When and how to use buccal mucosa grafts in penile and bulbar urethroplasty.
The surgical treatment of adult anterior urethral strictures has been a constantly evolving process, and renewed controversy exists over the best means of reconstructing the anterior urethra. Recently, considerable changes have been introduced: the wider use of buccal mucosa graft versus the use of genital or extragenital skin, and the use of dorsal onlay urethroplasties, also named Barbagli procedures. Moreover, in the penile urethra the dorsal placement of the graft is now combined with the incision and the augmentation of the urethral plate, as suggested for childhood hypospadias surgery. In adult male patients, the urethral strictures involving the penile and bulbar urethra are due to failed hypospadias repair, ischemia, lichen sclerosus, congenital anomalies of the mucosal membrane, traumatic scar after blunt perineal trauma. Buccal mucosa is receiving increased attention in the urological literature for penile and bulbar urethroplasty. We present here, step by step, 4 different surgical techniques for penile and bulbar urethroplasty, using buccal mucosa grafts. The surgical procedures are selected according to the current and updated literature and to the new classification of anterior urethral diseases. The ideal surgical technique should be simple, safe, reliable and reproducible in the hands of any surgeon, as well as being based on sound anatomical principles. We believe the technique we present here fulfil all these criteria.


Great expectations: using whole-brain computational connectomics for understanding neuropsychiatric disorders.
The study of human brain networks with in vivo neuroimaging has given rise to the field of connectomics, furthered by advances in network science and graph theory informing our understanding of the topology and function of the healthy brain. Here our focus is on the disruption in neuropsychiatric disorders (pathoconnectomics) and how whole-brain computational models can help generate and predict the dynamical interactions and consequences of brain networks over many timescales. We review methods and emerging results that exhibit remarkable accuracy in mapping and predicting both spontaneous and task-based healthy network dynamics. This raises great expectations that whole-brain modeling and computational connectomics may provide an entry point for understanding brain disorders at a causal mechanistic level, and that computational neuropsychiatry can ultimately be leveraged to provide novel, more effective therapeutic interventions, e.g., through drug discovery and new targets for deep brain stimulation.


Molecular phylogeny of clade III nematodes reveals multiple origins of tissue parasitism.
Molecular phylogenetic analyses of 113 taxa representing Ascaridida, Rhigonematida, Spirurida and Oxyurida were used to infer a more comprehensive phylogenetic hypothesis for representatives of 'clade III'. The posterior probability of multiple alignment sites was used to exclude or weight characters, yielding datasets that were analysed using maximum parsimony, likelihood, and Bayesian inference methods. Phylogenetic results were robust to differences among inference methods for most high-level taxonomic groups, but some clades were sensitive to treatments of characters reflecting differences in alignment ambiguity. Taxa representing Camallanoidea, Oxyurida, Physalopteroidea, Raphidascarididae, and Skrjabillanidae were monophyletic in all 9 analyses whereas Ascaridida, Ascarididae, Anisakidae, Cosmocercoidea, Habronematoidea, Heterocheilidae, Philometridae, Rhigonematida and Thelazioidea were never monophyletic. Some clades recovered in all trees such as Dracunculoidea and Spirurina included the vast majority of their sampled species, but were non-monophyletic due to the consistent behaviour of one or few 'rogue' taxa. Similarly, 102 of 103 clade III taxa were strongly supported as monophyletic, yet clade III was paraphyletic due to the grouping of Truttaedacnitis truttae with the outgroups. Mapping of host 'habitat' revealed that tissue-dwelling localization of nematode adults has evolved independently at least 3 times, and relationships among Spirurina and Camallanina often reflected tissue predilection rather than taxonomy.


