Neurochemical lesion of the nucleus locus coeruleus increases neophobia in a specific exploration task but does not modify endocrine response to moderate stress.
In order to test more specifically the role of the nucleus locus coeruleus (LC) in reaction to novelty, rats with bilateral 6-hydroxydopamine lesions of this nucleus, vehicle injected rats and non-operated animals were tested in the open-field and in the Hughes apparatus where motor activity is recorded in both a familiar and a non-familiar environment. In the open-field, the LC lesioned animals were significantly less active. A similar decrease of locomotor activity was observed in the Hughes test: the number of passages between the two boxes of the LC lesioned rats was significantly decreased. Likewise when the locomotor activities in the two boxes were pooled, the activity of the rats with lesions was significantly lower than the activity of the control rats, but in this case the locomotor deficit appeared only in the familiar box, the locomotor activity in the novel enclosure being the same in both LC lesioned and control animals. This result suggests that exploratory induced locomotion is not disturbed by the locus coeruleus lesion. The significant locomotor deficit showed by the LC lesioned rats in the familiar box could be due to an increased immobility induced by the stressful situation. Moreover, the deficit observed was the same whether the behavioral test began 4 days or 4 weeks after the lesion. Finally, at the end of the experiment, all rats were submitted to a moderate novel environmental stress and blood samples collected to measure the plasma levels of different stress hormones (ACTH, glucocorticoids, PRL, catecholamines).(ABSTRACT TRUNCATED AT 250 WORDS)


Results of a prospective controlled two-dose crossover study with intravenous immunoglobulin and comparison (retrospective) with plasma treatment.
Results of a two-dose (150 vs 500 mg/kg/month) crossover study with intravenous immunoglobulin (Endobulin, Immuno) (IVIG) carried out on 12 children with primary immunodeficiency syndromes over a period of 2 years are reported. Eight children had received human plasma (20 mg/kg/month) during the 2 years prior to the IVIG study. As these children had been thoroughly monitored during plasma treatment, a retrospective analysis of these data allowed for comparison with IVIG treatment. Children on low-dose IVIG therapy had significantly (P less than 0.01) fewer days with clinical illness, e.g., sinusitis, pneumonia, diarrhea, and arthritis, than did those receiving plasma treatment. High-dose IVIG therapy led to further significant clinical improvement. Lung function tests (MEF25) improved significantly as well. The difference between high- and low-dose therapy with respect to the improvement in clinical symptoms (e.g., cold, fever, otitis) was more pronounced in children with severe clinical symptoms at the initiation of the study. Children with fewer symptoms did comparably well on high- and low-dose treatment, except for those with acute febrile illness, which was less frequent in children on high-dose IVIG. Regular monitoring of liver enzymes in the group of patients on IVIG therapy gave no indication of the transmission of viral hepatitis in the course of the 2-year IVIG treatment.


PERK-Mediated Cholesterol Excretion from IDH Mutant Glioma Determines Anti-Tumoral Polarization of Microglia.
Isocitrate dehydrogenase (IDH) mutation, a known pathologic classifier, initiates metabolic reprogramming in glioma cells and has been linked to the reaction status of glioma-associated microglia/macrophages (GAMs). However, it remains unclear how IDH genotypes contribute to GAM phenotypes. Here, it is demonstrated that gliomas expressing mutant IDH determine M1-like polarization of GAMs, while archetypal IDH induces M2-like polarization. Intriguingly, IDH-mutant gliomas secrete excess cholesterol, resulting in cholesterol-rich, pro-inflammatory GAMs without altering their cholesterol biosynthesis, and simultaneously exhibiting low levels of tumoral cholesterol due to expression remodeling of cholesterol transport molecules, particularly upregulation of ABCA1 and downregulation of LDLR. Mechanistically, a miR-19a/LDLR axis-mediated novel post-transcriptional regulation of cholesterol uptake is identified, modulated by IDH mutation, and influencing tumor cell proliferation and invasion. IDH mutation-induced PERK activation enhances cholesterol export from glioma cells via the miR-19a/LDLR axis and ABCA1/APOE upregulation. Further, a synthetic PERK activator, CCT020312 is introduced, which markedly stimulates cholesterol efflux from IDH wild-type glioma cells, induces M1-like polarization of GAMs, and consequently suppresses glioma cell invasion. The findings reveal an essential role of the PERK/miR-19a/LDLR signaling pathway in orchestrating gliomal cholesterol transport and the subsequent phenotypes of GAMs, thereby highlighting a novel potential target pathway for glioma therapy.


Genetics and neuropathology of Huntington's disease.
Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder that prominently affects the basal ganglia, leading to affective, cognitive, behavioral and motor decline. The basis of HD is a CAG repeat expansion to >35 CAG in a gene that codes for a ubiquitous protein known as huntingtin, resulting in an expanded N-terminal polyglutamine tract. The size of the expansion is correlated with disease severity, with increasing CAG accelerating the age of onset. A variety of possibilities have been proposed as to the mechanism by which the mutation causes preferential injury to the basal ganglia. The present chapter provides a basic overview of the genetics and pathology of HD.


Effectiveness of individualized 3D titanium-printed Orthognathic osteotomy guides and custom plates.
Computer-aided design/manufacturing (CAD/CAM) technology was developed to improve surgical accuracy and minimize errors in surgical planning and orthognathic surgery. However, its accurate implementation during surgery remains a challenge. Hence, we compared the accuracy and stability of conventional orthognathic surgery and the novel modalities, such as virtual simulation and three-dimensional (3D) titanium-printed customized surgical osteotomy guides and plates. This prospective study included 12 patients who were willing to undergo orthognathic surgery. The study group consisted of patients who underwent orthognathic two-jaw surgery using 3D-printed patient-specific plates processed by selective laser melting and an osteotomy guide; orthognathic surgery was also performed by the surgeon directly bending the ready-made plate in the control group. Based on the preoperative computed tomography images and intraoral 3D scan data, a 3D virtual surgery plan was implemented in the virtual simulation module, and the surgical guide and bone fixation plate were fabricated. The accuracy and stability were evaluated by comparing the results of the preoperative virtual simulation (T0) to those at 7 days (T1) and 6 months (T2) post-surgery. The accuracy (ΔT1‒T0) and stability (ΔT2‒T1) measurements, using 11 anatomical references, both demonstrated more accurate results in the study group. The mean difference of accuracy for the study group (0.485 ± 0.280 mm) was significantly lower than in the control group (1.213 ± 0.716 mm) (P < 0.01). The mean operation time (6.83 ± 0.72 h) in the control group was longer than in the study group (5.76 ± 0.43 h) (P < 0.05). This prospective clinical study demonstrated the accuracy, stability, and effectiveness of using virtual preoperative simulation and patient-customized osteotomy guides and plates for orthognathic surgery.


Mechanistic and structural complexity in the site-specific recombination pathways of Int and FLP.
This review focuses on two of the approximately 30 members of the diverse Int family of site-specific recombinases. The lambda recombination system represents those reactions involving accessory proteins and a complex higher-order structure. The FLP system represents the most streamlined reactions and has been the subject of detailed and informative studies on the mechanisms of DNA cleavage and ligation.


Maternal and fetal Toll-like receptor 4 genotype and chorionic plate inflammatory lesions.
The objective of the study was to explore the relation between maternal and fetal genetic variation in Toll-like receptor 4 (TLR4) and chorionic plate inflammation In this prospective observational cohort of 109 women with singleton gestations, 13 tag single nucleotide polymorphisms (SNPs) were genotyped in the TLR4 gene. The diagnosis of chorionic plate inflammation was made by a single blinded perinatal pathologist. After adjustment for multiple comparisons, 1 maternal SNP (rs10759932) and 1 fetal SNP (rs1554973) in the TLR4 gene demonstrated highly significant association with chorionic plate inflammation. After adjustment for race, smoking, and bacterial vaginosis, carriage of these alleles was associated with chorionic plate inflammation (maternal rs1554973: odds ratio [OR] 5.2, 95% confidence interval, 3.2-6.4, P = .006; fetal rs10759932: OR 4.95, 95% confidence interval, 3.0-5.6, P = .005). There was no evidence of interaction between these 2 SNPs. Maternal and fetal genetic variation in TLR4 is strongly associated with chorionic plate inflammation. This maternal and fetal genotypic effect are independent of each other as well as other environmental covariates.


Experimental study of peritoneal blood flow and insufflation pressure during laparoscopy.
Port-site metastases after laparoscopic surgery may occur with greater frequency than would be expected following open resection of intra-abdominal malignancies, but the causal mechanism for this is incompletely understood. The possibility that insufflation may increase peritoneal blood flow producing a wound environment conducive to the formation of metastases was investigated. The effects of insufflation gas type and pressure were studied in 30-kg female pigs. Pigs were divided into five groups, which were subjected to insufflation at 12 mmHg pressure with helium, insufflation at 12, 8 or 4 mmHg pressure with carbon dioxide, or laparotomy. A microsphere technique utilizing two distinct radiotracers, 99mTc-labelled macroaggregated albumin (MAA) and 51Cr-labelled MAA, was used to study blood flow to the peritoneum, liver and kidneys. Insufflation with carbon dioxide or helium gases had no effect on renal (P < 0.09) or hepatic blood flow (P = 0.54). However, insufflation significantly increased peritoneal blood flow when carbon dioxide (P < 0.05), but not when helium (P = 0.99), was used as the insufflating gas. These data suggest that blood flow within the peritoneum is influenced by insufflation with carbon dioxide. It is conceivable that such hyperaemia could increase the propensity for implanted tumour cells to metastasize in these sites following laparoscopy.


Effects of gonadectomy on immunoreactivity for choline acetyltransferase in the cortex, hippocampus, and basal forebrain of adult male rats.
Androgens are known to affect cognitive and mnemonic aspects of spatial processing. The cholinergic system is thought to play an important role in cognition and memory, but little is known about the interaction between androgen and cholinergic neurons. The present study focused on the effects of testosterone on the cholinergic neurons in the anterior cingulate cortex, the posterior parietal cortex, the hippocampus, and the basal forebrain including the medial septum, i.e., regions related to spatial processing. We examined choline acetyltransferase (ChAT) immunoreactivity in three groups of adult male rats: sham-operated (Sham), 28-day gonadectomized (GDX), and 28-day gonadectomized with immediate implantation of testosterone propionate (GDX+TP). Comparison of the Sham and GDX+TP groups demonstrated that the GDX group had significantly decreased cell counts of ChAT-immunoreactive neurons in anterior cingulate cortex layer II/III, posterior parietal cortex layer II/III, and the medial septum, but not in the other basal forebrain subregions examined (the horizontal part of the diagonal band of Broca and the substantia innominata). The GDX group also had significantly reduced hippocampal ChAT-immunoreactive fiber pixel density. The GDX+TP group maintained ChAT-immunoreactive cell counts in the anterior cingulate cortex, posterior parietal cortex, and medial septum equivalent to those in the Sham group. Less than 1% of identified cells showed colocalization of immunoreactivity for ChAT and androgen receptor in the cell bodies of the cortex and basal forebrain. Our observations demonstrate that the presence or absence of testosterone for 4 weeks influenced the cholinergic population region-specifically in the adult rat brain.


