carbon monoxide in the IPF patients (r = 0.583, p = 0.018). Proliferation and activation of Tfh cells and a decrease in Breg cells were observed in the peripheral blood of patients with IPF. The profile of the Tfh-cell subset also changed. Specific humoral immunity aberration would likely underlie complicated pathophysiology of IPF.


INCA 2.0: A tool for integrated, dynamic modeling of NMR- and MS-based isotopomer measurements and rigorous metabolic flux analysis.
Metabolic flux analysis (MFA) combines experimental measurements and computational modeling to determine biochemical reaction rates in live biological systems. Advancements in analytical instrumentation, such as nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS), have facilitated chemical separation and quantification of isotopically enriched metabolites. However, no software packages have been previously described that can integrate isotopomer measurements from both MS and NMR analytical platforms and have the flexibility to estimate metabolic fluxes from either isotopic steady-state or dynamic labeling experiments. By applying physiologically relevant cardiac and hepatic metabolic models to assess NMR isotopomer measurements, we herein test and validate new modeling capabilities of our enhanced flux analysis software tool, INCA 2.0. We demonstrate that INCA 2.0 can simulate and regress steady-state 13C NMR datasets from perfused hearts with an accuracy comparable to other established flux assessment tools. Furthermore, by simulating the infusion of three different 13C acetate tracers, we show that MFA based on dynamic 13C NMR measurements can more precisely resolve cardiac fluxes compared to isotopically steady-state flux analysis. Finally, we show that estimation of hepatic fluxes using combined 13C NMR and MS datasets improves the precision of estimated fluxes by up to 50%. Overall, our results illustrate how the recently added NMR data modeling capabilities of INCA 2.0 can enable entirely new experimental designs that lead to improved flux resolution and can be applied to a wide range of biological systems and measurement time courses.


Effects of differentiation on purinergic and neurotensin-mediated calcium signaling in human HT-29 colon cancer cells.
Calcium signaling is a key regulator of processes important in differentiation. In colon cancer cells differentiation is associated with altered expression of specific isoforms of calcium pumps of the endoplasmic reticulum and the plasma membrane, suggesting that differentiation of colon cancer cells is associated with a major remodeling of calcium homeostasis. Purinergic and neurotensin receptor activation are known regulators of cytosolic free Ca(2+) levels in colon cancer cells. This study aimed to assess changes in cytosolic free Ca(2+) levels in response to ATP and neurotensin with differentiation induced by sodium butyrate or culturing post-confluence. Parameters assessed included peak cytosolic free Ca(2+) level after activation; time to reach peak cytosolic free Ca(2+) and the EC50 of dose response curves. Our results demonstrate that differentiation of HT-29 colon cancer cells is associated with a remodeling of both ATP and neurotensin mediated Ca(2+) signaling. Neurotensin-mediated calcium signaling appeared more sensitive to differentiation than ATP-mediated Ca(2+) signaling.


Annexin V expression in human placenta is influenced by the carriership of the common haplotype M2.
In a group of placentas from patients with preeclampsia or fetal growth restriction, reduced annexin V gene expression in those carrying the M2 haplotype was observed. This is the first "ex vivo" demonstration that annexin V gene expression in placentas is dependent on the M2 haplotype.


