Effect of clothing layers in combination with fire fighting personal protective clothing on physiological and perceptual responses to intermittent work and on materials performance test results.
Personal protective clothing (PPC) shields firefighters from thermal and other occupational hazards; however, it also contributes to physiological and perceptual strain. This study examined the effect of clothing layers worn under structural fire fighting turnout gear (TOG) on physiological and perceptual responses during alternating work/recovery cycles and assessed the clothing ensembles' (PPC + base layer) material performance. Values are reported as mean ± standard error of the mean. Ten men (age, 21 ± 0.3 yr; height, 1.74 ± 0.02 m; weight, 74.3 ± 2.3 kg; VO2max, 58.9 ± 2.0 mL/kg/min) completed a 110-min alternating work/recovery walking protocol (three 20-min exercise bouts/10-, 20-, and 20-min recovery sessions) in a thermo-neutral (21.0°C, 58.7% RH) laboratory while wearing a cotton t-shirt (COT) or COT and a station uniform (SU) shirt under fire fighting TOG (COT+TOG and COT+SU+TOG, respectively). Changes in heart rate (HR), core temperature (Tco), skin temperature (Tsk), rating of perceived exertion (RPE), and thermal sensations (TS) were compared across exercise and recovery periods. During exercise sessions, HR, Tco, Tsk, and RPE reached similar levels for COT+TOG and COT+SU+TOG. During Recoveries 1, 2, and 3, mean chest Tsk decreased by 3.96, 6.64, and 6.49°C, respectively, for COT+TOG compared with 2.24, 3.78, and 4.09°C for COT+SU+TOG (p < 0.05 for each period). Change in TS differed during Exercise 1; however, mean peak TS corresponded to "hot" for both ensembles. This study demonstrates that the additional layer of clothing in the COT+SU+TOG ensemble imposed no greater level of physiological or perceptual strain during moderate-intensity work bouts compared with the COT+TOG ensemble. However, some modest benefits were experienced during the recovery sessions for the COT+TOG ensemble as evidenced by a lower chest Tsk. In addition, materials performance testing revealed COT+SU+TOG provided greater thermal protection (64.8 ± 1.9 vs. 56.4 ± 0.3 cal/cm(2); p < 0.05) and equivalent heat dissipation compared with COT+TOG. These findings could guide departmental decisions about the use of station shirts.


A meta-analysis comparing the prognostic accuracy of six diagnostic tests for predicting perioperative cardiac risk in patients undergoing major vascular surgery.
To evaluate the discriminatory value and compare the predictive performance of six non-invasive tests used for perioperative cardiac risk stratification in patients undergoing major vascular surgery. Meta-analysis of published reports. Eight studies on ambulatory electrocardiography, seven on exercise electrocardiography, eight on radionuclide ventriculography, 23 on myocardial perfusion scintigraphy, eight on dobutamine stress echocardiography, and four on dipyridamole stress echocardiography were selected, using a systematic review of published reports on preoperative non-invasive tests from the Medline database (January 1975 and April 2001). Random effects models were used to calculate weighted sensitivity and specificity from the published results. Summary receiver operating characteristic (SROC) curve analysis was used to evaluate and compare the prognostic accuracy of each test. The relative diagnostic odds ratio was used to study the differences in diagnostic performance of the tests. In all, 8119 patients participated in the studies selected. Dobutamine stress echocardiography had the highest weighted sensitivity of 85% (95% confidence interval (CI) 74% to 97%) and a reasonable specificity of 70% (95% CI 62% to 79%) for predicting perioperative cardiac death and non-fatal myocardial infarction. On SROC analysis, there was a trend for dobutamine stress echocardiography to perform better than the other tests, but this only reached significance against myocardial perfusion scintigraphy (relative diagnostic odds ratio 5.5, 95% CI 2.0 to 14.9). On meta-analysis of six non-invasive tests, dobutamine stress echocardiography showed a positive trend towards better diagnostic performance than the other tests, but this was only significant in the comparison with myocardial perfusion scintigraphy. However, dobutamine stress echocardiography may be the favoured test in situations where there is valvar or left ventricular dysfunction.


Nutrient tasting and signaling mechanisms in the gut. II. The intestine as a sensory organ: neural, endocrine, and immune responses.
The lining of the gastrointestinal tract is the largest vulnerable surface that faces the external environment. Just as the other large external surface, the skin, is regarded as a sensory organ, so should the intestinal mucosa. In fact, the mucosa has three types of detectors: neurons, endocrine cells, and immune cells. The mucosa is in immediate contact with the intestinal contents so that nutrients can be efficiently absorbed, and, at the same time, it protects against the intrusion of harmful entities, such as toxins and bacteria, that may enter the digestive system with food. Signals are sent locally to control motility, secretion, tissue defense, and vascular perfusion; to other digestive organs, for example, to the stomach, gallbladder, and pancreas; and to the central nervous system, for example to influence feeding behavior. The three detecting systems in the intestine are more extensive than those of any other organ: the enteric nervous system contains on the order of 10(8) neurons, the gastroenteropancreatic endocrine system uses more than 20 identified hormones, and the gut immune system has 70- 80% of the body's immune cells. The gastrointestinal tract has an integrated response to changes in its luminal contents. When this response is maladjusted or is overwhelmed, the consequences can be severe, as in cholera intoxication, or debilitating, as in irritable bowel syndrome. Thus it is essential to obtain a full understanding of the sensory functions of the intestine, of how the body reacts to the information, and of how neural, hormonal, and immune signals interact.


The effect of age on radiocephalic fistula patency.
Inferior patency rates for radiocephalic fistulae in the elderly have been reported and may explain the increasing use of prosthetic grafts for vascular access. The aim of this study was to assess whether the patency rates of primary radiocephalic fistulae are affected by age. A retrospective casenote review of 53 consecutive patients undergoing primary fistula formation between 1995 and 1998 under the care of a single consultant vascular surgeon. The setting was a specialist vascular surgical unit where the protocol is to offer all new patients a radiocephalic fistula. Fistula patency was defined as successful use for dialysis. Cumulative patency rates at 2 years were 60% in patients over 60 years (n=27), and 53% in patients under 60 years (n=26). The higher patency rates in the older age group were not significant on log rank testing (p=0.39). Age over 60 years did not influence patency rates of primary radiocephalic fistulae, which should remain the haemodialysis access procedure of choice at all ages.


Maintaining Treatment Fidelity of Mindfulness-Based Relapse Prevention Intervention for Alcohol Dependence: A Randomized Controlled Trial Experience.
Treatment fidelity is essential to methodological rigor of clinical trials evaluating behavioral interventions such as Mindfulness Meditation (MM). However, procedures for monitoring and maintenance of treatment fidelity are inconsistently applied, limiting the strength of such research. To describe the implementation and findings related to fidelity monitoring of the Mindfulness-Based Relapse Prevention for Alcohol Dependence (MBRP-A) intervention in a 26-week randomized controlled trial. 123 alcohol dependent adults were randomly assigned to MM (MBRP-A and home practice, adjunctive to usual care; N = 64) or control (usual care alone; N = 59). Treatment fidelity assessment strategies recommended by the National Institutes of Health Behavior Change Consortium for study/intervention design, therapist training, intervention delivery, and treatment receipt and enactment were applied. Ten 8-session interventions were delivered. Therapist adherence and competence, assessed using the modified MBRP Adherence and Competence Scale, were high. Among the MM group participants, 46 attended ≥4 sessions; over 90% reported at-home MM practice at 8 weeks and 72% at 26 weeks. They also reported satisfaction with and usefulness of MM for maintaining sobriety. No adverse events were reported. A systematic approach to assessment of treatment fidelity in behavioral clinical trials allows determination of the degree of consistency between intended and actual delivery and receipt of intervention.


Effect of emergency department immunizations on immunization rates and subsequent primary care visits.
The Standards for Pediatric Immunization Practices recommend the routine use of emergency department (ED) encounters for screening the immunization status of children and, if indicated, immunizing them. To test the hypothesis that ED immunizations will improve immunization rates without decreasing subsequent primary care visits. A randomized controlled trial of 2 interventions. Children (aged 6-36 months) (n = 1835) were enrolled in the study in the ED; informed consent was obtained from their parents. They were randomized into 1 of 3 groups: (1) the control group (n = 614), in which no intervention was undertaken; (2) the letter group (n = 610), in which a letter to the primary care physician was written indicating the child's estimated likelihood of being underimmunized; and (3) the ED vaccination group (n = 611), in which, based on a decision rule, those likely to be underimmunized were offered immunizations in the ED. After randomization, parents were interviewed in the ED using a decision rule to estimate the likelihood of the child being underimmunized. One year after enrollment in the study, the medical records of the children at their primary care sites were reviewed to determine the immunization status of the children and primary care use patterns. An urban ED and 54 primary care sites in Monroe County, New York. The mean age of the participants was 17.9 months. Medical record review-verified underimmunization rates at the time of the ED visit were 33%, 31%, and 28% for the control, letter, and ED vaccination groups, respectively. The demographic characteristics and baseline immunization rates were not different among study groups. According to the decision rule, 248 children (41%) in the ED vaccination group were likely to be underimmunized. Parents of these 248 children were offered immunizations for their children; 117 (47%) accepted, and their children were immunized (with 230 separate immunizations). One month after the ED visits, the underimmunization rates of the study groups were 31%, 28% (P = .40 compared with the control group), and 23% (P = .002). One year later, these rates were 28%, 25% (P = .20), and 25% (P = .20). No clinically meaningful differences were present at either of these times. One year after the ED visit, no differences in the rates of primary care use were found among groups. This study provides evidence that the immunization of children in this ED was ineffective at raising their immunization rates; primary care attendance was also unaltered. Major obstacles were as follows: (1) an inability to ascertain accurately the immunization status in the ED and (2) a high rate of parental refusal to accept immunizations in the ED. The standards should be modified to de-emphasize the ED as a routine immunization site for children with access to primary care. Efforts and resources should be directed toward strengthening the primary care system and tracking immunization status.