Stressor effects of adrenaline on the immature fowl.
Chicks were injected with L-adrenaline (500 microgram/kg) thrice weekly from hatching for one, two or three weeks. The growth rate of treated chicks was depressed, particularly in the first week. When four-week-old chicks were given nine injections of adrenaline over a three-week period, growth rate was also depressed but less severely. The greater sensitivity of the younger chicks is thought to result from an immature blood-brain barrier. Relative adrenal mass (mg/kg) was generally increased but adrenal cholesterol depletion occurred only in three-week-old birds treated with adrenaline throughout. Plasma glucose and cholesterole concentrations were within the normal range after three weeks of treatment but there was a significant hypolipacidaemia in the younger birds treated for two or three weeks.


Beta-adrenergic stimulation inhibits calcium efflux and alters the morphology of cultured arterial muscle cells.
Beta-adrenoreceptor stimulation with isoproterenol (IP) rapidly and reversibly rounded and arborized smooth muscle cells (SMC) cultured from rat aorta. The arborized SMC remained firmly attached to the substratum via a network of long, dendritelike processes. Arborization of the SMC correlated closely with increases in cellular cAMP produced by IP and a variety of other compounds. The intracellular calcium antagonist 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8) also rounded and arborized the SMC. Antitubulin compounds potently blocked arborized by IP, dibutyryl cAMP, and TMB-8. The release of cell-bound 45Ca2+ was followed in the presence and absence of IP. IP strikingly increased the amount of 45Ca2+ that remained cell bound between 20 and 120 min. Propranolol and colchicine prevented IP from inhibiting the release of cell-bound 45Ca2+. These results suggest that the modulation of Ca2+ transport is involved in the arborization of cultured SMC by cAMP.


Combined effects of ocean deoxygenation, acidification, and phosphorus limitation on green tide macroalga, Ulva prolifera.
Ocean deoxygenation, acidification, and decreased phosphorus availability are predicted to increase in coastal ecosystems under future climate change. However, little is known regarding the combined effects of such environmental variables on the green tide macroalga Ulva prolifera. Here, we provide quantitative and mechanistic understanding of the acclimation mechanisms of U. prolifera to ocean deoxygenation, acidification, and phosphorus limitation under both laboratory and semi-natural (mesocosms) conditions. We found that there were significant interactions between these global environmental conditions on algal physiological performance. Although algal growth rate and photosynthesis reduced when the nitrogen-to‑phosphorus (N/P) ratio increased from 16:1 to 35:1 under ambient CO2 and O2 condition, they remained constant with further increasing N/P ratios of 105:1, 350:1, and 1050:1. However, the increasing alkaline phosphatase activities at high N/P ratios suggests that U. prolifera could use organic P to support its growth under phosphorus limitation. Deoxygenation had no effect on specific growth rate (SGR) but decreased photosynthesis under low N/P ratios of 16:1, 35:1, and 105:1, with reduced activities of several enzymes involved in N assimilation pathway being observed. Elevated CO2 promoted algal growth and alleviated the negative effect of deoxygenation on algal photosynthesis. The patterns of responses to high CO2 and low O2 treatments in in situ experiments were generally consistent with those observed in laboratory experiments. Our results generally found that the strong physiological acclimation capacity to elevated CO2, low O2, and high N/P could contribute to its large-scale blooming in coastal ecosystem.


Conditional unnecessity of head CT for whole-body CT of traffic accident victims: a pilot study.
To investigate whether head CT should be included in whole-body CT in road traffic accident victims. A review of electronic medical records identified 124 patients (81 males, 43 females; age 4 to 92 years, mean 47.7 years) involved in a road traffic accident in a 12-month period. All had undergone whole-body CT and physical and neurologic examinations. We recorded their age, sex, Glasgow Coma Scale (GCS), systolic blood pressure (SBP), the type of traffic accident, and the presence/absence of visible trauma above the clavicles (VTCs) and of acute traumatic brain injury (TBI) on CT. Statistical analyses were performed to evaluate predictors of acute TBI. Of 124 patients, 34 (27%) manifested acute TBI on CT. Univariate analysis identified their age, GCS, SBP, VTCs, and the accident type as statistically significant factors for acute TBI (p < 0.05). Multivariate analysis demonstrated VTCs, GCS score < 15, and SBP ≤ 90 mmHg were significant independent predictors of acute TBI (p = 0.001, p = 0.001, and p = 0.004, respectively); the odds ratio was 16.07 for VTCs, 14.85 for GCS score < 15, and 13.78 for SBP ≤ 90 mmHg. No patients without both decrease in GCS score and VTCs manifested acute TBI. Our pilot study showed that visible trauma above the clavicles and decrease in GCS score were highly associated with the presence of acute TBI in road traffic accident victims. In whole-body CT, a head CT may not be indicated in patients without these factors.


Lipmann and Anfinsen: Nobel biochemists of Beecher's anesthesia laboratory.
Henry K. Beecher performed blood pH and gas analysis on patients in the 1940s, though the biochemical technology was not widely available until the 1950s. Two of Beecher's biochemist coworkers, Fritz Lipmann and Christian B. Anfinsen, went on to earn Nobel Prizes.


Phosphodiesterase type 4 inhibitor rolipram inhibits activation of monocytes during extracorporeal circulation.
Cardiopulmonary bypass is associated with systemic inflammatory response syndrome and risk of multiorgan injury mediated by activated leukocytes. Phosphodiesterase type 4 is the predominant phosphodiesterase isozyme in leukocytes and plays a key role in the regulation of leukocyte activation. The aim of this study was to examine the effect of rolipram, a selective phosphodiesterase type 4 inhibitor, on functional changes of monocytes during simulated extracorporeal circulation. Simulated extracorporeal circulation was established by recirculating heparinized human blood for 120 minutes on a membrane oxygenator with or without 10 micromol/L of rolipram. L-selectin and CD11b expression of monocytes were measured with flow cytometry. C4d fragment, Bb fragment, C5b-9, and interleukin-6 were measured with enzyme immunoassay. Rolipram reduced the increase in CD11b expression and the decrease in L-selectin expression of monocytes in response to simulated extracorporeal circulation. Rolipram inhibited the increase in C4d fragment and interleukin-6, but it did not affect the increase in Bb fragment or C5b-9. Rolipram inhibited changes in adhesion molecule expression and interleukin-6 release by activated monocytes in simulated extracorporeal circulation. This study suggests that phosphodiesterase type 4 inhibition could be feasible therapeutic strategy to prevent exaggerated inflammatory response and organ injury in patients undergoing cardiopulmonary bypass.


WITHDRAWN: Multidrug Transporter LmrP allows Relocation of Catalytic Carboxylates.
This article has been withdrawn by the authors. Some lanes in the immunoblots were used to represent different experimental conditions in Figs 3A and 5A. The transport measurements shown in Figs 3D and 5D were the same. Less relevant features were obscured in the immunoblot in Fig 7A.


Cogan syndrome masquerading as corneal ectasia.
To report a case of Cogan syndrome that presented with the appearance of bilateral asymmetric corneal ectasia on Scheimpflug tomography. Case Report and Literature Review. A 43-year-old woman previously diagnosed with keratoconjunctivitis sicca and presumed keratoconus presented with seven months of episodic eye pain and progressive bilateral blurry vision with new onset bilateral monocular diplopia. Review of symptoms were significant for tinnitus, vertigo, and sensorineural hearing loss that began many months after her initial presentation for visual symptoms. Scheimpflug tomography showed asymmetric focal steepening on anterior curvature with corresponding focal total corneal thinning, focal posterior elevation, and abnormal ARTMax (205 OD, 103 OS) and BAD-D (2.75 OD, 5.6 OS) values. Clinical examination was notable only for faint anterior corneal stromal inflammation without neovascularization, but there was significant corresponding focal hyperreflectivity on anterior segment optical coherence tomography (OCT) examination with focal epithelial hypertrophy rather than thinning. Given the combined findings of interstitial keratitis and sensorineural hearing loss the patient was diagnosed with Cogan syndrome. She responded well to topical steroids and systemic immunosuppressive therapy, with near resolution of her abnormal topographic and tomographic findings and resolution of monocular diplopia in both eyes. Cogan syndrome should be suspected for any patient with corneal stromal findings and associated with vertigo and/or hearing loss. Anterior segment optical coherence tomography (OCT) can distinguish between ectatic and inflammatory diseases and may help make the appropriate diagnosis in subtle cases.


Automated urinary steroid profiles by capillary column gas-liquid chromatography and a computing integrator.
13 Urinary steroid metabolites have been determined by automated gas-liquid chromatography with a 20-m glass capillary column and a computing integrator. Concentrations up to 2 mg/24 h computed by the integrator compare well with those obtained by peak height measurements. At higher concentrations discrepancies occurred, paticularly for the C21 steroids where falsely low values were calculated using peak heights. Mean excretion by healthy males and females of seven steroid metabolities is presented.


Use of Remote Monitoring by E-mail for Long-Term Management of the Classic Ketogenic Diet.
The classic ketogenic diet (cKD) requires constant nutritional monitoring over time both to ensure its effectiveness and to reduce the likelihood of short- and long-term adverse effects. We retrospectively described the use of remote monitoring by e-mail during the first year of follow-up on cKD in 34 children (47% males; age range: 2-17 years) diagnosed with drug-resistant epilepsy (DRE; n = 14) or glucose transporter type 1 deficiency syndrome (GLUT1-DS; n = 20). All the e-mails were evaluated analyzing their frequency and content at 3, 6 and 12 months. Three families never sent e-mails. A median of 36.0 (IQR 23.0-64.0) e-mails per family were sent during the 12 follow-up months by the 31 patients. GLUT1-DS patients sent a greater number of e-mails than the DRE group (median 39.0 (IQR 25.5-56.5) vs. median 26.0 (IQR 19.0-65.0)). At the end of the follow-up period, a greater number of e-mails had been exchanged between the nutritional team and the families belonging to the group that increased its linear growth (median 83.5; IQR 48.0-102.0), compared to the other ones. Constant remote monitoring by e-mail could be a feasible and effective way for a better cKD management.