Administrative and research policies required to bring cellular therapies from the research laboratory to the patient's bedside.
The research process is a balance between the inherent risks of new discoveries and the risks of research participant safety. Conflicts of interest, inherent to the research process, as well as those introduced by emerging cellular therapies, have the potential to compromise safety. The relationship of trust between the researcher and the clinical trial participant facilitates objective decision making, in the best interest of both parties. In the setup of each clinical trial, investigators incorporate ethical, political, legal, financial, and regulatory considerations as protocols are established. Responsibility to abide by these decisions ensures a systematic process and safeguards participants in this process. The integrity of the research process is strengthened by identifying potential conflicting issues with the guiding principles established in the protocols, which may threaten the objectivity of involved parties and jeopardize safety of the participants. The rapid pace and changing paradigms of new discoveries in cellular therapies exaggerate existing conflicts and introduce new ones. Ethical issues raised by emerging cellular therapies include the division of opinions regarding the use of embryonic and fetal tissue to develop stem cell lines for research, the individual versus professional conscience of a researcher, overselling of outcomes as a result of the researcher's desire to be the first to discover a cellular therapy, and therapeutic misconception resulting from a participant's desire for a miracle cure. The basic ethical issue of whether stem cells should be utilized as a cellular therapy raises heated debates because some believe that it is not acceptable to use fetal material as a source of research material for future cures and others feel equally as strong that inaction is unethical because it results in needless suffering and death owing to the absence of this research. Political issues include the divergent position statements of presidential administrations on cellular therapy, variations in individual state laws, and states becoming involved in research funding, such as California's Proposition 71. Legal concerns include expanding private litigation with diversity of lawsuits, expanding lists of defendants, and the use of class-action lawsuits in research cases. Ownership issues also arise in terms of intellectual property, patents, and ownership of stem cells collected from minors, as in umbilical cord blood donations. Situations that challenge the regulatory processes established to ensure participant safety include differences in reporting requirements for private- and public-funded research and the lack of adequate funding and resources to implement and support the institutional review board (IRB) process. Financial considerations influence the development of clinical protocols, because funding is often limited. Financial incentives, personal investment in companies funding research activities, and fundraising pressures may present potential conflicts. In addition, the increasing role of emerging biotechnology start-up companies and pharmaceutical companies in clinical research introduces additional financial considerations. Administrative policies are needed to address these possible conflicts and ensure research participant safety as cellular therapies progress from the research laboratories to the patient's bedside. Administrative policies to ensure minimum standards of quality for emerging products before human clinical trials, policies to enforce consistent reporting requirements for private and public cellular research, policies to minimize financial conflicts of interest, policies to strengthen implementation of the existing IRB process and to structure into the process a consistent, systematic review of these identified conflicts, and policies to limit private litigation will help to preserve the objectivity of the review process and ultimately increase participant safety.


Diagnosis and prevention of equine infectious diseases: present status, potential, and challenges for the future.
The frequent transfers of horses, whether on a permanent or temporary basis, make strict control of infectious diseases essential. Such control needs a reliable and rapid means to accurately diagnose the relevant diseases. Indirect diagnosis based on antibody detection remains certainly the best method to secure the epidemiologic surveillance of the diseases at regional, national, or even world level, while direct diagnosis is the only way to diagnose a new outbreak. New diagnostic methods resulting from advances in biochemistry, molecular biology, and immunology are now available. As far as antibody detection is concerned, the new methods are mainly based on immunoassays, especially ELISAs. Regarding the identification of the pathogens, while isolation is still of importance, much progress has been made with immunocapture tests including capture ELISA based on monoclonal antibodies. DNA probes and amplification tests such as PCR or RT-PCR are representing a real breakthrough. Factors common to all of these tests are specificity, sensitivity, rapid implementation, and quick results. Such tests are, however, often still at the development stage. They absolutely need to be validated under multicentric evaluations prior to being used on a larger scale. At the same time there is an obvious need for the standardization of the reagents used. The technical and economic impact of a false (either positive or negative) diagnosis justifies such an harmonization which could effectively be achieved worldwide under the aegis of the Office International des Epizooties (OIE), which is itself the primary source of disease information. Vaccines are also essential for the control of equine infectious diseases. Most vaccines used in the prevention of viral or bacterial diseases are inactivated adjuvanted vaccines, which may cause unacceptable side effects. Also, their efficacy can sometimes be questioned. Subunit vaccines, when available, represent significant advances especially with regards to safety. Greater progress is expected from the use of new technologies taking advantage of recent developments in molecular biology (recombinant DNA technology) and in immunology (immunomodulators). Significant results have been obtained with subunit vaccines or with live vectored vaccines using recombinant DNA technology. Good results are on the way to be achieved with genetic (or naked-DNA) vaccines. It is therefore possible to expect the availability of a new generation of vaccines in the rather short term. Such vaccines will not only be safer and more efficacious, but they will also make it possible to differentiate vaccinated from infected animals, which will contribute to better control of the infection. Whatever the quality of the vaccines of the future may be, vaccination alone will never be sufficient to control infectious diseases. It is therefore essential to keep on making the animal owners and their veterinarians aware of the importance of the management and the hygiene in the diseases control and to organize them under "Common Codes of Practice."


Milk fat depression and the influence of diet on milk composition.
Milk composition depends on inheritance, stage of lactation, age, infection, and diet. Fat is the most variable component of milk, and its concentration depends on the supply of acetate, butyrate, and performed fatty acids to the mammary gland. This supply depends on diet and competition among organs. Adequate, effective fiber is the critical dietary consideration.