Enhancement of High-Intensity Actions and Physical Performance During a Simulated Brazilian Jiu-Jitsu Competition With a Moderate Dose of Caffeine.
Although caffeine is one of the most commonly used substances in combat sports, information about its ergogenic effects on these disciplines is very limited. To determine the effectiveness of ingesting a moderate dose of caffeine to enhance overall performance during a simulated Brazilian jiu-jitsu (BJJ) competition. Fourteen elite BJJ athletes participated in a double-blind, placebo-controlled experimental design. In a random order, the athletes ingested either 3 mg/kg body mass of caffeine or a placebo (cellulose, 0 mg/kg) and performed 2 simulated BJJ combats (with 20 min rest between them), following official BJJ rules. Specific physical tests such as maximal handgrip dynamometry, maximal height during a countermovement jump, permanence during a maximal static-lift test, peak power in a bench-press exercise, and blood lactate concentration were measured at 3 specific times: before the first combat and immediately after the first and second combats. The combats were video-recorded to analyze fight actions. After the caffeine ingestion, participants spent more time in offensive actions in both combats and revealed higher blood lactate values (P < .05). Performance in all physical tests carried out before the first combat was enhanced with caffeine (P < .05), and some improvements remained after the first combat (eg, maximal static-lift test and bench-press exercise; P < .05). After the second combat, the values in all physical tests were similar between caffeine and placebo. Caffeine might be an effective ergogenic aid for improving intensity and physical performance during successive elite BJJ combats.


The S RNA segment of Sandfly Fever Sicilian virus: evidence for an ambisense genome.
The complete nucleotide sequence of the S RNA segment of Sandfly Fever Sicilian (SFS) virus (Phlebovirus, Bunyaviridae) was determined from overlapping cDNA clones and by primer extension. The RNA is 1746 nucleotides in length and has two large open reading frames (ORF), one of which (24.8 kDa) is viral-complementary in sense, and the other (30.4 kDa) is in the viral sense. This ambisense genome arrangement has been seen in another member of the Phlebovirus genus, Punta Toro (PT) virus (T. Ihara, H. Akashi, and D. H. L. Bishop, 1984, Virology 136, 293-306), but not in representatives of either the Bunyavirus or Hantavirus genera of the Bunyaviridae. Comparison of the predicted amino acid sequences for SFS virus with the recognized products of PT S RNA (T. Ihara, Y. Matsuura, and D. H. L. Bishop, 1985, Virology 147, 317-325; H. A. Overton, T. Ihara, and D. H. L. Bishop, 1987, Virology 157, 338-350) indicated that the 24.8-kDa ORF encodes the nucleoprotein (N) of SFS virus, and the 30.4-kDa ORF codes for a nonstructural protein (NSs). Subgenomic messenger RNAs, from which these two proteins are presumably translated, were detected in virus-infected cells.


Zinc-65 imaging of rat brain tumors.
The uptake of zinc, an essential nutrient, is critical for cell proliferation. On the basis of the idea that zinc uptake can be an index of viability in proliferating cells, tumor imaging with (65)Zn was performed using autoradiography. After s.c. implantation of ascites hepatoma (AH7974F) cells into the dorsum, 1 h after i.v. injection of (65)ZnCl(2), (65)Zn uptake in the tumor was higher than in the brain tissue but lower than in the liver, which suggests that brain tumors can be positively imaged with (65)Zn. After implantation of AH7974F cells into the periaqueductal gray, 1 h after i.v. injection of (65)ZnCl(2), (65)Zn uptake in the tumor was approximately 10 times higher than in other brain regions. After implantation of C6 glioma cells into the hippocampus, (65)Zn uptake in the tumor was also much higher than in other brain regions. The present findings demonstrate that brain tumors can be imaged with radioactive zinc. To compare brain tumor imaging with (65)Zn with that of [(18)F]fluorodeoxyglucose (FDG), which is widely used for the diagnosis of brain tumors, (14)C-FDG imaging of the C6 glioma was performed in the same manner. (14)C-FDG uptake in the tumor was approximately 1.5 times higher than in the contralateral region in which (14)C-FDG uptake was relatively high. It is likely that zinc uptake is more specific for brain tumors than is FDG uptake, which suggests that there is great potential for the use of (69m)Zn, a short half-life gamma emitter, in the diagnosis of brain tumors.


Use of sensitivity vector variations to determine absolute displacements in double exposure hologram interferometry.
Two solutions are presented to the problem of unknown absolute fringe order in double exposure hologram interferometry, a problem that confronts systems that require a single view of an object. One solution determines the vectorial object displacements relative to one reference point on the object. The other employs variations of the sensitivity vectors to provide absolute displacement analysis. For absolute displacements, a minimum of four illuminations is required.