Postnatal inflammation increases seizure susceptibility in adult rats.
There are critical postnatal periods during which even subtle interventions can have long-lasting effects on adult physiology. We asked whether an immune challenge during early postnatal development can alter neuronal excitability and seizure susceptibility in adults. Postnatal day 14 (P14) male Sprague Dawley rats were injected with the bacterial endotoxin lipopolysaccharide (LPS), and control animals received sterile saline. Three weeks later, extracellular recordings from hippocampal slices revealed enhanced field EPSP slopes after Schaffer collateral stimulation and increased epileptiform burst-firing activity in CA1 after 4-aminopyridine application. Six to 8 weeks after postnatal LPS injection, seizure susceptibility was assessed in response to lithium-pilocarpine, kainic acid, and pentylenetetrazol. Rats treated with LPS showed significantly greater adult seizure susceptibility to all convulsants, as well as increased cytokine release and enhanced neuronal degeneration within the hippocampus after limbic seizures. These persistent increases in seizure susceptibility occurred only when LPS was given during a critical postnatal period (P7 and P14) and not before (P1) or after (P20). This early effect of LPS on adult seizures was blocked by concurrent intracerebroventricular administration of a tumor necrosis factor alpha (TNFalpha) antibody and mimicked by intracerebroventricular injection of rat recombinant TNFalpha. Postnatal LPS injection did not result in permanent changes in microglial (Iba1) activity or hippocampal cytokine [IL-1beta (interleukin-1beta) and TNFalpha] levels, but caused a slight increase in astrocyte (GFAP) numbers. These novel results indicate that a single LPS injection during a critical postnatal period causes a long-lasting increase in seizure susceptibility that is strongly dependent on TNFalpha.


Pathogenesis of deep endometriosis.
The pathophysiology of (deep) endometriosis is still unclear. As originally suggested by Cullen, change the definition "deeper than 5 mm" to "adenomyosis externa." With the discovery of the old European literature on uterine bleeding in 5%-10% of the neonates and histologic evidence that the bleeding represents decidual shedding, it is postulated/hypothesized that endometrial stem/progenitor cells, implanted in the pelvic cavity after birth, may be at the origin of adolescent and even the occasionally premenarcheal pelvic endometriosis. Endometriosis in the adolescent is characterized by angiogenic and hemorrhagic peritoneal and ovarian lesions. The development of deep endometriosis at a later age suggests that deep infiltrating endometriosis is a delayed stage of endometriosis. Another hypothesis is that the endometriotic cell has undergone genetic or epigenetic changes and those specific changes determine the development into deep endometriosis. This is compatible with the hereditary aspects, and with the clonality of deep and cystic ovarian endometriosis. It explains the predisposition and an eventual causal effect by dioxin or radiation. Specific genetic/epigenetic changes could explain the various expressions and thus typical, cystic, and deep endometriosis become three different diseases. Subtle lesions are not a disease until epi(genetic) changes occur. A classification should reflect that deep endometriosis is a specific disease. In conclusion the pathophysiology of deep endometriosis remains debated and the mechanisms of disease progression, as well as the role of genetics and epigenetics in the process, still needs to be unraveled.


Comparison of isotope labeling patterns of purines in three specific transfer RNAs.
Purine C-8 tritium-labeling rates have been measured at specific sites in Escherichia coli tRNAIle and tRNA2Tyr. The results are compared with those obtained for yeast tRNAPhe (preceding paper(Gamble et al., 1976)). The tRNAIle and tRNAPhe fall into the same general class of tRNA structures, while tRNA2Tyr is in a differint class; in particular, the latter is characterized by a large extra loop. In each of the three tRNAs the 3'-terminal A has the same labeling rate and, on a relative basis, appears to be the most rapidly labeled site. Bases in cloverleaf helical sections have markedly retarded labeling rates that collectively fall within an approximately threefold range of time constants. At some of the common purines, believed to be essential for the construction of a general system of tertiary interactions, exchange rates for yeast tRNAPhe are significantly different than those for the two Escherichia coli tRNAs. these differences may arise from variations among the tRNAs in the relative stabilities of specific tertiary interactions, or from other factors as well. In the case of tRNA2Tyr, labeling rates for bases in the large variable region are sufficiently retarded to suggest some structural organization for this part of the molecule. In addition, since exchange rates are similar for some of the bases common to Escherichia coli tRNAIle and tRNA2Tyr, it is likely that the large variable loop of tRNA2Tyr does not interact with or perturb these common sites. Finally, for all three tRNAs, structure formation (e.g., base pairing, base stacking) invariably decreases the labeling rate, even though the variety of base environments in the three-dimensional structures of these tRNAs might be expected to affect the acidity of C-8 and other chemical properties in diverse ways. Although these chemical effects no doubt bear influence, in these studies the dominant influence on exchange may be the effect of structure on the accessibility of solvent molecules, i.e. water.


Opposing roles of STAT4 and Dnmt3a in Th1 gene regulation.
The STAT transcription factor STAT4 is a critical regulator of Th1 differentiation and inflammatory disease. Yet, how STAT4 regulates gene expression is still unclear. In this report, we define a STAT4-dependent sequence of events including histone H3 lysine 4 methylation, Jmjd3 association with STAT4 target loci, and a Jmjd3-dependent decrease in histone H3 lysine 27 trimethylation and DNA methyltransferase (Dnmt) 3a association with STAT4 target loci. Dnmt3a has an obligate role in repressing Th1 gene expression, and in Th1 cultures deficient in both STAT4 and Dnmt3a, there is recovery in the expression of a subset of Th1 genes that is sufficient to increase IFN-γ production. Moreover, although STAT4-deficient mice are protected from the development of experimental autoimmune encephalomyelitis, mice deficient in STAT4 and conditionally deficient in Dnmt3a in T cells develop paralysis. Th1 genes that are derepressed in the absence of Dnmt3a have greater induction after the ectopic expression of the Th1-associated transcription factors T-bet and Hlx1. Together, these data demonstrate that STAT4 and Dnmt3a play opposing roles in regulating Th1 gene expression, and that one mechanism for STAT4-dependent gene programming is in establishing a derepressed genetic state susceptible to transactivation by additional fate-determining transcription factors.


Formation of 3-monochloro-1,2-propanediol (3-MCPD) di- and monoesters from tristearoylglycerol (TSG) and the potential catalytic effect of Fe²⁺ and Fe³⁺.
This study investigated whether and how triacylglycerol (TAG) may serve as a precursor for 3-monochloro-1,2-propanediol (3-MCPD) fatty acid ester formation using tristearoylglycerol (TSG). TSG was reacted with inorganic chloride compounds including NaCl, KCl, FeCl2, CuCl2, ZnCl2, FeCl3 and dry HCl, or organic chlorine compound lindane at different temperatures. Only FeCl2 and FeCl3 were able to form 3-MCPD esters from TSG. Further electron spin resonance (ESR) determination of TSG, Fe2(SO4)3 and 5,5-dimethylpyrroline-N-oxide (DMPO) reactions revealed potential of Fe ion in promoting free radical generations under the experimental conditions. To further confirm the effect of Fe ion, chelating agent (EDTA-2Na) was added to the model reactions. The results showed for the first time that EDTA-2Na was able to reduce the generation of 3-MCPD esters. In addition, FT-IR examination indicated a possible involvement of a carbonyl group during the reaction. Taking all the observations together, the possible mechanisms, involving the formation of either a cyclic acyloxonium or a glycidol ester radical intermediate, were proposed for generating 3-MCPD fatty acid di- and mono- esters from TAG under a high temperature and low moisture condition, as well as the coformation of glycidol esters. The results from this study may be useful for reducing the level of 3-MCPD esters and related toxicants in the refined edible oils and food products.


[The importance of electrographic investigations for the diagnosis and treatment of acroparesthesias (author's transl)].
Acroparesthesias may develop as a result of various pathological processes which affect the nerves of the hand. Usually the diagnosis can be made from the history and the clinical findings. If objectifiable neurological findings are lacking, electrographic investigations must be carried out. If several diseases are present, electrography (stimulation and myography) is particularly important for diagnosis and therapy. In compression of the median nerve in the carpal tunnel, the speed of sensory conduction is delayed in about 85%, an anomalous motor latent duction is delayed in about 70%. A distal motor latency of the median nerve of more than 8 m/sec is an absolute indication for a surgical intervention. Signs of denervation of the thenar muscles also required operative treatment.


[Overdenture supported by natural teeth: analysis of clinical advantages].
Hybrid prosthesis supported by natural teeth (overdenture) is widely used in clinical practice and should be executed whenever the clinical conditions suggest it. Through a critical review of the literature, the anatomical, functional, psychological and clinical advantages are emphasized. Among the first ones, the prophylaxis of residual anatomical components, due to the limitation of bone resorption, and the preservation of sensorial proprioception are relevant. Important advantages are also represented by a better crown-root ratio of residual teeth supporting overdenture, with the consequent improvement of the longitudinal prognosis of such teeth. The greater retention and stability of overdenture in comparison with complete denture greatly improve the masticatory efficacy. The psychological advantages resulting from the dental anchorage, which allows the patient to be more confident in social life, are also relevant. Finally, when the dental support is lost, converting overdenture into complete denture is simple and quick, and makes easier the longitudinal clinical maintenance of the denture.


Acquired long QT syndrome from stress cardiomyopathy is associated with ventricular arrhythmias and torsades de pointes.
Stress cardiomyopathy (SCM) is a syndrome of transient ventricular dysfunction triggered by severe emotional or physical stress, likely resulting from catecholamine-mediated myocardial toxicity. Repolarization abnormalities associated with other hyperadrenergic states can cause QT prolongation and lethal arrhythmia including torsades de pointes (TdP). Despite the development of repolarization abnormalities and QT prolongation in SCM, little is known about the risk of ventricular fibrillation (VF) and TdP. The aim of this study was to assess the prevalence and clinical predictors of ventricular arrhythmias in a cohort of patients with SCM. Data from a registry of consecutive patients with SCM from 2 institutions were reviewed. Patients who developed VF or TdP were identified. Clinical characteristics and outcomes were analyzed and compared with a control group of patients with SCM without VF/TdP. Of 93 patients with SCM, 8 (8.6%) experienced VF/TdP. Of these 8 patients, 2 presented with VF and were subsequently diagnosed with SCM. Six other patients experienced pause-dependent TdP or VF after SCM diagnosis in the setting of substantial QT prolongation. Prolongation of the corrected QT interval (QTc) was significantly associated with the occurrence of ventricular arrhythmia (odds ratio 1.28 for each 10 ms increase in QTc, 95% confidence interval 1.10 to 1.50). SCM can be associated with life-threatening ventricular arrhythmia in over 8% of cases. SCM should be recognized among the causes of acquired long QT syndrome and can be associated with a risk of TdP.