Expression, localization, and erythrocyte binding activity of Plasmodium yoelii merozoite surface protein-8.
PyMSP-8 is a member of a family of merozoite surface proteins that have been described in Plasmodium that are characterized by the presence of a glycolipid membrane anchor and 1-2 epidermal growth factor-like domains. Immunization with recombinant PyMSP-8 has also been shown to protect mice against lethal Plasmodium yoelii malaria. In this report, we demonstrate that PyMSP-8 expression is detectable throughout the entire erythrocytic life cycle of P. yoelii 17XL, reaching peak level during trophozoite development. As determined by immunofluorescence, PyMSP-8 co-localizes with PyMSP-1 on the surface of merozoites in segmented schizonts and on the surface of ring stages in newly invaded erythrocytes. PyMSP-8 binds to the surface of uninfected mouse RBCs in a species-dependent manner, suggesting a potential role in merozoite attachment to and/or invasion of erythrocytes. The receptor for PyMSP-8 on RBCs is sensitive to trypsin digestion but is resistant to treatment with chymotrypsin or neuraminidase and is putatively identified as a approximately 105kDa membrane protein. Since PyMSP-8 binds to both mature RBCs as well as reticulocytes, it appears unlikely that the function of PyMSP-8 is restricted to the invasion of normocytes. While proper folding and conformation of PyMSP-8 are important, linear determinants of PyMSP-8 also contribute to erythrocyte binding. Unexpectedly, however, PyMSP-8 specific antibodies that are protective in vivo, do not disrupt the binding of rPyMSP-8 to its receptor on erythrocytes. The data indicate that protective anti-PyMSP-8 antibodies mediate their effect in vivo by an alternate mechanism(s).


Increased lipid peroxidation as a mechanism of methionine-induced atherosclerosis in rabbits.
Methionine is converted by the transmethylation/transsulfuration pathway to homocysteine which may exert atherogenic effects by several mechanisms, including lipid peroxidation. Therefore, the excessive dietary methionine may induce the development of atherosclerosis. To test this hypothesis, plasma and aortic thiobarbituric acid reactive substances (TBARS), as well as activities of aortic and erythrocyte superoxide dismutase (SOD), catalase and selenium-dependent glutathione peroxidase (GPX) were measured in rabbits fed a diet enriched with 0.3% methionine for 6 or 9 months. Histological examinations of aortas also were performed. Feeding rabbits a methionine-enriched diet for 6 or 9 months resulted in significant increases in plasma and aortic TBARS levels and aortic antioxidant enzyme activities. However, a decrease in plasma antioxidant activity (AOA) was observed. In erythrocytes, SOD activity increased, catalase remained normal and GPX decreased in the treated animals. Histological examination of aortas showed typical atherosclerotic changes, such as intimal thickening, deposition of cholesterol, and calcification in methionine-fed rabbits. These results confirm that high-methionine diet may induce atherosclerosis in rabbits and indicate disturbances in lipid peroxidation and antioxidant processes as possible mechanisms of its atherogenic influence.


Serum cholinesterase activity in burned patients. II: anaesthesia, suxamethonium and hyperkalaemia.
The importance of serum cholinesterase activity in burned patients was evaluated in relation to anaesthesia. Anaesthesia included a repeated administration of suxamethonium. Thirty-two patients with an estimated area of burn between 3 and 72% were studied during 39 anaesthetic procedures. A statistically significant inverse correlation was found between serum cholinesterase activity and the apnoea period following intravenous suxamethonium. In patients with very low enzyme activity, apnoea periods of 10 to 25 min were observed. No correlation was found between the changes in serum potassium following suxamethonium and either the serum cholinesterase activity or the changes in Pco2 and pH. The most reliable parameters in predicting a dangerous increase in serum potassium following intravenous suxamethonium were shown to be 1) the time elapsed from burn injury to anesthesia and 2) the degree of burn injury. However, abnormal reactions to suxamethonium were seen as early as 9 days following injury, and rises in serum potassium to over 6 mmol/l were observed even in patients with a total burn surface of around 8%, i.e., less than the surface of one arm.


Physical activity equivalent labeling vs. calorie labeling: a systematic review and meta-analysis.
Many countries are trying to identify strategies to control obesity. Nutrition labeling is a policy that could lead to healthy food choices by providing information to consumers. Calorie labeling, for example, could lead to consumers choosing lower calorie foods. However, its effectiveness has been limited. Recently, physical activity equivalent labeling (i.e., displaying calories in terms of estimated amount of physical activity to burn calories) has been proposed as an alternative to the calorie-only label. The aim of this review was to identify and evaluate the published literature comparing effects on health behavior between physical activity equivalent labeling and calorie-only labeling. We searched the following databases: Pubmed/medline, Scopus, Web of science, Agris, Cochrane library, Google Scholar. We also searched along with reference lists of included articles. Articles that were published between 1 January 2000 and 31 October 2016 were eligible for inclusion provided they reported on studies that examined the effects of both types of labeling and included at least one outcome of interest. Mean and standard deviations of the included results were combined using a fixed-effect model. The difference in calories purchased between people exposed to physical activity labeling and calorie-only labeling was calculated as weighted mean difference by using a fixed-effect model. The difference of calories ordered between physical activity label and calorie label groups was not statistically significant (SMD: -0.03; 95% CI: -0.13, 0.07). The difference of calories ordered between physical activity label and calorie label according to real vs unreal (e.g. web-based) condition was 65 Kcal fewer in real-world settings. Physical activity calorie equivalent labeling in minutes does not significantly reduce calories ordered compared to calorie-only labeling.


The Significance and Clinical Outcome of Lymphocytic Duodenosis in Children: Mayo Clinic Experience and Systematic Review.
Lymphocytic duodenosis (LD) defined as increased intraepithelial lymphocytes >25 intraepithelial lymphocytes (IELs) per 100 epithelial cells with normal villous architecture is associated with many gastrointestinal (GI) disorders. We aim to assess the rate and outcome of LD in children and perform a systematic review. We reviewed all children (<18 years) who underwent esophagogastroduodenoscopy (EGD) with duodenal biopsy between January 2000 and June 2019 to identify LD cases and control group. Demographics, clinical, and pathologic information were reviewed and recorded. A systematic review including our findings was performed. During the study period 12,744 children underwent an EGD with biopsies. Of those, we identified 426 children with LD (3%) and 474 controls. The median age in years was 10.7 and 12.6 and there were 254 (60%) and 278 (59%) girls in the LD and control group, respectively. The most common presenting symptoms in both groups were abdominal pain (52%), gastroesophageal acid reflux disease (18%), diarrhea (16%), and vomiting (12%). Diarrhea (21% vs 12%, P < 0.001) and constipation (2% vs 0.4%, P = 0.021) were statistically different between the LD and control group, respectively. Median follow-up (range) is 3.6 (0.0, 190.9) and 3.1 (0.0, 194.2) in the LD and control group, respectively. CD (5% vs 0%, P < 0.001), Crohn disease (9% vs 3%, P = 0.003) and Helicobacter pylori gastritis (3% vs 1%, P = 0.021) were more common in the LD group. The Rate of LD in children is similar to reported rate in adults. In the absence of Crohn disease, CD or H. Pylori, LD seems to be a benign and transient histologic finding in children.


Evolving Indications for Heart-Lung Transplant in Spain.
The outcomes of heart-lung transplant (HLT) are worse than those of heart transplant (HT) and lung transplant alone; this and the availability of mechanical assistance have meant that the indications for HLT have been changing. This study aims to analyze the evolution of indications for HLT in a country of 47 million inhabitants. We performed a retrospective observational study of all HLTs performed in Spain (performed in 2 centers) from 1990 to 2020. The total number of patients included was 1751 (HT 1673 and HLT 78). After clinical adjustment, overall survival was compared between the 2 groups. Seven etiological subgroups were considered within the HLT group: (1) cardiomyopathy with pulmonary hypertension (CM + PH);, (2) Eisenmenger syndrome, (3) congenital heart disease without Eisenmenger syndrome, (4) idiopathic pulmonary arterial hypertension (IPAH), (5) cystic fibrosis, (6) chronic obstructive pulmonary disease (COPD) and/or emphysema), and (7) diffuse interstitial lung disease. There were a large number of differences between patients with HLT vs HT. HLT had a 2.69-fold increased probability of death in the first year compared with HT. The indications for HLT have changed over the years. In the recent period the indications are mainly congenital heart disease and Eisenmenger syndrome, with some cases of CM + PH. Other indications for HLT have virtually disappeared, mainly lung diseases (IPAH, COPD, cystic fibrosis). Median survival was low in CM + PH (18 days), diffuse interstitial lung disease (29 days), and ischemic heart disease (114 days); intermediate in Eisenmenger syndrome (600 days); and longer in IPAH, COPD and/or emphysema, and cystic fibrosis. HLT is a procedure with high mortality. This and mechanical assists mean that the indications have changed over the years. Etiological analysis is of utmost interest to take advantage of organs and improve survival.


Prolyl hydroxylase mediated inhibition of fatty acid synthase to combat tumor growth in mammary gland carcinoma.
Cancer is a group of cells which grow in an uncontrolled manner and invades to the adjacent organs to form malignant tumors. Tumor hypoxia results due to contrast between the cellular oxygen expenditure and oxygen supply to the cells. Hypoxia inducible factor (HIF) is a heterodimeric transcription factor encompass of oxygen sensitive α subunit and constitutively expressed β subunit both of which are basic helix-loop-helix protein. The stability of HIF is primarily regulated by post translational prolyl hydroxylation, catalyzed by prolyl hydroxylase 2 (Phd-2). Phd-2 is a group of enzymes that acts as an oxygen sensor. Cancer cells have altered metabolism as they fulfil their energy needs through glycolysis and lipid biogenesis. HIF-1α is known to upregulate glycolysis by activating the transcription of enzymes on the glycolytic pathway and through lipogenesis. Cancer cells have over expressed fatty acid synthase owing to altered glycolytic pathway. Considering the above, it is hypothesized that chemical activation of Phd-2 can curtail down HIF-1α and subsequently fatty acid synthase expression.