Obstruction of the duodenum by a preduodenal portal vein in situs inversus.
Mirror image transposition of abdominal and thoracic viscera is termed situs inversus. Duodenal obstruction in situs inversus is rare. A preduodenal portal vein, though not uncommon in situs inversus, rarely causes duodenal obstruction. Where obstruction by a preduodenal portal vein is diagnosed, a duodeno-duodenostomy is the recommended treatment. A duodenal diaphragm and other more common causes of duodenal obstruction should also be excluded in these patients.


X-ray diffraction from a left ventricular wall of rat heart.
We studied x-ray diffraction from the left ventricular wall of an excised, perfused whole heart of a rat using x rays from the third-generation synchrotron radiation facility, SPring-8. With the beam at right angles to the long axis of the left ventricle, well-oriented, strong equatorial reflections were observed from the epicardium surface. The reflections became vertically split arcs when the beam passed through myocardium deeper in the wall, and rings were observed when the beam passed into the inner myocardium of the wall. These diffraction patterns were explained by employing a layered-spiral model of the arrangement of muscle fibers in the heart. In a quiescent heart with an expanded left ventricle, the muscle fibers at the epicardium surface were found to have a (1,0) lattice spacing smaller than in the rest of the wall. The intensity ratio of the (1,0) and (1,1) equatorial reflections decreased on contraction with a similar time course in all parts of the wall. The results show that it is possible to assign the origin of reflections in a diffraction diagram from a whole heart. This study offers a basis for interpretation of x-ray diffraction from a beating heart under physiologically and pathologically different conditions.


Utility of the ACE Inhibitor Captopril in Mitigating Radiation-associated Pulmonary Toxicity in Lung Cancer: Results From NRG Oncology RTOG 0123.
The primary objective of NRG Oncology Radiation Therapy Oncology Group 0123 was to test the ability of the angiotensin-converting enzyme inhibitor captopril to alter the incidence of pulmonary damage after radiation therapy for lung cancer; secondary objectives included analyzing pulmonary cytokine expression, quality of life, and the long-term effects of captopril. Eligible patients included stage II-IIIB non-small cell lung cancer, stage I central non-small cell lung cancer, or limited-stage small cell. Patients who met eligibility for randomization at the end of radiotherapy received either captopril or standard care for 1 year. The captopril was to be escalated to 50 mg three times a day. Primary endpoint was incidence of grade 2+ radiation-induced pulmonary toxicity in the first year. Eighty-one patients were accrued between June 2003 and August 2007. Given the low accrual rate, the study was closed early. No significant safety issues were encountered. Eight patients were ineligible for registration or withdrew consent before randomization and 40 patients were not randomized postradiation. Major reasons for nonrandomization included patients' refusal and physician preference. Of the 33 randomized patients, 20 were analyzable (13 observation, 7 captopril). The incidence of grade 2+ pulmonary toxicity attributable to radiation therapy was 23% (3/13) in the observation arm and 14% (1/7) in the captopril arm. Despite significant resources and multiple amendments, NRG Oncology Radiation Therapy Oncology Group 0123 was unable to test the hypothesis that captopril mitigates radiation-induced pulmonary toxicity. It did show the safety of such an approach and the use of newer angiotensin-converting enzyme inhibitors started during radiotherapy may solve the accrual problems.


A position effect in the control of transcription at yeast mating type loci.
The two mating type loci MATa and MAT alpha each produce two mRNAs that are transcribed in opposite and diverging directions from central promoters. Silent copies of MATa (HMRa) and MAT alpha (HML alpha) contain identical DNA sequences throughout the transcribed region, yet are not transcribed. It is concluded that sequences to the left of HMRa (and probably HML alpha) must somehow affect transcription initiated at the centre of each locus 700 to 1,400 base pairs away. A possible mechanism for this position effect is discussed.