Experimental pyelonephritis in the monkey. II. The prognostic value of radionuclide evaluation of the urinary tract.
The radionuclide scintiphoto study, a noninvasive technique, is abnormal in acute pyelonephritis. A delay in excretion of the isotope has also been observed in dehydrated studies in chronic pyelonephritis. To further elucidate this abnormal pattern in pyelonephritis, experimental renal infection was produced in monkeys. Dehydrated 131-I-hippuran scintiphoto studies were conducted weekly for 8 weeks after the initial infection. The scintiphoto studies showed significant delay in excretion of radionuclide in all bacteriuric monkeys at 1 week. After this time, delayed excretion was seen in only those monkeys later classified as having chronic pyelonephritis. This was statistically significant (P smaller than 0.01).


Treatment of metastatic non-small cell lung cancer with NY-ESO-1 specific TCR engineered-T cells in a phase I clinical trial: A case report.
This article presented a case of a human leukocyte antigen (HLA)-A2-positive patient with advanced cancer/testis antigen New York esophageal squamous cell carcinoma-1 (NY-ESO-1) expressing lung adenocarcinoma (LADC) who received adoptive cell therapy of T cell receptor engineered-T cells (TCR-T cells) targeting the cancer-testis antigen NY-ESO-1. The appropriate clinical and laboratory assessments were conducted to investigate the safety and efficacy of this therapy for this lung cancer patient. The patient had a clinical response to and was well-tolerated with this therapy in the clinical trial. In addition, a preliminary evaluation of the safety of NY-ESO-1 TCR-T cell therapy was performed in four patients with non-small cell lung cancer (NSCLC) enrolled in a clinical trial. It was well-tolerated and did not observe any serious adverse events post-infusion. Fever, anemia, and a decrease in white blood cell count were common adverse events, which were likely due to the TCR-T cell therapy. Two patients had clinical responses to NY-ESO-1 TCR-T cell therapy, including the 44-year-old female patient with LADC, who achieved a short-term partial response for 4 months, improved in Karnofsky performance status, and had a recovery of drug sensitivity. This suggests that TCR-T cell therapy targeting NY-ESO-1 antigen may be beneficial for HLA-A2-positive late-stage patients with NY-ESO-1-expressing NSCLC.


Cementation of proximal femoral nails of the very elderly subject in per-trochanteric fractures.
The management of pertrochanteric fractures (PTF) in the very elderly relies on early verticalisation to limit complications of the decubitus and this requires stable osteosynthesis allowing immediate full support without risk of mechanical failure. The aim of the study was to analyse the value of cementing the cervicocephalic blade during osteosynthesis with a proximal femoral nail. A prospective bicentric comparative study was con- ducted. Patients over 90 years of age with PTF were included. Centre A used a PFNA (Proximal Femoral Nail Antirotation) nail without blade cementing and Centre B used the same nail with blade cementing. The primary endpoint was the occurrence of disassembly of the osteosynthesis requiring revision surgery. Secondary endpoints were functional out- come (resumption of walking), postoperative pain and duration of surgery. Sixty-four patients were included in Centre A and 23 patients were included in Centre B. Mean age, gender, functional abilities before fracture, fracture type and tip-apex distance were comparable between the groups. Postoperative pain and duration of surgery did not show significant differences between the groups. Four patients operated on with an uncemented PFNA (6.25%) and one patient operated on with a cemented PFNA nail (4.35%) showed early dismantling. The rate of patients returning to walking was significantly higher in the cemented group (p=0.00005). No significant differences in the rate of dismantling were observed between the two groups. However, the group operated on with a cemented PFNA showed better functional recovery with a significantly higher rate of walking recovery.


The role of COX-2/PGE2 in gossypol-induced apoptosis of colorectal carcinoma cells.
Our previous study showed that gossypol (GOS) exhibits potent cytotoxic effects via apoptosis induction against human colorectal carcinoma cells; however, the role of cyclooxygenase (COX)-2/prostaglandin (PG)E(2) on GOS-induced apoptosis is still unknown. In the present study, 12-O-tetradecanoylphorbol-13-acetate (TPA) addition significantly inhibited GOS-induced apoptosis in human colorectal carcinoma HT-29 cells in accordance with inducing COX-2 protein/PGE(2) production. TPA inhibition of GOS-induced apoptosis was blocked by adding protein kinase (PK)C inhibitors including staurosporine (ST), GF109203X (GF), and H7, characterized by the occurrence of cleaved caspase 3 proteins and a decrease in COX-2 protein/PGE(2) production in HT-29 cells. The addition of COX activity inhibitors, including NS398 (NS), aspirin (AS), diclofenac (DI), and indomethacin (IN), suppressed TPA protection of GOS-induced apoptosis with decreased PGE(2) production in HT-29 cells. Application of PGE(2), but not it analogs PGD(2), PGJ(2), or PGF(2α), protected HT-29 cells from GOS-induced DNA ladders, and the E-prostanoid (EP(1)) receptor agonist, 17PT-PGE(2), mimicked the protection induced by PGE(2), whereas the selective EP(2) receptor agonist, butaprostol (BUT), the EP(3) receptor agonist, sulprostol (SUL), and the EP(4) receptor agonist, PGE(1) alcohol (PGE(1)), showed no significant effects on GOS-induced apoptosis in HT-29 cells. PGE(2) 's protection against GOS-induced apoptosis was reversed by adding the selective EP(1) receptor antagonist, SC-19220. Furthermore, GOS had an effective apoptotic effect on COLO205 colorectal carcinoma cells which expressed undetectable level of endogenous COX-2 protein than HT-29 cells, and the decreased COX-2 protein level via COX-2 siRNA or addition of COX-2 activity inhibitor NS significantly elevated GOS-induced cell death in HT-29 cells. COLO205-T cells were established through sustained TPA incubation of COLO205 cells, and COLO205-T cells showed a lower sensitivity to GOS-induced cell death with increased COX-2 (not Bcl-2 and Mcl-1) protein than parental COLO-205 cells. A decrease in COX-2 protein expression in COLO205-T cells by COX-2 siRNA transfection or enhanced GOS-induced cell death according to MTT assay and DNA integrity assay. The notion of COX-2/PGE(2) activation against GOS-induced apoptosis in colon carcinoma cells was demonstrated, and the combination of GOS and COX-2 inhibitors to treat colon carcinoma possesses clinical potential worthy of further investigation.


Environmental and Clinical Strains of Vibrio cholerae Non-O1, Non-O139 From Germany Possess Similar Virulence Gene Profiles.
Vibrio cholerae is a natural inhabitant of aquatic ecosystems globally. Strains of the serogroups O1 and O139 cause the epidemic diarrheal disease cholera. In Northern European waters, V. cholerae bacteria belonging to other serogroups (designated non-O1, non-O139) are present, of which some strains have been associated with gastrointestinal infections or extraintestinal infections, like wound infections or otitis. For this study, environmental strains from the German coastal waters of the North Sea and the Baltic Sea were selected (100 strains) and compared to clinical strains (10 isolates) that were from patients who contracted the infections in the same geographical region. The strains were characterized by MLST and examined by PCR for the presence of virulence genes encoding the cholera toxin, the toxin-coregulated pilus (TCP), and other virulence-associated accessory factors. The latter group comprised hemolysins, RTX toxins, cholix toxin, pandemic islands, and type III secretion system (TTSS). Phenotypic assays for hemolytic activity against human and sheep erythrocytes were also performed. The results of the MLST analysis revealed a considerable heterogeneity of sequence types (in total 74 STs). The presence of virulence genes was also variable and 30 profiles were obtained by PCR. One profile was found in 38 environmental strains and six clinical strains. Whole genome sequencing (WGS) was performed on 15 environmental and 7 clinical strains that were ST locus variants in one, two, or three alleles. Comparison of WGS results revealed that a set of virulence genes found in some clinical strains is also present in most environmental strains irrespective of the ST. In few strains, more virulence factors are acquired through horizontal gene transfer (i.e., TTSS, genomic islands). A distinction between clinical and environmental strains based on virulence gene profiles is not possible for our strains. Probably, many virulence traits of V. cholerae evolved in response to biotic and abiotic pressure and serve adaptation purposes in the natural aquatic environment, but provide a prerequisite for infection of susceptible human hosts. These findings indicate the need for surveillance of Vibrio spp. in Germany, as due to global warming abundance of Vibrio will rise and infections are predicted to increase.


Sleep Disturbance in Caregivers of Children With Respiratory and Atopic Disease.
To examine sleep patterns and sleep disturbances in caregivers of children with chronic illness. Caregivers of children with atopic dermatitis (AD, n = 35), asthma (AS, n = 27), atopic dermatitis and asthma (AD + AS, n = 57), ventilator assistance (VENT, n = 61), or typically developing (HEALTHY, n = 63) completed the Pittsburgh Sleep Quality Index, the Insomnia Severity Index, and three items examining reasons for parent sleep disruption. Compared with healthy families, caregivers of children with chronic illness reported poorer sleep quality, more symptoms of insomnia, and chronic partial sleep deprivation. VENT and AD caregivers had higher rates of sleep disruptions due to caregiving, whereas AS caregivers reported more sleep disruptions from stress about the child's health. Deficient and poor-quality sleep in caregivers of children with chronic illness may have a significant impact on their health and well-being, as well as caregiving responsibilities. These data provide important information for pediatric psychologists working with these families.


Elicitor and resistance-inducing activities of beta-1,4 cellodextrins in grapevine, comparison with beta-1,3 glucans and alpha-1,4 oligogalacturonides.
Cellodextrins (CD), water-soluble derivatives of cellulose composed of beta-1,4 glucoside residues, have been shown to induce a variety of defence responses in grapevine (Vitis vinifera L.) cells. The larger oligomers of CD rapidly induced transient generation of H2O2 and elevation in free cytosolic calcium, followed by a differential expression of genes encoding key enzymes of the phenylpropanoid pathway and pathogenesis-related (PR) proteins as well as stimulation of chitinase and beta-1,3 glucanase activities. Most of these defence reactions were also induced by linear beta-1,3 glucans (betaGlu) and alpha-1,4 oligogalacturonides (OGA) of different degree of polymerization (DP), but the intensity of some reactions induced by CD was different when compared with betaGlu and OGA effects. Moreover, desensitization assays using H2O2 production showed that cells treated with CD remained fully responsive to a second application of OGA, suggesting a different mode of perception of these oligosaccharides by grape cells. None of CD, betaGlu, or OGA induced HSR gene expression nor did they induce cell death. In accordance with elicitor activity in grapevine cells, CD-incubated leaves challenged with Botrytis cinerea also resulted in a significant reduction of the disease. Data suggest that CD could operate via other distinct reaction pathways than betaGlu and OGA. They also highlight the requirement of a specific DP for each oligosaccharide to induce the defence response.