Treatment of early postinfarction ventricular aneurysm by intra-aortic balloon pumping and surgery.
In nine patients with medically refractory left ventricular failure and/or ventricular arrhythmias, secondary to acute formation of a ventricular aneurysm, intra-aortic balloon pumping (IABP) was instituted 24 to 36 hours before diagnostic angiographic studies. Ventricular irritability was reduced and heart failure was controlled in all patients. Eight patients underwent operation, four within 3 weeks of an acute myocardial infarction and four within 3 months. All had resection of the recent infarction and two had myocardial revascularization as well. Two of the eight patients died in the early postoperative period from intractable ventricular fibrillation. All six patients who survived the operation (mean follow-up 12 months) had excellent clinical results. Ventricular irritability was suppressed and only one patient had residual heart failure. However, there was one late death 7 months after operation. The results suggest that surgical therapy may be effective in the management of medically unresponsive arrhythmias and/or congestive heart failure in the acute or intermediate postinfarction phase. IABP assistance was helpful in supporting the circulation and reducing ventricular irritability during the preoperative and postoperative periods.


Age-Related Performance on the Brixton Spatial Anticipation Test in Healthy Child and Adolescent Girls: A Preliminary Evaluation.
The Brixton Spatial Anticipation Test assesses individuals' cognitive flexibility in terms of rule detection and attainment. It has been used to assess executive functioning in both clinical and nonclinical adult samples. However, little is currently known about the suitability of this task for younger populations. The current study therefore aimed to provide an initial exploration of this task's suitability for young people. Brixton responses from a healthy sample of children and adolescents were presented to investigate performance in both rule detection and rule attainment, respectively. A convenience sample of 72 female participants (Mage = 14.95 years, SD = 1.53 years, range = 11-17 years; MIQ = 103.76, SD = 10.81) was studied. The sample was divided according to age into four groups (11-12 years, 13-14 years, 15 years, and 16-17 years) to allow for developmental trajectory. No significant age performance differences were found. Small effect sizes between age groups lend support to the null findings. The current study suggests that the Brixton task norms are suitable for use with individuals aged 11 to 17 years old. However, normative work is still needed in this area, incorporating an adult sample for comparison, to comment upon the developmental trajectory specific to this task.


Sensitive measurement of polyols in urine by capillary zone electrophoresis coupled with amperometric detection using on-column complexation with borate.
Little is known about human polyol metabolism, but recent studies indicate that abnormal polyol concentrations in body fluids are related to several diseases. In this study, a rapid and sensitive method for the determination of seven major polyols in urine including two groups of polyol isomers, C5-polyols (Rib+Arb+Xyl) and C6-polyols (Sor+Gal+Man), was developed using capillary zone electrophoresis coupled with amperometric detection (CZE-AD). The effects of the working electrode potential, pH, running buffer components and concentrations, separation voltage and injection times were investigated. Under the optimised conditions, seven types of polyols could be perfectly separated via the formation of anionic polyol-borate complexes in a borate buffer solution. Highly linear current responses to the polyol concentrations were obtained with good correlation (0.9984<R(2)<0.9997), and the limits of detection (LODs) ranged from 1.33×10(-6) to 5.8×10(-7) mol L(-1) (S/N=3). The proposed method has been successfully used to detect polyols in urinary samples from healthy subjects and diabetes patients, demonstrating accurate and reliable results. This method has potential applications in the recognition of inborn errors affecting polyol metabolism.


Anti-idiotypic antibody identifies the cellular receptor of reovirus type 3.
The binding and subsequent infectivity of reovirus to target cells are mediated by interaction with specific cell surface viral receptors. To gain a more detailed understanding of the biochemistry of the reovirus receptor and the cellular consequences of viral attachment, we have studied the binding of type 3 reovirus (Dearing strain) in a quantitative manner utilizing an antiidiotypic antibody probe. A syngeneic monoclonal antiidiotypic antibody (87.92.6) was prepared by immunization with hybridoma cells which secrete an antireovirus hemagglutinin-specific antibody. This antiidiotypic antibody was previously shown to specifically recognize the cell surface receptor for reovirus type 3. In this report, we demonstrate that antiidiotype mimicked reovirus tropism in binding to murine thymomas; antiidiotype inhibited the binding of reovirus to specific targets, but not the binding of anti-H-2; and cross linking of receptor-bound antiidiotype by antiimmunoglobulin induced patching, but not capping of reovirus receptors. Utilizing radiolabeled antiidiotype, we next quantitate the number of reovirus receptors on R1.1 and YAC thymoma cells and, finally, report on the preliminary identification of the reovirus receptor as a 67,000-Da membrane glycoprotein.


Dietary α-tocopherol and atorvastatin reduce high-fat-induced lipid accumulation and down-regulate CD36 protein in the liver of guinea pigs.
The increased uptake and storage of lipids in the liver are important features of steatotic liver diseases. The fatty acid translocase/scavenger receptor cluster of differentiation (CD)36 facilitates the hepatic uptake of lipids. We investigated if RRR-α-tocopherol (αT) alone or in combination with atorvastatin (ATV) is capable of preventing hepatic lipid accumulation via down-regulation of CD36. To this end, Dunkin Hartley guinea pigs were fed a control diet (5% fat); or a high-fat control diet (21% fat, 0.15% cholesterol); or a high-fat control diet fortified with αT (250 mg/kg diet), ATV (300 mg/kg diet) or both ATV+αT for 6 weeks. Hepatic triacylglycerols, hepatic protein and mRNA expression of CD36 as well as the mRNA expression of the controlling nuclear receptors LXRα, PXR and PPARγ were determined. Animals fed the high-fat control diet accumulated significantly more triacylglycerols in the liver than control animals. This was significantly reduced by ATV and numerically by αT and ATV+αT. Hepatic CD36 protein concentrations were significantly higher in the high-fat than in the control group, and both αT and ATV reduced CD36 expression to the level observed in the control group. However, no synergistic effect of the combined treatment was observed. Neither CD36 mRNA nor that of the nuclear receptors (LXRα, PXR and PPARγ) differed between groups, suggesting a posttranslational regulatory mechanism. Our results indicate that orally administered ATV and αT individually, but not synergistically, prevent diet-induced lipid accumulation in the liver of guinea pigs by down-regulation of hepatic CD36 protein.


Primary adult T-cell leukemia/lymphoma of bone.
A 77-year-old man developed primary adult T-cell leukemia/lymphoma (ATL) of the bone with osteolytic lesions. A biopsy of the lesion revealed proliferation of atypical, large lymphoid cells with a local increase of osteoclasts. The clonal integration of human T-lymphotropic virus type I proviral DNA revealed the tumor cells to be ATL. They produced macrophage inflammatory protein 1alpha (MIP-1alpha) but not parathyroid hormone-related protein or other osteoclast-activating factors. Because MIP-1 produced by tumor cells enhances the expression of receptor activator of nuclear factor kappaB ligand (RANKL) of local osteoblasts and stromal cells, even of tumor cells, the increase of osteoclasts in the close vicinity of ATL cells was considered to result in local bone destruction.


Variability of the protein sequences of lcrV between epidemic and atypical rhamnose-positive strains of Yersinia pestis.
Sequencing of lcrV genes and comparison of the deduced amino acid sequences from ten Y. pestis strains belonging mostly to the group of atypical rhamnose-positive isolates (non-pestis subspecies or pestoides group) showed that the LcrV proteins analyzed could be classified into five sequence types. This classification was based on major amino acid polymorphisms among LcrV proteins in the four "hot points" of the protein sequences. Some additional minor polymorphisms were found throughout these sequence types. The "hot points" corresponded to amino acids 18 (Lys --> Asn), 72 (Lys --> Arg), 273 (Cys --> Ser), and 324-326 (Ser-Gly-Lys --> Arg) in the LcrV sequence of the reference Y. pestis strain CO92. One possible explanation for polymorphism in amino acid sequences of LcrV among different strains is that strain-specific variation resulted from adaptation of the plague pathogen to different rodent and lagomorph hosts.


Correlates and participation in community-based exercise programming for cancer patients before and during COVID-19.
COVID-19 pandemic restrictions ceased the opportunity for face-to-face group exercise classes with at risk populations, such as cancer patients, forcing an adaptation to online exercise programming. The purpose of this study was to compare the attendance rates and correlates of face-to-face exercise programming pre-COVID-19 to online programming delivered during the first year of pandemic restrictions. The sample was comprised from 1189 patient records between 2018 and 2021. Data analysis was based around the three primary research questions: (i) whether the volume of attendance in online exercise programming differed from the previous face-to-face programming; (ii) whether there were any differences in attendee demographics between online and face-to-face classes; and (iii) whether there were specific correlates of online attendance that can inform future exercise programming. Class attendance increased significantly when online exercise classes were introduced during the first year of the pandemic when compared to face-to-face attendance the prior years (p < .01). Multiple demographic findings were also observed including age, gender, and geographic differences. While COVID-19 has effected the ability to deliver face-to-face exercise programs for cancer patients, online programming has proved a promising delivery model with greater geographical reach. The approach, however, has gender and age differences in program attendance so targeted programming to reach specific cancer patient demographics may need attention. These results add to the continuing research in the area of online exercise and online programming strategies offering an effective option for cancer patients to achieve targeted exercise prescription.


Lower TSH and higher T4 levels are associated with current depressive syndrome in young adults.
The relationship of individual thyroid function indices to depression in those without a history of prior thyroid dysfunction is uncertain. We examined the relationship between thyroid-stimulating hormone (TSH) and thyroxine (T4) levels and current or lifetime history of depressive symptoms using information from 6869 participants, aged 17-39 years, in the Third National Health and Nutrition Examination Survey without history of thyroid-related illness. We found that lower TSH and higher T4 levels were associated with current depressive syndrome in men, but only higher T4 levels correlated with current depressive syndrome in women. Lifetime depressive syndrome was associated with neither TSH level nor T4 levels in men or women. These findings suggest that transient or 'state dependent' changes are associated with depression in those without a history of thyroid illness. Further studies to discern whether these depression-associated changes represent distinct endophenotypes of depression should be encouraged.