Educational programs improve the preparation for dialysis and survival of patients with chronic kidney disease.
Preparation for end-stage renal disease (ESRD) is widely acknowledged to be suboptimal in the United States. We sought to determine whether participation in a kidney disease screening and education program resulted in improved ESRD preparation and survival in 595 adults who developed ESRD after participating in the National Kidney Foundation Kidney Early Evaluation Program (KEEP), a community-based screening and education program. Non-KEEP patients were selected from a national ESRD registry and matched to KEEP participants based on demographic and clinical characteristics. The main outcomes were pre-ESRD nephrologist care, placement of permanent vascular access, use of peritoneal dialysis, pre-emptive transplant wait listing, transplantation, and mortality after ESRD. Participation in KEEP was associated with significantly higher rates of pre-ESRD nephrologist care (76.0% vs. 69.3%), peritoneal dialysis (10.3% vs. 6.4%), pre-emptive transplant wait listing (24.2% vs. 17.1%), and transplantation (9.7% vs. 6.4%) but not with higher rates of permanent vascular access (23.4% vs. 20.1%). Participation in KEEP was associated with a lower risk for mortality (hazard ratio 0.80), but this was not statistically significant after adjusting for ESRD preparation. Thus, participation in a voluntary community kidney disease screening and education program was associated with higher rates of ESRD preparation and survival.


How the chance of missing the alarm during an on-call shift affects pre-bed anxiety, sleep and next day cognitive performance.
This study investigated how the chance of missing an alarm affects pre-bed anxiety, sleep and next day cognitive performance during on-call shifts. Participants (n = 24) completed one adaptation night, one control night and two on-call nights in a time-isolated sleep laboratory. On one of the on-call nights, participants were informed that they would be woken by a loud alarm that they would definitely not be able to sleep through (low chance of missing the alarm). On the other on-call night, participants were informed that they would be woken by a quiet alarm that they may sleep through (high chance of missing the alarm). The two on-call nights were counterbalanced. Pre-bed anxiety was measured using the State Trait Anxiety Inventory x-1, while sleep macro- and micro-architecture was examined via routine polysomnography and power spectral analyses respectively. Following each sleep, cognitive performance was assessed four times (0930, 1200, 1430, 1700) using the 10-min psychomotor vigilance task (PVT). Results indicated that while pre-bed anxiety was similarly increased during both high and low chance of missing the on-call alarm conditions compared with control, only in the high chance condition was total sleep time shorter and sleep efficiency lower compared with the control condition. However, more wake after sleep onset was found in the low chance condition compared with control. PVT data indicate that response times (mean reciprocal and mean fastest 10% of reaction time) were fastest in the low chance condition, indicating better performance when compared with both other conditions. However, there were significantly more lapses in the low chance condition compared with control. No significant EEG power spectral differences were observed. As such, it appears that there are detrimental effects of both on-call conditions on anxiety, sleep and performance, with sleep poorest when the chance of missing the alarm is high. The adverse impacts on sleep and performance outcomes while on-call may be mitigated by the implementation of workplace systems to reduce the chance of missing alarms (e.g., having two available options for contacting on-call workers).


Evaluating implementation of methicillin-resistant Staphylococcus aureus (MRSA) prevention guidelines in spinal cord injury centers using the PARIHS framework: a mixed methods study.
To prevent methicillin-resistant Staphylococcus aureus (MRSA) in Spinal Cord Injury and Disorder (SCI/D) Centers, the "Guidelines for Implementation of MRSA Prevention Initiative in the Spinal Cord Injury Centers" were released in July 2008 in the Veterans Affairs (VA) Health Care System. The purpose of this study was to use the Promoting Action on Research Implementation in Health Systems (PARiHS) framework to evaluate the experiences of implementation of SCI/D MRSA prevention guidelines in VA SCI/D Centers approximately 2-3 years after the guidelines were released. Mixed methods were used across two phases in this study. The first phase included an anonymous, web-based cross-sectional survey administered to providers at all 24 VA SCI/D Centers. The second phase included semi-structured telephone interviews with providers at 9 SCI/D Centers. The PARiHS framework was used as the foundation of both the survey questions and semi-structured interview guide. The survey was completed by 295 SCI/D providers (43.8 % response rate) from 22 of the 24 SCI/D Centers (91.7 % participation rate). Respondents included nurses (57.3 %), therapists (24.4 %), physicians (11.1 %), physician assistants (3.4 %), and other health care professionals (3.8 %). Approximately 36 % of the SCI/D providers surveyed had not seen, did not remember seeing, or had never heard of the MRSA SCI/D guidelines, whereas 42.3 % of providers reported that the MRSA SCI/D guidelines were fully implemented in their SCI/D Center. Data revealed numerous barriers and facilitators to guideline implementation. Facilitators included enhanced leadership support and provider education, focused guideline dissemination to reach SCI/D providers, and strong perceived evidence supporting the guidelines. Barriers included lack of awareness of the guidelines among physical therapists and physician assistants and challenges in cohorting/isolating MRSA-positive patients and following contact precautions. Successful implementation of MRSA infection prevention guidelines in SCI/D settings requires (1) guideline dissemination that reaches the full range of SCI/D providers working in inpatient, outpatient, and other care settings, (2) provider education that is frequent and systematic, (3) strong leadership support, and (4) that barriers unique to the recommendations are addressed. These findings may be used to inform selection of implementation strategies and optimize infection prevention beyond MRSA as well as in other specialty care populations.