Population Genomics Insights into the First Wave of COVID-19.
Full-genome-sequence computational analyses of the SARS-coronavirus (CoV)-2 genomes allow us to understand the evolutionary events and adaptability mechanisms. We used population genetics analyses on human SARS-CoV-2 genomes available on 2 April 2020 to infer the mutation rate and plausible recombination events between the Betacoronavirus genomes in nonhuman hosts that may have contributed to the evolution of SARS-CoV-2. Furthermore, we localized the targets of recent and strong, positive selection during the first pandemic wave. The genomic regions that appear to be under positive selection are largely co-localized with regions in which recombination from nonhuman hosts took place. Our results suggest that the pangolin coronavirus genome may have contributed to the SARS-CoV-2 genome by recombination with the bat coronavirus genome. However, we find evidence for additional recombination events that involve coronavirus genomes from other hosts, i.e., hedgehogs and sparrows. We further infer that recombination may have recently occurred within human hosts. Finally, we estimate the parameters of a demographic scenario involving an exponential growth of the size of the SARS-CoV-2 populations that have infected European, Asian, and Northern American cohorts, and we demonstrate that a rapid exponential growth in population size from the first wave can support the observed polymorphism patterns in SARS-CoV-2 genomes.


Design principles governing chemomechanical coupling of kinesin.
A systematic chemomechanical network model for the molecular motor kinesin is presented in this report. The network model is based on the nucleotide-dependent binding affinity of the heads to an microtubule (MT) and the asymmetries and similarities between the chemical transitions caused by the intramolecular strain between the front and rear heads. The network model allows for multiple chemomechanical cycles and takes into account all possible mechanical transitions between states in which one head is strongly bound and the other head is weakly bound to an MT. The results obtained from the model show the ATP-concentration dependence of the dominant forward stepping cycle and support a gated rear head mechanism in which the forward step is controlled by ATP hydrolysis and the resulting ADP-bound state of the rear head when the ATP level is saturated. When the ATP level is saturated, the energy from ATP hydrolysis is used to concentrate the chemical transition flux to a force-generating state that can produce the power stroke. In contrast, when the ATP level is low, the hydrolysis energy is consumed to avoid states in which the leading head is weakly bound to an MT and to inhibit frequent backward steps upon loading.


Regional distribution of calcium- and cyclic adenosine 3':5'-monophosphate-regulated protein phosphorylation systems in mammalian brain. II. Soluble systems.
The regional distribution of phosphoproteins whose phosphorylation is regulated either by cyclic AMP or by calcium in combination with calmodulin or phospholipid has been investigated in soluble preparations from rat CNS. About 40 distinct phosphoproteins were observed. These cytosolic phosphoproteins exhibited widely different patterns of regional distribution. Based upon distribution patterns, we have divided these phosphoproteins into three categories: category A, phosphoproteins found in all parts of the CNS in approximately equal amounts; category B, phosphoproteins which are widely distributed within the CNS, but which show large regional variations; and category C, phosphoproteins which show a highly restricted regional distribution. We have tentatively interpreted the results on cytosolic phosphoproteins in the following way: some are present in all or nearly all brain cells, others are present only in certain classes of brain cells, and still others have an even more limited distribution, being present in only a single type of brain cell. The regional distribution of soluble protein kinase activity was also studied. Calcium/phospholipid-dependent protein kinase and calcium/calmodulin-dependent protein kinase had marked regional distributions. Cyclic AMP-dependent protein kinase was more evenly distributed throughout the CNS. This investigation thus demonstrates striking differences in the regional distribution of cytosolic protein phosphorylation systems in mammalian brain. These regional differences may reflect highly specific functional roles for certain of these protein phosphorylation systems. Similar conclusions concerning particulate protein phosphorylation systems are described in the preceding paper.


Prognostic value and efficacy valuation of postoperative intravesical instillation in primary urothelial carcinomas of upper urinary tract.
Bladder tumor recurrence after surgery for upper urinary tract urothelial carcinoma (UUT-UC) is frequent. Intravesical instillation has been widely accepted as an effective way to prevent bladder tumor recurrence. We aimed to find whether postoperative instillation have benefits for bladder tumor recurrence of UUT-UC. A meta-analysis based on 6 studies from 5 publications was performed. Published literature from PubMed, EMBASE and Web of science was pooled and the hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to estimate the benefits. Conclusively, our results indicate a 62% benefit (HR = 0.38; 95% CI: 0.16-0.87) in recurrence free survival (RFS) among those treated with postoperative intravesical instillation compared with those not. Mitomycin C (MMC) and pirarubicin were found to provide more benefits than other regimens in stratified analysis. Further, after excluding one study for its heterogeneity, the results demonstrated a more reliable results of a 34% benefit (HR = 0.66; 95% CI = 0.44-0.98). This study reveals a relative benefit for postoperative instillation to improve the RFS of UUT-UC patients.


Spatial detection of fetal marker genes expressed at low level in adult human heart tissue.
Heart failure is a major health problem linked to poor quality of life and high mortality rates. Hence, novel biomarkers, such as fetal marker genes with low expression levels, could potentially differentiate disease states in order to improve therapy. In many studies on heart failure, cardiac biopsies have been analyzed as uniform pieces of tissue with bulk techniques, but this homogenization approach can mask medically relevant phenotypes occurring only in isolated parts of the tissue. This study examines such spatial variations within and between regions of cardiac biopsies. In contrast to standard RNA sequencing, this approach provides a spatially resolved transcriptome- and tissue-wide perspective of the adult human heart, and enables detection of fetal marker genes expressed by minor subpopulations of cells within the tissue. Analysis of patients with heart failure, with preserved ejection fraction, demonstrated spatially divergent expression of fetal genes in cardiac biopsies.


The regulation of neovascularization of matrix metalloproteinases and their inhibitors.
The process of new capillary formation from preexisting vessels, angiogenesis, is a complex physiological event which is strictly controlled, occurring only very rarely under normal conditions. In contrast, there are a number of serious diseases, among them solid tumor growth, rheumatoid arthritis and several eye diseases, which are characterized by unrestricted new capillary growth and which are described as "angiogenic diseases." One of the key events required for successful angiogenesis is extracellular proteolysis. Increased attention has been focused on matrix metalloproteinase (MMP) family of enzymes whose activity is a rate-limiting step in extracellular matrix remodeling. This review will present the accumulating body of evidence, from a number of laboratories, which documents the important role of MMP activity in the regulation of angiogenesis. Taken together, these data suggest that one strategy for controlling the deregulated angiogenesis characteristic of these serious angiogenic diseases may be one which is operative at the level of the control of MMP activity.


Association between glutathione S-transferase p1 polymorphisms and lung cancer risk in Caucasians: a case-control study.
Glutathione transferases (GSTs), a multiple gene family of phase II enzymes, catalyze detoxifying endogenous reactions with glutathione and protect cellular macromolecules from damage caused by cytotoxic and carcinogenic agents. Glutathione S-transferase p1 (GSTP1), the most abundant GST isoform in the lung, metabolizes numerous carcinogenic compounds including benzo[a]pyrene, a tobacco carcinogen. Previous studies suggest that genetic polymorphisms of GSTP1 exon 5 (Ile105Val) and exon 6 (Ala114Val) have functional effects on the GST gene product resulting in reduced enzyme activity. Individuals with reduced GST enzymatic activity may be at a greater risk for cancer due to decreased detoxification of carcinogenic and mutagenic compounds. Utilizing a hospital-based case-control study, we investigated the association between GSTP1 polymorphisms at exons 5 and 6 with lung cancer risk. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used to successfully genotype the GSTP1 exons 5 and 6 polymorphism in 582 Caucasian lung cancer cases and 600 frequency matched Caucasian controls. There was no association between the exon 5 variant genotypes (A/G+G/G) and overall lung cancer risk (OR=1.09; 95% CI 0.82-1.45) nor when stratified by age, gender, and smoking status. However, the exon 6 variant genotypes (C/T+T/T) were associated with a statistically significant elevated lung cancer risk (OR=1.40; 95% CI 1.06-1.92). Additionally, there was an increase in lung cancer risk for the exon 6 variant genotypes in younger individuals (<62 years) (OR=1.63; 95% C.I. 1.07-2.49) but no effect in older individuals (OR=1.14; 95% CI 0.72-1.81). A statistically significant increased risk of lung cancer was also observed for the exon 6 variant genotypes among men (OR=2.17; 95% CI 1.41-3.33), but not among women (OR=0.80; 95% CI 0.51-1.28). Among ever smokers, the exon 6 variant genotypes were associated with an elevated lung cancer risk (OR=1.58; 95% CI 1.14-2.19), which was not evident for never smokers (OR=0.53; 95% CI 0.21-1.33). These data demonstrate that the GSTP1 exon 6 polymorphism, but not the exon 5 polymorphism, is associated with lung cancer risk that is especially evident in men, younger individuals, and ever smokers.


Exercise training reduces ischemic myocardial dysfunction.
This study tested the hypothesis that exercise training improves myocardial blood flow and regional myocardial contractile function in a lateral border zone located adjacent to the ischemic zone during coronary artery occlusion. Fourteen dogs were subjected to either 12 wk of dynamic exercise training or cage rest. Dogs were anesthetized and instrumented to assess regional myocardial contractile function (percent segment length shortening and rate of shortening) and regional myocardial blood flow (tracer microspheres) in the central ischemic, lateral border, and nonischemic zones. Measurements were made preocclusion and at 2 min and 3 h after occlusion of the left anterior descending coronary artery (CAO). Contractile function and regional myocardial blood flow were not affected by CAO in the nonischemic zone in both cage-rested and exercise trained dogs. Regional myocardial contractile function and blood flow in the lateral border zone were significantly higher in exercise trained dogs compared with cage-rested dogs, both at 2 min and 3 h after CAO. Ischemic dysfunction was similar in the central ischemic zone in both cage-rested and exercise trained dogs both at 2 min and 3 h after CAO. Regional myocardial blood flow was similarly reduced in the ischemic zone in both groups after 2 min of CAO, but was significantly higher in the inner (subendocardial) region of the exercised trained hearts after 3 h (P < 0.05). These data suggest that there was greater border zone perfusion in exercise trained animals during prolonged CAO, which was associated with significantly improved myocardial contractile function.