Comparative study of water uptake and photosynthetic gas exchange between scrub and fringe red mangroves, Rhizophora mangle L.
The red mangrove (Rhizophora mangle L.) occurs frequently in both scrub and fringe mangrove forests. Our previous study demonstrated that individuals of this mangrove species growing in scrub and fringe forests differ significantly in both morphological and physiological characteristics. To further characterize physiological differences between scrub and fringe mangroves, we compared their differences in water uptake and photosynthetic gas exchange during different seasons. In the wet season (June-October, 1990), scrub mangroves showed lower δD and δ18O values of stem water than fringe mangroves, indicating more usage of rain-derived freshwater. In the dry season (Jan-April, 1991), however, scrub mangroves utilized the same water source as fringe mangroves, reflected by their similar δD and δ18O values of stem water. Consistently, there were significant differences in predawn water potentials between scrub and fringe mangroves in the wet season (October 1990) with higher values for scrub mangroves, but no significant differences in the dry season (January 1991). Higher elevation in the scrub forest seems to be the major factor responsible for the shift of water sources in scrub mangroves. On Apr. 27 and Aug. 8, 1990, scrub mangroves showed lower CO2 assimilation rate, stomatal conductance, and intercellular CO2 concentration than fringe mangroves. There were no differences in these gas exchange characteristics on the other two measuring dates: Oct. 17, 1990 and Jan. 11, 1991. Instantaneous water use efficiency was significantly higher for scrub mangroves than for fringe mangroves on three of the four sampling dates. Similarly, leaf carbon isotope discrimination of scrub mangroves was always significantly lower than that of fringe mangroves, indicating higher long-term water use efficiency. Higher water use efficiency in scrub mangroves is a result of stomatal limitation on photosynthesis, which may entail considerable carbon cost to the plants.


FGFR2 mutations promote endometrial cancer progression through dual engagement of EGFR and Notch signalling pathways.
Mutations in the receptor tyrosine kinase gene fibroblast growth factor receptor 2 (FGFR2) occur at a high frequency in endometrial cancer (EC) and have been linked to advanced and recurrent disease. However, little is known about how these mutations drive carcinogenesis. Differential transcriptomic analysis and two-step quantitative real-time PCR (qRT-PCR) assays were applied to identify genes differentially expressed in two cohorts of EC patients carrying mutations in the FGFR2 gene as well as in EC cells harbouring mutations in the FGFR2. Candidate genes and target signalling pathways were investigated by qRT-PCR assays, immunohistochemistry and bioinformatics analysis. The functional roles of differently regulated genes were analysed using in vitro and in vivo experiments, including 3D-orthotypic co-culture systems, cell proliferation and migration protocols, as well as colony and focus formation assays together with murine xenograft tumour models. The molecular mechanisms were examined using CRISPR/Cas9-based loss-of-function and pharmacological approaches as well as luciferase reporter techniques, cell-based ectodomain shedding assays and bioinformatics analysis. We show that common FGFR2 mutations significantly enhance the sensitivity to FGF7-mediated activation of a disintegrin and metalloprotease (ADAM)17 and subsequent transactivation of the epidermal growth factor receptor (EGFR). We further show that FGFR2 mutants trigger the activation of ADAM10-mediated Notch signalling in an ADAM17-dependent manner, highlighting for the first time an intimate cooperation between EGFR and Notch pathways in EC. Differential transcriptomic analysis in EC cells in a cohort of patients carrying mutations in the FGFR2 gene identified a strong association between FGFR2 mutations and increased expression of members of the Notch pathway and ErbB receptor family. Notably, FGFR2 mutants are not constitutively active but require FGF7 stimulation to reprogram Notch and EGFR pathway components, resulting in ADAM17-dependent oncogenic growth. These findings highlight a pivotal role of ADAM17 in the pathogenesis of EC and provide a compelling rationale for targeting ADAM17 protease activity in FGFR2-driven cancers.


Glucokinase activation induces potent hypoglycemia without recruiting insulin and inhibits food intake in chicken.
Glucose homeostasis exhibits several peculiarities in chickens (in short, presence of high glycemia and resistance to high doses of exogenous insulin). Though the full chicken glucokinase gene sequence is still lacking, several results suggest its existence. The functionality of chicken glucokinase (GK) has been further investigated using an activator of mammalian GK (GKA). In vitro, GKA decreased GK's S0.5(a) in a glucose-dependent manner in liver homogenates from either fasted or fed chickens; it also increased GK Vmax(a) in homogenates from fed chickens. In vivo, acute oral GKA administration (10-100 mg/kg) induced a potent and dose dependent hypoglycemic effect in fed chickens (starting between 15 and 45 min with a maximum effect at 40 mg/kg, P<0.0001). At this dose, plasma insulin levels showed erratic and minor changes in the early times (an increase at 5 min and a decrease at 10 min, P<0.05). At 90 min, when hypoglycemia had developed plasma insulin levels decreased under controls and plasma pancreatic glucagon levels increased over controls. Also at 40 mg/kg, GKA transiently inhibited food intake at about 3h (P<0.0001). In conclusion, GKA is a potent activator of chicken GK evidencing that the structure and the activity of chicken GK are similar to those of mammalian GK. At variance with results obtained in mammals, the potent GKA hypoglycemic action appears to rely mostly on an effect on liver GK in chicken. This fits with previous results and further support the hypothesis of a "deficient coupling" between Β-cell metabolism and insulin release in this species.


Decreased expression of mucin 18 is associated with unfavorable postoperative prognosis in patients with clear cell renal cell carcinoma.
MUC18 is correlated with tumor progression and metastasis in types of malignancy. But the role of MUC18 in clear cell renal cell carcinoma remains unclear. In this study, we aimed to investigate the expression of MUC18 and its correlation with clinical outcomes in clear cell renal cell carcinoma. Immunohistochemical staining was performed in samples from 288 patients with clear cell renal cell carcinoma. We used Kaplan-Meier method and Cox proportional hazard models to value the association between MUC18 expression and clinical outcome. Nomogram was constructed to predict overall survival at 5 and 8 years after nephrectomy. MUC18 expression was significantly decreased in tumor compared to non-tumor tissue (P<0.001). Lower MUC18 expression in tumor predicted a shorter survival time (P=0.007). By multivariate cox analysis, MUC18 was defined as an independent prognostic factor (P=0.006). The nomogram performed better in predicting 5- and 8-year overall survival than the TNM stage alone in clear cell renal cell carcinoma. MUC18 is an independent prognostic factor for clear cell renal cell carcinoma and could be incorporated with the other parameters to predict 5- and 8-year overall survival for clear cell renal cell carcinoma patients.


Marked elevation of interleukin-6 in mild encephalopathy with a reversible splenial lesion (MERS) associated with acute focal bacterial nephritis caused by Enterococcus faecalis.
This report describes two cases of mild encephalitis/encephalopathy with reversible splenial lesion (MERS) associated with acute focal bacterial nephritis (AFBN). The patients, who presented with fever and delirious behavior, exhibited hyponatremia and markedly elevated interleukin (IL)-6 in cerebrospinal fluid (CSF) and serum. Enterococcus faecalis was detected in the urine culture. After ampicillin treatment, their consciousness improved without neurological sequelae. Moreover, a diffusion-weighted MRI abnormality, i.e., intensified signals in splenium of the corpus callosum, disappeared. MERS is a possible complication of AFBN. Elevated CSF IL-6 levels suggest that remote activation of intracerebral immune response through the immune-neuroendocrine pathway might play an important role in the pathophysiology of MERS.


The effects of reflexology on symptoms in pregnancy: A systematic review of randomized controlled trials.
This review assessed the effects of reflexology on symptoms in pregnancy. PubMed, Embase, Springer, Web of Science, the Cochrane Library, and reference lists of previous systematic reviews were searched for the eligible randomized controlled trials (RCT) from the inception date of each predefined database up to May 31st, 2023. Data were extracted, and methodological quality was evaluated by the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2). The efficacy of treatment was assessed using pooled effect sizes (Hedges' g) and 95% confidence intervals (CI). Meta-analysis was performed using the RevMan 5.4 manager, and publication bias was evaluated by Begg's test. The included a total of 13 RCTs in this review, of eleven was high risk of bias and two were low, reported the effects of reflexology on low back and/or pelvic pain (LBPP), labor pain, duration of labor, anxiety, fatigue, sleep quality, constipation symptoms, and ankle and foot edema in pregnancy. The effect sizes (Hedges' g) for reflexology in labor pain, duration of labor, anxiety, fatigue, and sleep quality showed statistical significance, which the meta-analysis also confirmed except for fatigue and sleep quality due to insufficient studies. Reflexology is probably effective and safe for labor pain, duration of labor, and anxiety in pregnancy, while the evidences for reflexology in LBPP, fatigue, sleep quality, constipation symptoms, and ankle and foot edema during pregnancy were insufficient. Based on the low to high quality of included studies, strong supportive evidence is not yet available. Rigorous-design and large-scale clinical trials should be conducted to provide higher-quality, reliable evidence.


Relationships between p53 mutation, HPV status and outcome in oropharyngeal squamous cell carcinoma.
This study aimed to examine the rate and type of p53 mutation in oropharyngeal cancer (OSCC). Relationships were sought between human papillomavirus (HPV) status and p53 mutation. The role of p53 mutation as a prognostic factor independent of HPV status and as a modifier of the effect of HPV on outcomes was also examined. The HPV status of 202 cases was determined by HPV DNA by RT-PCR and p16 immunohistochemistry. P53 mutation in exon 5-8 was determined by pyrosequencing. Findings were correlated with known clinicopathological factors and outcomes. 48% of the cases were HPV positive and they were significantly less likely to have a p53 mutation than HPV-negative OSCCs (25.8% vs 46.7%, p=0.0021). Mutation was most common in exon 5. Among patients with HPV-positive OSCC, there was no significant difference in p53 mutation by smoking status (22.2% for never smokers and 30.8% for current or ex-smokers). Patients with p53 mutant OSCC had significantly worse overall survival (p=0.01). There was no statistical evidence that p53 mutation modified the effect of HPV status on outcomes. In the multivariate analysis, positive HPV status remained the strongest predictor of outcomes. p53 mutation status was not a significant predictor of outcome after adjusting for age, gender, T stage, N stage and HPV status. In summary, HPV-positive OSCC are less likely to have mutant p53 than HPV-negative OSCC. Our study did not show any evidence that p53 mutation could modify the effect of HPV status on outcomes.


One-pot construction of pyrazoles and isoxazoles with palladium-catalyzed four-component coupling.
[reaction: see text] Four-component coupling of a terminal alkyne, hydrazine (hydroxylamine), carbon monoxide, and an aryl iodide furnishes pyrazole or isoxazole derivatives in the presence of a palladium catalyst. The reaction proceeds at room temperature and an ambient pressure of carbon monoxide in an aqueous solvent system.


Good health: the generic alternative.
By the year 2011, medical expenditures in the United States are projected to double from today's outlay of $1.5 trillion. This is in an environment where purchasers of health care coverage already think the rate of growth in health care expenditures is unsustainable.