Risk factors for cancer-related fatigue in patients with colorectal cancer: a systematic review and meta-analysis.
Cancer-related fatigue seriously affects the quality of life of cancer patients, yet few systematic reviews have evaluated the risk factors for cancer-related fatigue in patients with colorectal cancer. We therefore conducted a meta-analysis to assess the risk factors of cancer-related fatigue in patients with colorectal cancer. Literature databases, including PubMed, Ovid, Embase, the Cochrane Central Register of Controlled Trials, the Web of Science, the China National Knowledge Infrastructure, Wanfang, and VIP, were searched from their establishment to September 2021 to identify suitable studies. The quality of included studies was assessed using different tools and evaluated independently by two investigators. Review Manager version 5.4 (Cochrane Collaboration, London, UK) was used for statistical analysis, and sensitivity analysis was conducted. In total, 2642 articles were screened, and data from 25 studies involving 8733 subjects were included in this meta-analysis. After controlling for confounding variables, the following risk factors were associated with cancer-related fatigue: younger age, female sex, low physical activity level, a clinical stage of III or IV, surgery, chemotherapy, insomnia, pain, anxiety, and depression. Younger age, female sex, low physical activity level, a clinical stage of III or IV, chemotherapy, pain, insomnia, anxiety, and depression were identified as risk factors for cancer-related fatigue. Future research should focus on how multidisciplinary teams adopt targeted measures according to these risk factors to better reduce the incidence of cancer-related fatigue.


[High-risk stress fractures in competitive athletes].
Bone stress injuries are chronic overload reactions of the bone, which are characterized by the load-dependent occurrence of locally perceived pain and tenderness on palpation at the site of the injury. Structurally normal bone becomes fatigued as a result of repetitive submaximal loading and/or inadequate regeneration. Certain stress fractures of the femoral neck (tension side), patella, anterior tibial cortex, medial malleolus, talus, tarsal navicular bone, proximal fifth metatarsal, and sesamoid bones of the great toe tend to develop complications (complete fractures, delayed union, pseudarthrosis, dislocation, arthrosis). These injuries are classified as high-risk stress fractures. Aggressive diagnostics and treatment are recommended when a high-risk stress fracture is suspected. Treatment is frequently different from low-risk stress fractures, including prolonged non-weight-bearing immobilization. In rare cases, surgery is indicated when conservative treatment fails, when a complete or non-healing fracture develops, or in cases of dislocation. The outcomes of both conservative and operative treatment are described as less successful compared with low-risk stress injuries.


Developmental regulation of a constitutively expressed mouse mRNA encoding a 72-kDa heat shock-like protein.
Multiple heat shock cognate (hsc70) cDNA clones were isolated from the mouse embryonal carcinoma cell line F9. They all encode a single 72-kDa protein, which is constitutively expressed in all mouse cell lines and tissues tested, and which is only slightly induced by hyperthermia. hsc70 RNA is very abundant in F9 stem cells and brain, but very little is found in 14-day-old embryos. Upon differentiation of F9 stem cells induced by retinoic acid and cyclic AMP, expression of the hsc70 gene decreases only slightly, suggesting that hsc70 is highly expressed in early mouse development and is then down-regulated towards the end of embryogenesis. In adult tissues only the brain retains the high level of hsc70 gene expression found in F9 stem cells. We also show that expression of hsc70 protein and clathrin is uncoupled in F9 cells, indicating that the uncoating activity of coated vesicles may not be the only function of hsc70 protein.


Attributional styles of support staff working with people with intellectual disabilities exhibiting challenging behaviour.
Attributions are cognitive variables that influence a person's behaviour. Although a large volume of research has been conducted on the attributions of support staff with regard to challenging behaviour (CB) exhibited by people with intellectual disabilities (ID), studies on patterns of attributional dimensions (i.e. attributional styles) are scarce. Using semi-structured interviews, 19 support staff members were asked to describe incidents of aggressive, self-injurious and sexualized challenging behaviour. Data on attributions were analysed using the Leeds Attributional Coding System. Four attributional styles differed significantly for aggressive, self-injurious and sexualized challenging behaviour. In addition, support staff members largely attributed these three types of CB to characteristics and behaviour of clients with ID. The results indicate that it is important to train support staff to recognize and understand the ways in which their attributions and behaviour influence the existence and maintenance of CB.