Assessing the Ecotoxicity of Eight Widely Used Antibiotics on River Microbial Communities.
Global prevalence of antibiotic residues (ABX) in rivers requires ecotoxicological impact assessment. River microbial communities serve as effective bioindicators for this purpose. We quantified the effects of eight commonly used ABXs on a freshwater river microbial community using Biolog EcoPlates™, enabling the assessment of growth and physiological profile changes. Microbial community characterization involved 16S rRNA gene sequencing. The river community structure was representative of aquatic ecosystems, with the prevalence of Cyanobacteria, Proteobacteria, Actinobacteria, and Bacteroidetes. Our findings reveal that all ABXs at 100 µg/mL reduced microbial community growth and metabolic capacity, particularly for polymers, carbohydrates, carboxylic, and ketonic acids. Chloramphenicol, erythromycin, and gentamicin exhibited the highest toxicity, with chloramphenicol notably impairing the metabolism of all studied metabolite groups. At lower concentrations (1 µg/mL), some ABXs slightly enhanced growth and the capacity to metabolize substrates, such as carbohydrates, carboxylic, and ketonic acids, and amines, except for amoxicillin, which decreased the metabolic capacity across all metabolites. We explored potential correlations between physicochemical parameters and drug mechanisms to understand drug bioavailability. Acute toxicity effects at the river-detected low concentrations (ng/L) are unlikely. However, they may disrupt microbial communities in aquatic ecosystems. The utilization of a wide array of genetically characterized microbial communities, as opposed to a single species, enables a better understanding of the impact of ABXs on complex river ecosystems.


Successful Doxycycline Therapy in a Patient With Escherichia coli and Multidrug-Resistant Klebsiella pneumoniae Urinary Tract Infection.
To report on a patient with a symptomatic, polymicrobial Escherichia coli and multidrug-resistant (MDR), extended-spectrum β-lactamase (ESBL)-positive Klebsiella pneumoniae urinary tract infection (UTI) who was successfully treated with oral doxycycline hyclate. A 70-year-old white male inpatient with a history of recurrent UTI, type 2 diabetes, hypertension, obesity, and diverticular disease was diagnosed with UTI and empirically treated with oral ciprofloxacin. Symptoms persisted 2 days later, and the patient was transitioned to amoxicillin/clavulanate by a different provider. The next day, upon receipt of the urine culture and susceptibility panel revealing E coli and MDR, ESBL-positive K pneumoniae infection, treatment was switched to doxycycline hyclate, which resulted in clinical improvement. Complicated UTI involving multiple pathogens requires careful clinical judgment to select the appropriate antimicrobial agent, improve clinical outcomes, and prevent resistance. Treatment with doxycycline was based on the susceptibility panel and local resistance patterns. Advantages of doxycycline for UTI include its oral formulation, wide spectrum of activity, ability to achieve high concentration in the urine, and low toxicity. Doxycycline hyclate may be an effective treatment option for patients with susceptible MDR UTI.


Location, variations, and predictors of epicardial fat mapping using multidetector computed tomography to assist epicardial ventricular tachycardia ablation.
A significant number of ventricular tachycardia circuits are located close to the epicardial surface and are amendable to epicardial ablation. Epicardial fat often interferes with substrate mapping and ablation, though little is known regarding the distribution of fat and its fluctuation with the cardiac cycle. We studied 40 patients who underwent a 64-slice multidetector computed tomography in order to describe patterns of epicardial fat distribution, variation during cardiac cycle, and clinical predictors of epicardial fat. Multiplanar reconstructions were analyzed during systole and diastole in six cross-sections. Epicardial fat thickness was measured across multiple wall segments in each view. Epicardial fat was found to be thicker in areas overlying coronary vasculature (7.8 ± 2.6 mm vs 3.5 ± 0.9 mm, P = 0.001), along with the right ventricular wall (3.9 ± 0.8 mm vs 2.6 ± 0.6 mm, P = 0.001) and the ventricular base (6.1 ± 1.7 mm vs 4.6 ± 1.6 mm, P < 0.01). Epicardial fat thickness increased 27% during systole as compared to diastole (4.9 ± 2.7 mm vs 6.2 ± 3.0 mm, P = 0.04). Variation with cardiac cycle was most evident along the right ventricular wall (3.9 ± 0.8 mm vs 5.0 ± 1.3 mm, P = 0.001) and nonvascular areas (P = 0.001), especially at the ventricular base (3.7 ± 1.1 mm vs 5.3 ± 1.5 mm, P = 0.001). In multivariate logistic regression, we found that age >50 years (P = 0.031) and coronary artery disease (P = 0.023) were statistically correlated with epicardial fat >5-mm thickness and body mass index > 33 (P = 0.052) nearly so. Baseline epicardial fat thickness >5 mm is common in areas typically targeted during epicardial ablation and further increases during the cardiac cycle. Simple clinical characteristics can identify patients with >5 mm epicardial fat in which preprocedural computed tomography imaging and three-dimensional fat map reconstruction may facilitate epicardial ablation.


Optimal Energy Consumption of the Distillation Process and Its Product Purity Analysis Using Ultraviolet Spectroscopy.
This paper addresses the energy consumption of distillation process via an actuator, which is a challenging problem in process industries. Precise control action would enhance energy consumption and improve the productivity. This paper is an experimental validation of EPC-PI control algorithm and analysis of distillate purity of a lab-scale distillation column. The PI control scheme uses closed-loop data of extended predictive controller (EPC) that has been performed through off-line simulation. The performance of control method is compared with different schemes such as Hägglund's one-third rule and Skogestad's overshoot method. The issue of integral windup in the multivariable process is addressed in the aspect of optimal energy consumption. The energy consumption calculations are made with respect to power utility of actuators throughout the process. The distillate product of post-controller implementation is processed to qualitative analysis using UV spectroscopy. Performance index is carried out via integral time absolute error (ITAE) by perturbing plant parameters up to 30% uncertainty.


Identification of cDNA clones that encode hLAMP-1, a component of the particulate matrix associated with cardiac mesenchyme formation.
The heart extracellular matrix protein hLAMP-1 (lectin-associated matrix protein in the heart) is a component of the particulate matrix that activates the AV endothelium prior to its transformation into mesenchyme within the atrioventricular canal and proximal outflow tract of the heart. The role of hLAMP-1 in this process has yet to be determined, in part because of the limited amount of material available for analysis. To overcome this liability, a monoclonal antibody to hLAMP-1 has been used to recognize proteins expressed by cDNA clones. The isolated cDNAs encode an mRNA consistent with previously published immunohistochemical results. Expression profiles of these clones by in situ hybridization revealed staining in areas of the heart that expressed hLAMP-1 by immunocytochemistry. Taken together, these results suggest that these clones, which represent an expressed sequence tag for hLAMP-1, should provide the basis for isolating a full-length cDNA of hLAMP-1, a prerequisite for determining the functional role of this protein in heart development.


Cerebrovascular characterization of clazosentan, the first nonpeptide endothelin receptor antagonist shown to be clinically effective for the treatment of cerebral vasospasm. Part II: effect on endothelin(B) receptor-mediated relaxation.
The disturbed balance between nitric oxide and endothelin (ET)-1 in the cerebrovasculature seems to play a major role in the development of cerebral vasospasm after subarachnoid hemorrhage. Endothelin-1 represents the contractile part in this balance. In addition to the prevailing ET(A) receptor-dependent contractile effect, ET-1 also has ET(B) receptor-mediated vasodilatory attributes. The aim of the present study was to define the actual selectivity of clazosentan, the first putative highly ET(A) receptor-selective antagonist clinically proven to be effective in the treatment of vasospasm in the cerebrovasculature. Rat basilar artery ring segments with endothelial function were used for the measurement of isometric force. Concentration effect curves were constructed by cumulative application of sarafotoxin S6c, ET-1, or big ET-1 in the presence or absence of clazosentan (10(-9) to 10(-6) M) after a precontraction was induced by prostaglandin F2alpha. The inhibition by clazosentan was estimated by the value of the affinity constant (pA2). The relaxation induced by sarafotoxin S6c, ET-1, and big ET-1 was inhibited in a competitive manner by clazosentan, yielding pA2 values of 7.1, 6.7, and 6.5, respectively. The selectivity to the ET(A) receptor in the cerebrovascular system was approximately two logarithmic units. The present investigation shows a competitive inhibition of ET(B) receptor-mediated relaxation in cerebral vessels by clazosentan in therapeutically relevant concentrations. Thus, additional clinical trials should be undertaken to evaluate clazosentan concentrations in cerebrospinal fluid. Furthermore, the present data may be taken to describe the pharmacological properties for an ET receptor antagonist specifically tailored for the treatment of pathological conditions of impaired cerebral blood flow.


The assessment of the hematopoietic reservoir after immunosuppressive therapy or bone marrow transplantation in severe aplastic anemia.
We investigated the hematopoietic reservoir in 43 severe aplastic anemia (SAA) patients following immunosuppression (IS) (n = 15) or bone marrow transplantation (BMT) (n = 28), at a median interval of 5 years (range, 2-20) from treatment. All patients had normal blood counts, good marrow cellularity, and normal numbers of colony forming unit-granulocyte macrophages (CFU-GM). Burst forming unit-erythroid (BFU-E) and colony forming unit-granulocyte erythroid megakaryocyte macrophages (CFU-GEMM) numbers were reduced when compared with normal controls. However, the most pronounced defect was observed at the level of long-term culture-initiating cells (LTC-IC), which significantly differed from controls (P < .00001) both for IS and BMT patients. Their number did not improve with time and was not affected by transplant or treatment-related variables. When IS patients were compared with BMT we found comparable numbers of CFU-GEMM (P = .8) and LTC-IC (P = .9), but lower numbers of BFU-E and CFU-GM (P = .05 and P = .004, respectively), suggestive of a persistent suppressive mechanism. These data indicate that LTC-IC numbers are severely reduced in BMT and IS patients, contradicting the common belief that the former are fully reconstituted as compared with the latter. In addition, the number of mature cells and committed progenitors does not seem to reflect the real size of the hematopoietic reservoir and few stem cells may be sufficient to guarantee normal hematopoiesis long term.