An Assessment of Nursing Skills Required for Sustaining a Casualty during Prolonged Casualty Care: Implications for Training and Preparing for the Next Major War.
The US military is transitioning rapidly from the Global War on Terrorism in preparation for near-peer combat in a multidomain operations (MDO) and/or large scale combat operations (LSCO) setting. Due to potentially contested freedom of movement in this setting, casualty evacuation may be significantly delayed, resulting in medics and other prehospital medical personnel taking on patient care duties normally performed by nurses in a hospital-based setting. However, the frequency of nursing-type care remains unclear. We seek to determine the nursing interventions typically performed in a facility with patient holding capability during the first 72 hours of care in the deployed setting. This is a sub-analysis of previously described data from the Department of Defense Trauma Registry of US and North Atlantic Treaty Organization (NATO) military personnel from January 2007 to March 2020 with a focus on relevant nursing procedures identified in current Individual Critical Task Lists (ICTL) for critical care, emergency, medical-surgical nurses, and combat medics. Among all casualties, the most common nursing-related skills performed in the prehospital setting were wound dressing application (33%), administration of parenteral opioids (35%), and administration of ketamine (7%); in the hospital setting were preparation for transfer (60%), managing a post-operative patient (59%), and managing a traumatic brain injury (44%). In the hospital setting, most patients had a blood gas performed (73%), ventilator management occurred for 21% of patients, and administration of packed red blood cells occurred for 21% of patients. Nursing-type interventions were frequently required during the first 72 hours of casualty care. The frequency of the required interventions demonstrates the need for ongoing nursing skills training for medics supporting casualties in the setting of prolonged casualty care.


[Conditions contributing to late diagnosis of Wegener's granulomatosis--own experience].
The paper presents two cases of Wegener's granulomatosis, diagnosed in the phase of advanced renal failure, requiring dialysis therapy. Analysis of factors resulting in delayed diagnosis was performed.


Significance of myeloperoxidase plasma levels as a predictor for cardiac resynchronization therapy response.
This study aimed to determine if changes in myeloperoxidase (MPO) levels correlate with response to cardiac resynchronization therapy (CRT) and the potential role of MPO as a predictor of response to CRT. CRT is a well-established treatment option in chronic heart failure (CHF) with 50-80% of patients benefiting. Inflammation and oxidative stress play a key role in CHF pathophysiology. Previous studies have demonstrated increased levels of MPO in CHF patients, but the correlation with CRT response remains incompletely understood. Fifty-three patients underwent CRT implantation. During follow-up, patients were divided into two groups, responders and non-responders to CRT, based on improved physical capacity and NYHA classification. Levels of MPO and NT-pro-brain-natriuretic-peptide (NT-proBNP) were determined prior to implantation, 30 and 90 days after. Physical capacity, including a 6-min walking-test, NYHA class, and LVEF were evaluated at baseline and during follow-up. Thirty-four patients (64%) responded to CRT, showing improved physical capacity and LVEF. All responders revealed a significant decrease of MPO levels (503.8 ng/ml vs. 188.4 ng/ml; p < 0.001). Non-responding patients did not show any significant changes in clinical parameters or MPO levels (119.6 ng/ml vs. 134.3 ng/ml; p = 0.672) during follow-up. At baseline, physical capacity and NYHA class, as well as MPO levels differed significantly between both groups (p < 0.001). A ROC analysis identified an MPO cut-off value for response to CRT of 242 ng/ml with a sensitivity of 93.5% and specificity of 71.4%. There was a strong correlation between MPO and improvement of LVEF (Spearman's rho: - 0.453; p = 0.005) and physical capacity (Spearman's rho: - 0.335; p = 0.042). Response to CRT and course of MPO levels correlate significantly. MPO levels differ between responders and non-responders prior to CRT, which may indicate an additional value of MPO as a predictor for CRT response. Further randomized studies are required to confirm our data in larger patient cohorts.


Evidence that insulin increases the proportion of polysomes that are bound to the cytoskeleton in 3T3 fibroblasts.
The association of polysome redistribution with changes in protein synthesis was investigated in insulin-stimulated fibroblasts. Free polysomes were released by Nonidet-P40 and 25 mM KCl, cytoskeletal-bound polysomes were retained at 25 mM KCl but released at 130 mM, while membrane-bound polysomes were released by deoxycholate. Insulin increased the proportion of polysomes which were retained at 25 mM KCl but had no effect when extraction was carried out at 130 mM KCl, suggesting that more polysomes were associated with the cytoskeleton. Insulin also reduced the amount of actin released from the detergent-insoluble cytoskeleton indicating that the hormone affects microfilament organization.


Urinary tract infection and indirect hyperbilirubinemia in newborns.
Jaundice is a common problem during the neonatal period. About 60% of the full term and 80% of premature infants develop jaundice. It can be associated with serious illnesses such as Urinary tract infections. The aim of this study is to evaluate the incidence and prevalence of urinary tract infection in newborns with indirect hyperbilirubinemia and to find a relationship with prolonged jaundice. We retrospectively evaluated asymptomatic, jaundiced neonates for evidence of a urinary tract infection. Data reviewed including demographic and historical data were included with data of blood studies, radiological evaluation and treatment. 32 neonates of 152 cases had urinary tract infection. Most commonly isolated organisms were Klebsiella and Escherishia coli. Maximum duration of phototherapy was 4 days in the urinary tract infection group versus 7 in the non-urinary tract infection group. Intensive phototherapy was used in 18.7% in the urinary tract infection group versus 29.16% in the non-urinary tract infection group. None of the newborns in the urinary tract infection group underwent exchange transfusion therapy. Urinary tract infection can occur in asymptomatic, jaundiced newborns. Thus, it may be the first in these babies before other signs become evident.


Longitudinal associations between executive control and body mass index across childhood.
Childhood obesity remains a prevalent public health concern. Executive control, a set of higher-order cognitive abilities for directing attention and behaviour, has been identified as a malleable factor potentially related to weight outcomes in youth. However, the directionality of this relationship remains unclear. This study examined reciprocal associations between three executive control components-inhibitory control, working memory and flexible shifting-and BMI (body mass index) percentile during childhood. At four points throughout elementary school, a community sample (N = 294) completed executive control tasks and had their height and weight objectively measured. Controlling for sex and socioeconomic risk status, random intercept cross-lagged panel models were tested. Better inhibitory control performance predicted lower subsequent BMI at each timepoint, and better working memory and flexible shifting performance in grade three both predicted lower subsequent BMI in grade 4. However, BMI did not predict subsequent executive control performance at any timepoint. Executive control abilities, including automatic response modulation, being able to hold and manipulate mental information, and being able to make flexible mental transitions, may be protective against weight problems, particularly in middle childhood when these abilities have had more time to mature and children begin to gain more independence.


Evidence-based training of health professionals to inform families about disability.
The development, delivery and evaluation of a training programme for medical and nursing professionals on best practice for informing families of their child's disability. A 2 h training course on 'Best practice guidelines for informing families of their child's disability' was designed based on the findings of a nationally representative study of parents and professionals. The classroom-based course comprised a presentation of the research and recommendations of the best practice guidelines; a DVD film of parent stories and professional advice; group discussion; and a half-hour input from a parent of two children with disabilities. An anonymous, pretraining and post-training questionnaire was administered to measure knowledge and confidence levels, using scales adapted from a study by Ferguson et al (2006). 235 participants, including medical students, nursing students, and junior hospital doctors (JHDs). Knowledge of best practice and confidence in communicating diagnosis of disability. Significant improvements in knowledge (time 1 mean (M)=14.31, SD=2.961; time 2 M=18.17, SD=3.068) and confidence (time 1 M=20.87, SD=5.333; time 2 M=12.43, SD=3.803) following training were found. In addition, a significant interaction between time and cohort (medical students, nurses and JHDs) was found for knowledge. Further examination suggested medical students' knowledge was developing to the extent that post-training, their scores were higher than nurses, but not significantly different to JHDs. The increase in reported levels of knowledge and confidence following training in best practice for informing families of their child's disability indicates the potential for providing communication skills training in this area.


Nearly 100% selective and visible-light-driven methane conversion to formaldehyde via. single-atom Cu and Wδ.
Direct solar-driven methane (CH4) reforming is highly desirable but challenging, particularly to achieve a value-added product with high selectivity. Here, we identify a synergistic ensemble effect of atomically dispersed copper (Cu) species and partially reduced tungsten (Wδ+), stabilised over an oxygen-vacancy-rich WO3, which enables exceptional photocatalytic CH4 conversion to formaldehyde (HCHO) under visible light, leading to nearly 100% selectivity, a very high yield of 4979.0 μmol·g-1 within 2 h, and the normalised mass activity of 8.5 × 106 μmol·g-1Cu·h-1 of HCHO at ambient temperature. In-situ EPR and XPS analyses indicate that the Cu species serve as the electron acceptor, promoting the photo-induced electron transfer from the conduction band to O2, generating reactive •OOH radicals. In parallel, the adjacent Wδ+ species act as the hole acceptor and the preferred adsorption and activation site of H2O to produce hydroxyl radicals (•OH), and thus activate CH4 to methyl radicals (•CH3). The synergy of the adjacent dual active sites boosts the overall efficiency and selectivity of the conversion process.


Gender Differences and Mental Health: An Exploratory Study of Knowledge and Attitudes to Mental Health Among Scottish Teenagers.
A cross-sectional survey of 496 teenagers was conducted in order to explore their knowledge and attitude towards mental health and people with mental health problems. Boys reported lower levels of knowledge and different sources of stress than girls. Negative attitudes were more common among boys than girls. Boys were less likely to think that an understanding of mental health was important, less likely to want to know more about mental health issues and twice as likely to think that they had already been given enough education. Gender specific educational interventions may be more appropriate and effective than whole school approaches.


Gestational weight loss and perinatal outcomes in overweight and obese women subsequent to diagnosis of gestational diabetes mellitus.
To investigate whether gestational weight loss (GWL) after the diagnosis of gestational diabetes mellitus (GDM) in overweight and obese women is associated with improved perinatal outcomes. Obesity and GDM are risk factors for adverse perinatal outcomes, but few studies have investigated weight loss during pregnancy in women with these comorbidities. Retrospective cohort study of 26,205 overweight and obese gestational diabetic women enrolled in the California Diabetes and Pregnancy Program. Women with GWL during program enrollment were compared to those with weight gain. Perinatal outcomes were assessed using chi-square test and multivariable logistic regression analysis. About 5.2% of women experienced GWL. GWL was associated with decreased odds of macrosomia (aOR 0.63, 95% CI 0.52-0.77), NICU admission (aOR 0.51, 95% CI 0.27-0.95), and cesarean delivery (aOR 0.81, 95% CI 0.68-0.97). Odds of SGA status (aOR 1.69, 95% CI 1.32-2.17) and preterm delivery <34 weeks (aOR 1.71, 95% CI 1.23-2.37) were increased. In overweight and obese women with GDM, third trimester weight loss is associated with some improved maternal and neonatal outcomes, although this effect is lessened by increased odds of SGA status and preterm delivery. Further research on weight loss and interventions to improve adherence to weight guidelines in this population is recommended.