Cesarean delivery of the breech very-low-birth-weight infant: does it make a difference?
We evaluated the impact of cesarean section (CS) delivery on the outcome of breech very-low-birth-weight (VLBW) (500-1,499 g) infants. This retrospective study used data from a large perinatal data base with 109,428 consecutive deliveries including 1,564 VLBW infants born between 1982 and 1987. The study infants included 982 (62.8%) vertex and 582 (37.2%) breech presentations. The CS rate was higher for the breech group than for the vertex group (72.5% breech, 34.3% vertex, OR 5.1, 95% CI 4.0, 6.4). Breech infants delivered by CS were twice as likely to survive until discharge than those delivered vaginally (breech CS 71.7%, breech vaginal 36.5%, P < .0001). The increased survival with CS for breech presentation (mainly due to fewer deaths on day 1) was not seen with vertex presentation. The CS survival advantage for breech infants was seen in all 250g birth weight subgroups. However, breech VLBW infants delivered by CS had a mean birth weight 233 g more and gestational age 2.1 weeks more than those delivered vaginally. Further, breech infants delivered by CS were more likely to be intubated at birth than vaginally delivered breech infants (OR 4.2, 95% CI 2.0, 5.9). Central nervous system morbidity as measured by the occurrence of seizures and intraventricular hemorrhage was comparable for CS and vaginal infants. Cesarean birth of breech VLBW infants is associated with improved survival. However, breech CS infants were bigger, more mature, and more likely to be intubated at birth than vaginally delivered infants, indicating the presence of a strong selection bias. A prospective randomized trial is needed to evaluate the ideal delivery route for breech VLBW infants.


Complex drug interactions in an HIV-seropositive heart transplant recipient.
Highly active antiretroviral therapy has led to greater life expectancy for human immun-deficiency virus (HIV)-positive patients. This was a report of 11 years of follow-up of an HIV-seropositive patient who underwent heart transplantation in 2006, with emphasis on the management challenges of complex drug interactions over time.


Structural and functional properties of porin channels in E. coli outer membranes.
Porin is a channel-forming, voltage-dependent protein of E. coli outer membranes. It exhibits relatively unspecific molecular sieve properties (exclusion size 600 Da). The trimer (110 kDa) consists of three identical polypeptides. Its secondary structure is mostly beta-structure, part of which can be visualized by electron microscopy to form a single beta-pleated sheet near the protein-lipid interface of the trimer. This folding pattern is significantly different from those of the reaction centers and of bacteriorhodopsin. Moreover, it contains many polar and ionizable side chains. It is argued that local as well as global electroneutrality, and complete saturation of the entire hydrogen bonding potential not only allow the protein to reside in the hydrophobic membrane core, but also confer upon it its unusual stability.


Manual physical therapy, cervical traction, and strengthening exercises in patients with cervical radiculopathy: a case series.
A case series of consecutive patients with cervical radiculopathy. A multitude of physical therapy interventions have been proposed to be effective in the management of cervical radiculopathy. However, outcome studies using consistent treatment approaches on a well-defined sample of patients are lacking. The purpose of this case series is to describe the outcomes of a consecutive series of patients presenting to physical therapy with cervical radiculopathy and managed with the use of manual physical therapy, cervical traction, and strengthening exercises. Eleven consecutive patients (mean age, 51.7 years; SD, 8.2) who presented with cervical radiculopathy on the initial examination were treated with a standardized approach, including manual physical therapy, cervical traction, and strengthening exercises of the deep neck flexors and scapulothoracic muscles. At the initial evaluation all patients completed self-report measures of pain and function, including a numeric pain rating scale (NPRS), the Neck Disability Index (NDI), and the Patient-Specific Functional Scale (PSFS). All patients again completed the outcome measures, in addition to the global rating of change (GROC), at the time of discharge from therapy and at a 6-month follow-up session Ten of the 11 patients (91%) demonstrated a clinically meaningful improvement in pain and function following a mean of 7.1 (SD, 1.5) physical therapy visits and at the 6-month follow-up. Ninety-one percent (10 of 11) of patients with cervical radiculopathy in this case series improved, as defined by the patients classifying their level of improvement as at least "quite a bit better" on the GROC. However, because a cause-and-effect relationship cannot be inferred from a case series, follow-up randomized clinical trials should be performed to further investigate the effectiveness of manual physical therapy, cervical traction, and strengthening exercises in a homogeneous group of patients with cervical radiculopathy.


CHK1-driven histone H3.3 serine 31 phosphorylation is important for chromatin maintenance and cell survival in human ALT cancer cells.
Human ALT cancers show high mutation rates in ATRX and DAXX. Although it is well known that the absence of ATRX/DAXX disrupts H3.3 deposition at heterochromatin, its impact on H3.3 deposition and post-translational modification in the global genome remains unclear. Here, we explore the dynamics of phosphorylated H3.3 serine 31 (H3.3S31ph) in human ALT cancer cells. While H3.3S31ph is found only at pericentric satellite DNA repeats during mitosis in most somatic human cells, a high level of H3.3S31ph is detected on the entire chromosome in ALT cells, attributable to an elevated CHK1 activity in these cells. Drug inhibition of CHK1 activity during mitosis and expression of mutant H3.3S31A in these ALT cells result in a decrease in H3.3S31ph levels accompanied with increased levels of phosphorylated H2AX serine 139 on chromosome arms and at the telomeres. Furthermore, the inhibition of CHK1 activity in these cells also reduces cell viability. Our findings suggest a novel role of CHK1 as an H3.3S31 kinase, and that CHK1-mediated H3.3S31ph plays an important role in the maintenance of chromatin integrity and cell survival in ALT cancer cells.


The need for harmonisation and innovation of neuropsychological assessment in neurodegenerative dementias in Europe: consensus document of the Joint Program for Neurodegenerative Diseases Working Group.
Cognitive, behavioural, and functional assessment is crucial in longitudinal studies of neurodegenerative dementias (NDD). Central issues, such as the definition of the study population (asymptomatic, at risk, or individuals with dementia), the detection of change/decline, and the assessment of relevant outcomes depend on quantitative measures of cognitive, behavioural, and functional status.Currently, we are far from having available reliable protocols and tools for the assessment of dementias in Europe. The main problems are the heterogeneity of the tools used across different European countries, the lack of standardisation of administration and scoring methods across centres, and the limited information available about the psychometric properties of many tests currently in widespread use. This situation makes it hard to compare results across studies carried out in different centres, thus hampering research progress, in particular towards the contribution to a "big data" common data set.We present here the results of a project funded by the Joint Program for Neurodegenerative Diseases (JPND) and by the Italian Ministry of Health. The project aimed at providing a consensus framework for the harmonisation of assessment tools to be applied to research in neurodegenerative disorders affecting cognition across Europe. A panel of European experts reviewed the current methods of neuropsychological assessment, identified pending issues, and made recommendations for the harmonisation of neuropsychological assessment of neurodegenerative dementias in Europe.A consensus was achieved on the general recommendations to be followed in developing procedures and tools for neuropsychological assessment, with the aim of harmonising tools and procedures to achieve more reliable data on the cognitive-behavioural examination. The results of this study should be considered as a first step to enhancing a common view and practise on NDD assessment across European countries.


Preoperative nursing assessment of the adult patient.
The preoperative patient assessment must be very focused, providing detail and specificity in several essential assessment areas. The preoperative patient assessment helps to determine whether the patient is a high surgical risk. Patients who are determined to be high surgical risks are at a higher risk for perioperative and postoperative mortality and morbidity.


Porcine extrahepatic vascular endothelial asialoglycoprotein receptor 1 mediates xenogeneic platelet phagocytosis in vitro and in human-to-pig ex vivo xenoperfusion.
Asialoglycoprotein receptor-1 (ASGR1) mediates capture and phagocytosis of platelets in pig-to-primate liver xenotransplantation. However, thrombocytopenia is also observed in xenotransplantation or xenoperfusion of other porcine organs than liver. We therefore assessed ASGR1 expression as well as ASGR1-mediated xenogeneic platelet phagocytosis in vitro and ex vivo on porcine aortic, femoral arterial, and liver sinusoidal endothelial cells (PAEC/PFAEC/PLSEC). Porcine forelimbs were perfused with whole, heparinized human or autologous pig blood. Platelets were counted at regular intervals. Pig limb muscle and liver, as well as PAEC/PFAEC/PLSEC, were characterized for ASGR1 expression. In vitro, PAEC cultured on microcarrier beads and incubated with non-anticoagulated human blood were used to study binding of human platelets and platelet-white blood cell aggregation. Carboxyfluorescein diacetate succinimidyl ester-labeled human platelets were exposed to PAEC/PFAEC/PLSEC and analyzed for ASGR1-mediated phagocytosis. Human platelet numbers decreased from 102 ± 33 at beginning to 13 ± 6 × 10/μL (P < 0.0001) after 10 minutes of perfusion, whereas no significant decrease of platelets was seen during autologous perfusions (171 ± 26 to 122 ± 95 × 10/μL). The PAEC, PFAEC, and PLSEC all showed similar ASGR1 expression. In vitro, no correlation was found between reduction in platelet count and platelet-white blood cell aggregation. Phagocytosis of human carboxyfluorescein diacetate succinimidyl ester-labeled platelets by PAEC/PFAEC/PLSEC peaked at 15 minutes and was inhibited (P < 0.05 to P < 0.0001) by rabbit anti-ASGR1 antibody and asialofetuin. The ASGR1 expressed on aortic and limb arterial pig vascular endothelium plays a role in binding and phagocytosis of human platelets. Therefore, ASGR1 may represent a novel therapeutic target to overcome thrombocytopenia associated with vascularized pig-to-primate xenotransplantation.


Gene expression changes related to bone mineralization, blood pressure and lipid metabolism in mouse kidneys after space travel.
Space travel burdens health by imposing considerable environmental stress associated with radioactivity and microgravity. In particular, gravity change predominantly impacts blood pressure and bone homeostasis, both of which are controlled mainly by the kidneys. Nuclear factor erythroid-2-related transcription factor 2 (Nrf2) plays essential roles in protecting the kidneys from various environmental stresses and injuries. To elucidate the effects of space travel on mammals in preparation for the upcoming space era, our study investigated the contribution of Nrf2 to kidney function in mice two days after their return from a 31-day stay in the International Space Station using Nrf2 knockout mice. Meaningfully, expression levels of genes regulating bone mineralization, blood pressure and lipid metabolism were found to be significantly altered in the kidneys after space travel in an Nrf2-independent manner. In particular, uridine diphosphate-glucuronosyltransferase 1A (Ugt1a) isoform genes were found to be expressed in an Nrf2-dependent manner and induced exclusively in the kidneys after return to Earth. Since spaceflight elevated the concentrations of fatty acids in the mouse plasma, we suggest that Ugt1a isoform expression in the kidneys was induced to promote glucuronidation of excessively accumulated lipids and excrete them into urine after the return from space. Thus, the kidneys were proven to play central roles in adaptation to gravity changes caused by going to and returning from space by controlling blood pressure and bone mineralization. Additionally, kidney Ugt1a isoform induction after space travel implies a significant role of the kidneys for space travelers in the excretion of excessive lipids.