Genome information of the cellulolytic soil actinobacterium Isoptericola dokdonensis DS-3 and comparative genomic analysis of the genus Isoptericola.
The actinobacterial group is regarded as a reservoir of biologically active natural products and hydrolytic enzymes with the potential for biomedical and industrial applications. Here, we present the complete genome sequence of Isoptericola dokdonensis DS-3 isolated from soil in Dokdo, small islets in the East Sea of Korea. This actinomycete harbors a large number of genes encoding carbohydrate-degrading enzymes, and its activity to degrade carboxymethyl cellulose into glucose was experimentally evaluated. Since the genus Isoptericola was proposed after reclassification based on phylogenetic analysis, strains of Isoptericola have been continuously isolated from diverse environments and the importance of this genus in the ecosystem has been suggested by recent culturomic or metagenomic studies. The phylogenic relationships of the genus tended to be closer among strains that had been isolated from similar habitats. By analyzing the properties of published genome sequences of seven defined species in the genus, a large number of genes for carbohydrate hydrolysis and utilization, as well as several biosynthetic gene clusters for secondary metabolites, were identified. Genomic information of I. dokdonensis DS-3 together with comparative analysis of the genomes of Isoptericola provides insights into understanding this actinobacterial group with a potential for industrial applications.


Therapeutic potential of low-intensity ultrasound (part 2): biomolecular effects, sonotransfection, and sonopermeabilization.
Part one of this review focused on the thermal and mechanical effects of low-intensity ultrasound (US). In this second and final part of the review, we will focus on and discuss various aspects of low-intensity US, with emphasis on the biomolecular effects, US-mediated gene transfection (sonotransfection), and US-mediated permeabilization (sonopermeabilization). Sonotransfection of different cell lines in vitro and target tissues in vivo have been reported. Optimization experiments have been done and different mechanisms investigated. It has also been found that several genes can be up-regulated or down-regulated by sonication. As to the potential therapeutic applications, systemic or local sonotransfection might also be a safe and effective gene therapy method in effecting the cure of local and systemic disorders. Gene regulation of target cells may be utilized in modifying cellular response to a treatment, such as increasing the sensitivity of diseased cells while making normal cells resistant to the side effects of a treatment. Advances in sonodynamic therapy and drug sonopermeabilization also offer an ever-increasing array of therapeutic options for low-intensity US.


Asymmetry is defined during meiosis in the oocyte of the parthenogenetic nematode Diploscapter pachys.
Asymmetric cell division is an essential feature of normal development and certain pathologies. The process and its regulation have been studied extensively in the Caenorhabditis elegans embryo, particularly how symmetry of the actomyosin cortical cytoskeleton is broken by a sperm-derived signal at fertilization, upstream of polarity establishment. Diploscapter pachys is the closest parthenogenetic relative to C. elegans, and D. pachys one-cell embryos also divide asymmetrically. However how polarity is triggered in the absence of sperm remains unknown. In post-meiotic embryos, we find that the nucleus inhabits principally one embryo hemisphere, the future posterior pole. When forced to one pole by centrifugation, the nucleus returns to its preferred pole, although poles appear identical as concerns cortical ruffling and actin cytoskeleton. The location of the meiotic spindle also correlates with the future posterior pole and slight actin enrichment is observed at that pole in some early embryos along with microtubule structures emanating from the meiotic spindle. Polarized location of the nucleus is not observed in pre-meiotic D. pachys oocytes. All together our results are consistent with the idea that polarity of the D. pachys embryo is attained during meiosis, seemingly based on the location of the meiotic spindle, by a mechanism that may be present but suppressed in C. elegans.


Recording of pacing stimulus artifacts by endovascular defibrillation lead systems: comparison of true and integrated bipolar circuits.
The occurrence ICD undersensing of ventricular fibrillation due to the presence of a pacing stimulus artifact (PSA) is in part related to the amplitude of the artifact recorded on the ICD rate sensing circuit. There is little comparative data regarding PSA amplitude recorded by commercial ICD rate-sensing circuits. To compare PSA amplitude recorded by commercial endovascular defibrillation leads utilizing integrated or true bipolar sensing circuits. Nineteen large (60-120 kg) pigs were utilized. Two different commercial endovascular defibrillation leads were evaluated, each with its distal tip located at the right ventricular apex: (1) Medtronic Transvene; and (2) CPI Endotak. Three different rate-sensing circuits were evaluated: (1) Transvene true bipolar (tip-ring); (2) Transvene integrated bipolar (tip-coil); and (3) Endotak integrated bipolar (tip-coil). Using a separate pacing lead located at the left ventricular apex (n = 19 animals) or right ventricular outflow tract (n = 10 animals), pacing was performed at a pulse width of 0.5 milliseconds at outputs of 1.5, 5 and 10 volts. PSA amplitude was recorded at each output by each circuit. During pacing from the left ventricular apex, at each pacing output voltage the PSA amplitude recorded by the true bipolar circuit (0.6 +/- 0.1 mV at 1.5 volts, 2.0 +/- 0.5 mV at 5 volts, 3.7 +/- 0.8 mV at 10 volts) was significantly smaller than recorded by the Transvene integrated circuit (1.4 +/- 0.3 mV at 1.5 volts, 3.8 +/- 0.7 mV at 5 volts, 4.1 +/- 0.8 mV at 10 volts) or the Endotak integrated circuit (1.8 +/- 0.4 mV at 1.5 volts, 4.2 +/- 1.0 mV at 5 volts, 6.3 +/- 1.8 mV at 10 volts). During pacing from the right ventricular outflow tract, at each pacing output voltage the PSA amplitude recorded by the true bipolar circuit (0.7 +/- 0.1 mV at 1.5 volts, 1.7 +/- 0.4 mV at 5 volts, 4.0 +/- 0.7 mV at 10 volts) was significantly smaller than recorded by the Transvene integrated circuit (1.1 +/- 0.4 mV at 1.5 volts, 3.9 +/- 1.2 mV at 5 volts, 7.5 +/- 1.8 mV at 10 volts) or the Endotak integrated circuit (1.6 +/- 0.7 mV at 1.5 volts, 4.3 +/- 1.7 mV at 5 volts, 7.5 +/- 2.6 mV at 10 volts). For both pacing sites, the PSA amplitude recorded by the two integrated circuits was not significantly different. For a given pacing output voltage, PSA amplitude recorded by commercial endovascular rate sensing/defibrillation leads is greater when the sensing circuit is integrated than when it is true bipolar. These data may be helpful in planning ICD implantation in patients with previously implanted permanent pacemakers.


Territorial spacing and interspecific competition in three species of reed warblers.
Ecological and temporal aspects of the occurrence and dispersion patterns in three reed warbler species were examined. This provided insight into their intra-and interspecific territoriality. Seasonal changes in the occurrence of territorial males in a reed bed along a gradient from the shore landward were studied. The results demonstrate that intra- and interspecific spacing depends on interspecific dominance and/or ecological constraints. In this case it was shown that there is competition for common habitats between reed warblers and great reed warblers, whereas the moustached warbler is ecologically segregated. The reasons for these dispersal patterns are discussed. They do not appear to enhance the availability of food resources. It seems more likely that territorial spacing might function to reduce nest predation.


Cis mutagenesis in vivo reveals extensive noncanonical functions of Dscam1 isoforms in neuronal wiring.
Drosophila Down syndrome cell adhesion molecule 1 (Dscam1) encodes tens of thousands of cell recognition molecules via alternative splicing, which are required for neural function. A canonical self-avoidance model seems to provide a central mechanistic basis for Dscam1 functions in neuronal wiring. Here, we reveal extensive noncanonical functions of Dscam1 isoforms in neuronal wiring. We generated a series of allelic cis mutations in Dscam1, encoding a normal number of isoforms, but with an altered isoform composition. Despite normal dendritic self-avoidance and self-/nonself-discrimination in dendritic arborization (da) neurons, which is consistent with the canonical self-avoidance model, these mutants exhibited strikingly distinct spectra of phenotypic defects in the three types of neurons: up to ∼60% defects in mushroom bodies, a significant increase in branching and growth in da neurons, and mild axonal branching defects in mechanosensory neurons. Remarkably, the altered isoform composition resulted in increased dendrite growth yet inhibited axon growth. Moreover, reducing Dscam1 dosage exacerbated axonal defects in mushroom bodies and mechanosensory neurons but reverted dendritic branching and growth defects in da neurons. This splicing-tuned regulation strategy suggests that axon and dendrite growth in diverse neurons cell-autonomously require Dscam1 isoform composition. These findings provide important insights into the functions of Dscam1 isoforms in neuronal wiring.


Synthesis and pharmacological evaluation of peptide-mimetic protease-activated receptor-1 antagonists containing novel heterocyclic scaffolds.
Protease-activated receptor-1 (PAR-1) is a G-coupled receptor activated by alpha-thrombin and other proteases. In this paper we describe the synthesis and the pharmacological evaluation of novel peptide-mimetic antagonists (compounds 1-16) characterized by the presence of new heterocyclic nuclei such as 2-methyl-indole (5- and 6-substituted) and 1,4-benzodiazepine moiety. The new derivatives, tested in order to evaluate their antagonist potency by using human platelet aggregation induced by PAR-1AP, resulted in some cases (compounds 1 and 4) more potent than the reference. The compounds, tested on aortic rings, confirmed the results obtained in the aggregation assay.


Production and isolation of large quantities of monoclonal antibody using serum-free medium and fast protein liquid chromatography.
A method for the production and purification of monoclonal antibody on a large laboratory scale is described. It involves the growth of monoclonal antibodies in serum-free medium, ultrafiltration through an Amicon XM100A filter and fast protein liquid chromatography on a mono Q column with an ionic strength and pH elution gradient. Up to 30 mg of antibody per litre of cell culture supernatant was purified in one day. The procedure can be carried out at 4 degrees.


Binding properties of drospirenone with human serum albumin and lysozyme in vitro.
The interaction of drospirenone (DP) with human serum albumin (HSA)/lysozyme (LYZ) was investigated using different optical techniques and molecular models. Results from the emission and time resolved fluorescence studies revealed that HSA/LYZ emission quenching with DP was initiated by static quenching mechanism. The LYZ-DP system was more easily influenced by temperature than the HSA-DP system. Displacement experiments demonstrated that the DP binding site was mainly located in site 1 of HSA. Based on the docking methods, DP was mainly bound in the active site hinge region where Trp-62 and Trp-63 are located. Conformation study showed that DP had different effects on the local conformation of HSA and LYZ molecules.