Auxin-induced differential sensitivity of the H+-ATPase in plasma membrane subfractions from tobacco cells.
Plasma membrane vesicles form suspension cultured tobacco cells were fractionated by counter-current phase partitioning. The subfractions exhibited identical biochemical characteristics and differed mainly by their sidedness. In addition, fluorescence polarization experiments indicated slight fluidity or order differences. These characteristics remained unchanged when cells were treated with auxin, prior to membrane purification. The sensitivity to auxin of the H+-ATPase catalysed proton translocation was investigated in plasma membrane subfractions. Identical sensitivity was measured in all subfractions from control cells. After auxin treatment of cells, a dramatic increase in the sensitivity was observed in one subfraction. Results are discussed in relation to the recent report of an auxin-induced clustering of the putative auxin-receptor (Diekmann et al., Proc. Natl. Acd. Sci USA 92, 3425-3429, 1995).


A passion for improving the wellbeing of young families, with a focus on children.
Nicola Dyke, Health Visitor, Rotherham Doncaster and South Humber NHS Foundation Trust (firstname.lastname@example.com), winner of the Silver Award in the Public Health Nurse of the Year category of the BJN Awards 2023.


Total MRI load of cerebral small vessel disease and cognitive ability in older people.
Cerebral small vessel disease (SVD) may cause cognitive dysfunction. We tested the association between the combined presence of magnetic resonance imaging (MRI) features of SVD and cognitive ability in older age. Cognitive testing and brain MRI were performed in 680 older participants. MRI presence of lacunes, white matter hyperintensities, microbleeds, and perivascular spaces were summed in a score of 0-4 representing all SVD features combined. We also applied latent variable modeling to test whether the 4 MRI features form a unitary SVD construct. The SVD score showed significant associations with general cognitive ability. Latent variable modeling indicated that the 4 MRI markers formed a unitary construct, which showed consistent associations with cognitive ability compared with the SVD score. Total MRI load of SVD is associated with lower general cognitive ability in older age. The total SVD score performed consistently with the more complex latent variable model, suggesting validity and potential utility in future research for determining total SVD load.


MRI radiomic features are associated with survival in melanoma brain metastases treated with immune checkpoint inhibitors.
Melanoma brain metastases historically portend a dismal prognosis, but recent advances in immune checkpoint inhibitors (ICIs) have been associated with durable responses in some patients. There are no validated imaging biomarkers associated with outcomes in patients with melanoma brain metastases receiving ICIs. We hypothesized that radiomic analysis of magnetic resonance images (MRIs) could identify higher-order features associated with survival. Between 2010 and 2019, we retrospectively reviewed patients with melanoma brain metastases who received ICI. After volumes of interest were drawn, several texture and edge descriptors, including first-order, Haralick, Gabor, Sobel, and Laplacian of Gaussian (LoG) features were extracted. Progression was determined using Response Assessment in Neuro-Oncology Brain Metastases. Univariate Cox regression was performed for each radiomic feature with adjustment for multiple comparisons followed by Lasso regression and multivariate analysis. Eighty-eight patients with 196 total brain metastases were identified. Median age was 63.5 years (range, 19-91 y). Ninety percent of patients had Eastern Cooperative Oncology Group performance status of 0 or 1 and 35% had elevated lactate dehydrogenase. Sixty-three patients (72%) received ipilimumab, 11 patients (13%) received programmed cell death protein 1 blockade, and 14 patients (16%) received nivolumab plus ipilimumab. Multiple features were associated with increased overall survival (OS), and LoG edge features best explained the variation in outcome (hazard ratio: 0.68, P = 0.001). In multivariate analysis, a similar trend with LoG was seen, but no longer significant with OS. Findings were confirmed in an independent cohort. Higher-order MRI radiomic features in patients with melanoma brain metastases receiving ICI were associated with a trend toward improved OS.


Moral identity as moral ideal self: links to adolescent outcomes.
The purposes of this study were to conceptualize moral identity as moral ideal self, to develop a measure of this construct, to test for age and gender differences, to examine links between moral ideal self and adolescent outcomes, and to assess purpose and social responsibility as mediators of the relations between moral ideal self and outcomes. Data came from a local school sample (Data Set 1: N = 510 adolescents; 10-18 years of age) and a national online sample (Data Set 2: N = 383 adolescents; 15-18 years of age) of adolescents and their parents. All outcome measures were parent-report (Data Set 1: altruism, moral personality, aggression, and cheating; Data Set 2: environmentalism, school engagement, internalizing, and externalizing), whereas other variables were adolescent-report. The 20-item Moral Ideal Self Scale showed good reliability, factor structure, and validity. Structural equation models demonstrated that, even after accounting for moral identity internalization, in Data Set 1 moral ideal self positively predicted altruism and moral personality and negatively predicted aggression, whereas in Data Set 2 moral ideal self positively predicted environmentalism and negatively predicted internalizing and externalizing symptoms. Further, purpose and social responsibility mediated most relations between moral ideal self and the outcomes in Data Set 2. Moral ideal self was unrelated to age but differentially predicted some outcomes across age. Girls had higher levels of moral ideal self than boys, although moral identity did not differentially predict outcomes between genders. Thus, moral ideal self is a salient element of moral identity and may play a role in morally relevant adolescent outcomes.


Revisiting the role of sucrose in PLGA-PEG nanocarrier for potential intranasal delivery.
The efficient design of nanocarriers is a major challenge and must be correlated with the route of administration. Intranasal route is studied for local, systemic or cerebral treatments. In order to develop nanocarriers with suitable properties for intranasal delivery, to achieve brain and to market the product, it is extremely important the simplification of the formulation in terms of raw materials. Surfactants and cryoprotectants are often added to improve structuration and/or storage of polymeric nanoparticles. PLGA-PEG nanocarriers were prepared by nanoprecipitation method evaluating the critical role of sucrose as surfactant-like and cryoprotectant, with the aim to obtain a simpler formulation compared to those proposed in other papers. Photon correlation spectroscopy and Turbiscan analysis show that sucrose is a useful excipient during the preparation process and it effectively cryoprotects nanoparticles. Among the investigated nanocarriers with different degree of PEG, PEGylated PLGA (5%) confers weak interaction between nanoparticles and mucin as demonstrated by thermal analysis and mucin particle method. Furthermore, in vitro biological studies on HT29, as epithelium cell line, does not show cytotoxicity effect for this nanocarrier at all texted concentrations. The selected nanosystem was also studied to load docetaxel, as model drug, and characterized by a technological point of view.


thin films of poly(isoprene-b-ethylene oxide) diblock copolymers on mica: an atomic force microscopy study.
The structural behavior of three amphiphilic semicrystalline poly(isoprene-b-ethylene oxide) block copolymers (PI-b-PEO) with different PEO volume fraction (f(PEO) = 0.32, 0.49, and 0.66), spin-coated on freshly cleaved mica surfaces from aqueous solutions, was investigated by atomic force microscopy. We focus on the dependence of the resulting thin film nanostructures on the molecular characteristics (f(PEO) and molecular weight) and the adsorbed amount. The nanostructures obtained immediately after spin-coating were robust and remained unchanged after annealing and/or aging. The PEO affinity for the highly hydrophilic mica and the tendency of the hydrophobic and low surface energy PI to dewet and be at the free interface caused the soft PI-b-PEO micelles to collapse leading to the formation of 2D dendritic networks over mica. We show that, for all three polymers, the dendritic monolayer thickness can be predicted by a model consisting of a PEO crystallized layer (directly on top of mica) of the same thickness in all cases and a PI brush layer on top. In thicker areas, polymer material self-assembled into conelike multilamellar bilayers on top of the monolayer and oriented parallel to the substrate for both symmetric and asymmetric diblock copolymers with the lowest f(PEO). We compare the lateral morphology of the films and discuss the thickness heterogeneity, which results from the coupling and competition of crystallization kinetics, phase separation, and wetting/dewetting phenomena highlighting the role of the two blocks to inhibit or enhance certain morphologies. We show that the deviation of the f(PEO) = 0.32 thin film from its bulk phase structure (cylinders in hexagonal lattice) continues for several lamellar bilayers away from the substrate. For the asymmetric PI-b-PEO polymer with the higher PEO volume fraction (f(PEO) = 0.66) and higher APT, laterally extensive stacks of flat-on lamellar crystallites formed on the surface demonstrating the crucial role of the PEO crystallization.


Lectin-like oxidized LDL receptor-1 is an enhancer of tumor angiogenesis in human prostate cancer cells.
Altered expression and function of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) has been associated with several diseases such as endothelial dysfunction, atherosclerosis and obesity. In these pathologies, oxLDL/LOX-1 activates signaling pathways that promote cell proliferation, cell motility and angiogenesis. Recent studies have indicated that olr1 mRNA is over-expressed in stage III and IV of human prostatic adenocarcinomas. However, the function of LOX-1 in prostate cancer angiogenesis remains to be determined. Our aim was to analyze the contribution of oxLDL and LOX-1 to tumor angiogenesis using C4-2 prostate cancer cells. We analyzed the expression of pro-angiogenic molecules and angiogenesis on prostate cancer tumor xenografts, using prostate cancer cell models with overexpression or knockdown of LOX-1 receptor. Our results demonstrate that the activation of LOX-1 using oxLDL increases cell proliferation, and the expression of the pro-angiogenic molecules VEGF, MMP-2, and MMP-9 in a dose-dependent manner. Noticeably, these effects were prevented in the C4-2 prostate cancer model when LOX-1 expression was knocked down. The angiogenic effect of LOX-1 activated with oxLDL was further demonstrated using the aortic ring assay and the xenograft model of tumor growth on chorioallantoic membrane of chicken embryos. Consequently, we propose that LOX-1 activation by oxLDL is an important event that enhances tumor angiogenesis in human prostate cancer cells.