Revised guidelines for the diagnosis and control of tuberculosis: impact on management in the elderly.
Despite major progress in the development of new strategies for diagnosing and treating tuberculosis, the disease still remains a major challenge for healthcare workers throughout the world. A number of causes are responsible for this threat but, unfortunately, many of these cannot be resolved easily because of cultural and social factors. Furthermore, not all countries throughout the world have enough financial resources to support educational and therapeutic programmes. The major challenges with tuberculosis are 2-fold: (i) to deal with the growing epidemic around the world (and especially in 'low-income' [developing] countries), and; (ii) to ensure correct use of antituberculosis medications in order to protect these drugs for future use. In 'high-income' countries, a major decline in the incidence of tuberculosis has been observed. Nevertheless, tuberculosis remains an important challenge in some risk groups, particularly the elderly patient, in these countries. The clinical and radiological presentations are often nonspecific, leading to delayed diagnosis and appropriate treatment, which often results in a large proportion of cases being discovered at autopsy only. Considering tuberculosis in the differential diagnosis remains the cornerstone of a fast and accurate diagnosis of this condition. Management of active tuberculosis in the elderly does not differ fundamentally from that in younger patients with respect to outcomes or adverse effects of treatment. However, empirical treatment perhaps may be considered more readily in the elderly patient. Elderly persons infected with tuberculosis at the beginning of the 20th century constitute a large reservoir of latent tuberculosis infection. Furthermore, these individuals are at increased risk of reactivation of this remote infection as their immunological status declines with aging. Compared with the past, modern guidelines are less reluctant to recommend use of tuberculin skin testing, treatment of latent tuberculosis infection in elderly persons, and prevention of transmission of tuberculosis in nursing homes.


The PWWP2A Histone Deacetylase Complex Represses Intragenic Spurious Transcription Initiation in mESCs.
Transcriptional fidelity depends on accurate promoter selection and initiation from the correct sites. In yeast, H3K36me3-mediated recruitment of the Rpd3S HDAC complex to gene bodies suppresses spurious transcription initiation. Here we describe an equivalent pathway in metazoans. PWWP2A/B is an H3K36me3 reader that forms a stable complex with HDAC1/2. We used CAGE-seq to profile all transcription initiation sites in wild-type mESCs and cells lacking PWWP2A/B. Loss of PWWP2A/B enhances spurious initiation from intragenic sites present in wild-type mESCs, and this effect is associated with increased levels of initiating Pol-II and histone acetylation. Spurious initiation events in Pwwp2a/b DKO mESCs do not overlap in genomic location or chromatin features with spurious sites that arise in Dnmt3b KO mESCs, previously reported to function in the suppression of intragenic transcriptional initiation, suggesting these pathways function cooperatively in maintaining the fidelity of transcription initiation in metazoans.


Metabolic glycoengineering bacteria for therapeutic, recombinant protein, and metabolite production applications.
Metabolic glycoengineering is a specialization of metabolic engineering that focuses on using small molecule metabolites to manipulate biosynthetic pathways responsible for oligosaccharide and glycoconjugate production. As outlined in this article, this technique has blossomed in mammalian systems over the past three decades but has made only modest progress in prokaryotes. Nevertheless, a sufficient foundation now exists to support several important applications of metabolic glycoengineering in bacteria based on methods to preferentially direct metabolic intermediates into pathways involved in lipopolysaccharide, peptidoglycan, teichoic acid, or capsule polysaccharide production. An overview of current applications and future prospects for this technology are provided in this report.


Management of chronic sternal osteomyelitis.
The management of 2 patients in whom chronic sternal osteomyelitis developed after apparently uncomplicated coronary artery bypass operations is described. Each patient had become totally disabled because of chronic, draining sinus tracts. Eradication of the infection required total sternectomy and excision of all infected costal cartilage. Subsequent reconstruction was accomplished by using bilateral pectoralis major myocutaneous advancement flaps without any maneuvers to stabilize the anterior chest wall. Both patients have resumed full activity and have returned to work with only minimal residual compromise of pulmonary function.


Involvement of Bcl-2 family proteins in germ cell apoptosis during testicular development in the rat and pro-survival effect of stem cell factor on germ cells in vitro.
A large part of germ cells die apoptotically during testicular development in rodents. In the present study, a wave of germ cell apoptosis was observed between days 10 and 30 of postnatal life by in situ 3'-end labeling and DNA fragmentation analysis. To explore the potential involvement of Bcl-2 family members in this process, the expression and localization of some Bcl-2 family proteins (Bcl-2, Bcl-xL, Bcl-w, Bak, Bax, and Bad) and p53 were analyzed during testicular development in the rat by Western blotting and immunohistochemistry. The dynamic changes in the expression profiles of Bcl-2 family proteins are consistent with a model in which germ cells are primed for apoptosis during the first cycle of spermatogenesis by de novo expression of the death effectors Bax and Bad in a p53-dependent manner and these proteins are prevented from triggering further apoptosis after the first spermatogenic cycle has been set up by anti-apoptotic Bcl-2 family proteins Bcl-xL and Bcl-w. To examine whether the pro-survival effect of stem cell factor (SCF) on germ cells in vitro is mediated by Bcl-2 family proteins, the correlation between the pro-survival effect of SCF on germ cells and the expression of the above-mentioned apoptosis-related gene products in the seminiferous tubules at stage XII of the epithelial cycle were also investigated using a tubular culture system. The data suggest that SCF supports germ cell survival during spermatogenesis by up-regulating pro-survival Bcl-2 family proteins, Bcl-w and Bcl-xL, and down-regulating pro-apoptosis Bcl-2 family proteins, e.g. Bax.


Visual function after removal of subretinal neovascular membranes in patients with age-related macular degeneration.
Retinal pigment epithelial (RPE) cells have been transplanted to replace the RPE cells lost after surgical excision of choroidal neovascular membranes (CNV) associated with age-related macular degeneration. The purpose of this study was to analyze the visual function of eyes with altered RPE after surgical excision of choroidal neovascular membranes (CNV) associated with age-related macular degeneration, and to determine the effect of proliferated or migrated RPE cells on visual function. Forty-seven patients with age-related macular degeneration underwent excision of CNVs following vitrectomy and tamponade with sulfur hexafluoride (SF6) or silicone oil. The appearance of pre- or subretinal fibrosis and pigmentation of the lesion was considered to indicate proliferation and migration of RPE cells. Microperimetry was also performed. A significant correlation was found between the size of CNVs removed by surgery and the size estimated by indocyanine green angiography (P=0.0126). The mean number of RPE cells lost was estimated at 1.52 x 10(4). Pre- or subretinal fibrosis or pigmentation was observed in 37 patients (75.5%). The number of eyes with fibrosis was significantly higher in eyes with silicone oil tamponade than with SF6 tamponade (P=0.0016). A statistically significant correlation was not found between the presence of fibrosis or pigmentation and the postoperative visual acuity. Not all patients used the area of pigmentation for fixation, and microperimetry showed that some of the patients had scotomas in well-pigmented areas. Fibrosis and pigmentation after excision of CNVs may not always indicate normal function in these areas. These observations are especially relevant for transplantation of pigment epithelial cells in the future.


Fagerstrom's Tolerance Questionnaire: clarification of item and scoring ambiguities.
Fagerstrom's Tolerance Questionnaire has often been used as a measure of physical dependence on nicotine. Inadequate delineation of scoring criteria has made reliability of scoring across users questionable. Standardized cutoffs and the correct translation of one item are presented with recommendations for future use.


G6PD deficiency assessment in Freetown, Sierra Leone, reveals further insight into the molecular heterogeneity of G6PD A-.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency in Africa is of high prevalence, although precise data are lacking in many individual nations. We investigated 129 unrelated subjects (71 male subjects, 58 female subjects) visiting a teaching hospital in Freetown, Sierra Leone, to collect baseline data on the distribution of G6PD deficiency among respective ethnic groups in the country. We confirmed eight G6PD-deficient male subjects by two formazan-based blood tests (11.3% of the male subjects examined), and also detected the common 376A > G mutation in 11 male subjects and eight female subjects by sequencing exons 3-5 of the G6PD gene. Selected samples were further sequenced for exons 2-13 and introns 5, 7, 8, and 11. Among the deficient male subjects, six were G6PD A- carrying the double mutations (202G > A and 376A > G), all of whom were in the Temne and Mende ethnic groups. Others included A- Betica, and a novel variant having double mutations in exon 5 (311G > A and 376A > G forming 104 Arg > His and 126 Asn > Asp, respectively), which we designate as G6PD Sierra Leone. Subsequent haplotype analysis linked this novel variant to the G6PD A- "family".


Comparison of haemodynamic response to muscle reflex in heart failure with reduced vs. preserved ejection fraction.
Isometric handgrip (IHG) training reduces the blood pressure in patients with hypertension. It is unclear how IHG exercise affects the haemodynamics and cardiovascular function through the muscle reflex in patients with heart failure (HF) with reduced (HFrEF) and preserved ejection fraction (HFpEF). Twenty patients (HFrEF: n = 10, HFpEF: n = 10) underwent left ventricular (LV) pressure-volume assessments using a conductance catheter and microtip manometer to evaluate haemodynamics, LV and arterial function, and LV-arterial coupling during 3 min of IHG at 30% of maximal voluntary contraction (MVC), followed by 3 min of post-exercise circulatory arrest (PECA). Three minutes of IHG exercise produced significant and modest increases in the heart rate (HR) and LV end-systolic pressure (LVESP), respectively, in both HFpEF and HFrEF groups. In HFrEF, the increase in LVESP was caused by the variable increase in effective arterial elastance (Ea), which was counterbalanced by the increase in LV end-systolic elastance (Ees), resulting in a maintained Ees/Ea. In HFpEF, the increase in LVESP was not accompanied by changes in Ea, Ees, Ees/Ea, or LV end-diastolic pressure. LVESP during PECA was not maintained in HFpEF, suggesting smaller metabo-reflex activity in HFpEF. The IHG exercise used in this study may increase the LVESP and LVEDP without detrimental effects on cardiac function or ventricular-arterial coupling, especially in HFpEF patients. The effects of IHG exercise on haemodynamics and ventricular-arterial coupling may be affected by the patient background and the type and intensity of the exercise.