Intravenous Ondansetron and the QT Interval in Adult Emergency Department Patients: An Observational Study.
Ondansetron is known to cause QT interval prolongation, but this effect and clinical significance has not been prospectively studied in adult emergency department (ED) patients. The primary objective was to determine the mean maximal corrected QT interval (QTc) prolongation after intravenous (IV) administration of 4 mg of ondansetron. The secondary objective was to report any serious adverse cardiac electrical events. This was a prospective, observational, single-center cohort study conducted between 2012 and 2013 in an academic, military hospital ED. Adult patients ordered to receive 4 mg of IV ondansetron were eligible for the study. A six-lead electrocardiogram was recorded at baseline and every 2 minutes after ondansetron administration for 20 minutes. The QTc was calculated using the Bazett formula. Serious adverse cardiac electrical events (nonsinus rhythm, severe bradycardia, and sudden cardiac death) were also recorded. Twenty-two adult ED patients were enrolled. Ondansetron caused a mean prolongation of the QTc by 20 ms (95% confidence interval [CI] = 14 to 26 ms), with a mean proportion change from baseline of 5.2% (95% CI = 3.8% to 6.6%). There were zero (95% CI = 0 to 13%) reported serious adverse cardiac electrical events. While QTc prolongation does occur in adult ED patients receiving IV ondansetron, the clinical impact is questionable.


Combinatorial immune refocusing within the influenza hemagglutinin head elicits cross-neutralizing antibody responses.
The head domain of influenza hemagglutinin (HA) elicits potently neutralizing yet mostly strain-specific antibodies during infection and vaccination. Here we evaluated a series of immunogens that combined several immunofocusing techniques for their ability to enhance the functional breadth of vaccine-elicited immune responses. We designed a series of "trihead" nanoparticle immunogens that display native-like closed trimeric heads from the HAs of several H1N1 influenza viruses, including hyperglycosylated variants and hypervariable variants that incorporate natural and designed sequence diversity at key positions in the periphery of the receptor binding site (RBS). Nanoparticle immunogens displaying triheads or hyperglycosylated triheads elicited higher HAI and neutralizing activity against vaccine-matched and -mismatched H1 viruses than corresponding immunogens lacking either trimer-stabilizing mutations or hyperglycosylation, indicating that both of these engineering strategies contributed to improved immunogenicity. By contrast, mosaic nanoparticle display and antigen hypervariation did not significantly alter the magnitude or breadth of vaccine-elicited antibodies. Serum competition assays and electron microscopy polyclonal epitope mapping revealed that the trihead immunogens, especially when hyperglycosylated, elicited a high proportion of antibodies targeting the RBS, as well as cross-reactive antibodies targeting a conserved epitope on the side of the head. Our results yield important insights into antibody responses against the HA head and the ability of several structure-based immunofocusing techniques to influence vaccine-elicited antibody responses.


Processing and Bread-Making Quality Profile of Spanish Spelt Wheat.
Spelt wheat (Triticum aestivum L. ssp. spelta Thell.) is an ancient wheat that has been widely cultivated for hundreds of years. Recently, this species has been neglected in most of Europe; however, the desire for more natural and traditional foods has driven a revival of the crop. In the current study, eighty-eight traditional spelt genotypes from Spain, together with nine common wheat cultivars and one modern spelt (cv. Anna Maria) were grown during a period of two years in Andalucia (southern Spain). In each, several traits were measured in to evaluate their milling, processing, and end-use quality (bread-making). The comparison between species suggested that, in general, spelt and common wheat showed differences for most of the measured traits; on average, spelt genotypes had softer grains, higher protein content (14.3 vs. 11.9%) and gluten extensibility (alveograph P/L 0.5 vs. 1.8), and lower gluten strength (alveograph W 187 vs. 438 × 10-4 J). In the baking test, both species showed similar values. Nevertheless, the analysis of this set of spelt genotypes showed a wide range for all measured traits, with higher values than common wheat in some spelt genotypes for some traits. This opens up the possibility of using these materials in future breeding programs, to develop either new spelt or common wheat cultivars.


Gastrointestinal cancers in Mississippi.
According to a 2007 US Census Bureau report, Mississippi is the poorest state in the United States and is ranked last among all 50 states for overall quality of health. The objective of the study was to describe gastrointestinal (GI) cancers in Mississippi overall and the Mississippi Delta region in particular. The age-adjusted incidence rates for GI cancers for 2003-2007, compiled from the Mississippi Cancer Registry and the Centers for Disease Control and Prevention's National Program of Cancer Registries, were retrieved and compared among 18 Mississippi Delta counties, 64 non-Delta counties, the entire state of Mississippi, and the United States. Colorectal cancer incidence rates and national rankings were correlated with influencing factors of race, obesity, diabetes mellitus, education, unemployment rate, availability of health insurance and primary care physicians, physical activity, diet, and per capita income. Compared with the United States as a whole, Mississippi had higher rates of colon and rectal cancers and a lower overall rate of gallbladder cancers in both whites and African Americans. Of all GI cancers, only liver, intrahepatic bile duct, and gallbladder cancers had lower age-adjusted incidence rates in the Mississippi Delta region. There was a large difference between African Americans and whites in the Delta region. Whites residing in the Delta counties had higher incidence rates than African Americans of all cancers except liver and intrahepatic bile duct cancers. The majority of GI cancers had higher incidence rates in the Mississippi Delta than non-Delta counties and in the entire state than the United States. These disparities observed on a regional and ethnic basis call for targeted prevention efforts to eliminate disparities in GI cancer incidence rates.


Proximal Remote Sensing to Non-destructively Detect and Diagnose Physiological Responses by Host Insect Larvae to Parasitism.
As part of identifying and characterizing physiological responses and adaptations by insects, it is paramount to develop non-destructive techniques to monitor individual insects over time. Such techniques can be used to optimize the timing of when in-depth (i.e., destructive sampling of insect tissue) physiological or molecular analyses should be deployed. In this article, we present evidence that hyperspectral proximal remote sensing can be used effectively in studies of host responses to parasitism. We present time series body reflectance data acquired from individual soybean loopers (Chrysodeixis includens) without parasitism (control) or parasitized by one of two species of parasitic wasps with markedly different life histories: Microplitis demolitor, a solitary larval koinobiont endoparasitoid and Copidosoma floridanum, a polyembryonic (gregarious) egg-larval koinobiont endoparasitoid. Despite considerable temporal variation in reflectance data 1-9 days post-parasitism, the two parasitoids caused uniquely different host body reflectance responses. Based on reflectance data acquired 3-5 days post-parasitism, all three treatments (control larvae, and those parasitized by either M. demolitor or C. floridanum) could be classified with >85 accuracy. We suggest that hyperspectral proximal imaging technologies represent an important frontier in insect physiology, as they are non-invasive and can be used to account for important time scale factors, such as: minutes of exposure or acclimation to abiotic factors, circadian rhythms, and seasonal effects. Although this study is based on data from a host-parasitoid system, results may be of broad relevance to insect physiologists. Described approaches provide a non-invasive and rapid method that can provide insights into when to destructively sample tissue for more detailed mechanistic studies of physiological responses to stressors and environmental conditions.


Autofluorescence videoendoscopy system using the SAFE-3000 for assessing superficial gastric neoplasia.
Autofluorescence (AF) videoendoscopy has an advantage over ordinary videoendoscopy in the diagnosis of gastric neoplasias, and the aim of the present study was to evaluate the effectiveness of using the SAFE-3000 videoendoscopy system to diagnose superficial gastric neoplasias. Ordinary videoendoscopy, AF videoendoscopy, and chromoendoscopy (CE) were used to diagnose the tumor existence and extent in 14 patients with gastric adenoma, 40 patients with intestinal-type early gastric cancer (EGC) (10 protruded, and 30 depressed), and nine patients with diffuse-type EGC. The diagnostic accuracies of the three kinds of images were evaluated by comparison with the results of histopathological assessment of resected specimens. For gastric adenomas the diagnostic accuracy between the AF images and white light (WL) images did not differ significantly, and for protruded intestinal-type EGCs and diffuse-type EGCs the diagnostic accuracy did not differ significantly between any of the types of images. For depressed intestinal-type EGCs, the diagnostic accuracy of AF images tended to be higher than that of the WL images (P < 0.05) and it was not significantly different from that of the CE images. The detection rate of pink or orange color in AF images was significantly higher for protruded intestinal-type EGCs than gastric adenomas (P = 0.005), depressed intestinal-type EGCs (P < 0.001), and diffuse-type EGCs (P = 0.027). Autofluorescence videoendoscopy using the SAFE-3000 system for gastric neoplasias might be useful for diagnosing depressed intestinal-type early gastric cancers. The detection of orange or pink color in AF images may be efficacious in discriminating protruded intestinal-type early gastric cancers from gastric adenomas.


Applications of advanced technologies for detecting genomic structural variation.
Chromosomal structural variation (SV) encompasses a heterogenous class of genetic variants that exerts strong influences on human health and disease. Despite their importance, many structural variants (SVs) have remained poorly characterized at even a basic level, a discrepancy predicated upon the technical limitations of prior genomic assays. However, recent advances in genomic technology can identify and localize SVs accurately, opening new questions regarding SV risk factors and their impacts in humans. Here, we first define and classify human SVs and their generative mechanisms, highlighting characteristics leveraged by various SV assays. We next examine the first-ever gapless assembly of the human genome and the technical process of assembling it, which required third-generation sequencing technologies to resolve structurally complex loci. The new portions of that "telomere-to-telomere" and subsequent pangenome assemblies highlight aspects of SV biology likely to develop in the near-term. We consider the strengths and limitations of the most promising new SV technologies and when they or longstanding approaches are best suited to meeting salient goals in the study of human SV in population-scale genomics research, clinical, and public health contexts. It is a watershed time in our understanding of human SV when new approaches are expected to fundamentally change genomic applications.


The Effects of Endocrine Disruptors on Adipogenesis and Osteogenesis in Mesenchymal Stem Cells: A Review.
Endocrine-disrupting chemicals (EDCs) are prevalent in the environment, and epidemiologic studies have suggested that human exposure is linked to chronic diseases, such as obesity and diabetes. In vitro experiments have further demonstrated that EDCs promote changes in mesenchymal stem cells (MSCs), leading to increases in adipogenic differentiation, decreases in osteogenic differentiation, activation of pro-inflammatory cytokines, increases in oxidative stress, and epigenetic changes. Studies have also shown alteration in trophic factor production, differentiation ability, and immunomodulatory capacity of MSCs, which have significant implications to the current studies exploring MSCs for tissue engineering and regenerative medicine applications and the treatment of inflammatory conditions. Thus, the consideration of the effects of EDCs on MSCs is vital when determining potential therapeutic uses of MSCs, as increased exposure to EDCs may cause MSCs to be less effective therapeutically. This review focuses on the adipogenic and osteogenic differentiation effects of EDCs as these are most relevant to the therapeutic uses of MSCs in tissue engineering, regenerative medicine, and inflammatory conditions. This review will highlight the effects of EDCs, including organophosphates, plasticizers, industrial surfactants, coolants, and lubricants, on MSC biology.