Stimulus-dependent alterations in macrophage microtubules: increased tubulin polymerization and detyrosination.
Murine macrophage microtubules are very dynamic. The majority of the microtubules (approximately 80%) exist in a rapidly depolymerizing pool (t1/2 approximately 30 seconds). The remaining 20% of the microtubules are in a more slowly depolymerizing pool (t1/2 approximately 7 minutes). Macrophage microtubules are responsive to cell stimulation with phorbol esters; upon cell stimulation there is a rapid increase in total microtubule polymer and number. In addition there is stimulus-induced detyrosination of alpha-tubulin in macrophage microtubules that is rapid and essentially complete, occurring in all microtubules rather than a subset of microtubules. Detyrosination of the macrophage microtubules in response to phorbol esters does not confer increased stability to these microtubules, since treated cells have nocodazole-induced depolymerization kinetics similar to that in non-stimulated macrophages. Regrowth of microtubules following washout of nocodazole is also rapid. Interestingly the regrown microtubules are initially in the tyrosinated form even in the presence of phorbol ester. These experiments provide in vivo support for the model that detyrosination of alpha-tubulin occurs in polymeric tubulin while retyrosination occurs in dimeric tubulin. Macrophage microtubules also demonstrate an unusually rapid response to extracellular stimuli and thus provide a unique model system in which to examine signal transduction events and modulation of microtubules.


Surveillance of patients with breast cancer after curative-intent primary treatment: current practice patterns.
To determine how physicians monitor their patients after initial curative-intent treatment for breast carcinoma. A custom-designed survey instrument with four idealized patient vignettes (TNM stages 0 to III) was e-mailed to the 3,245 members of ASCO who had identified themselves as having breast cancer as a major focus of their practice. Respondents were asked how they use 12 specific follow-up modalities during post-treatment years 1 to 5 for each vignette. Mean, median, standard deviation, and range of the intensity of use for each modality were calculated for the four vignettes. Of the 3,245 ASCO members surveyed, 1,012 (31%) responded. Of these, 915 (90%) were evaluable and were included in our analysis. Office visit, mammogram, complete blood count, and liver function tests were the most commonly recommended surveillance modalities. There was marked variation in surveillance intensity. For example, office visit was recommended 4.1 ± 2.2 times (mean ± SD) in year 1 after curative treatment of a patient with stage III breast cancer. Similar variation was observed for all modalities. The intensity of post-treatment surveillance performed by ASCO members caring for patients with breast cancer varies markedly despite evidence from well-designed, adequately powered randomized controlled trials. Many modalities not recommended by ASCO guidelines are used routinely, which constitutes evidence of overuse. The lack of consensus is likely due to multiple factors and constitutes an appealing target for interventions to rationalize surveillance.


Population Pharmacokinetics and Pharmacodynamics Modeling of Torasemide and Furosemide After Oral Repeated Administration in Healthy Dogs.
Torasemide is a loop diuretic licensed in dogs for cardiogenic pulmonary oedema. The aim of this pharmacokinetic-pharmacodynamic (PK/PD) study was to define an optimally effective dosage regimen based on preclinical data. In a first study, 5 dogs received once-daily oral torasemide (0, 0.1, 0.2, 0.4, 0.8 mg/kg/day) for 14 days. A second study compared once-daily oral torasemide (0, 0.1, 0.2, 0.3, 0.4 mg/kg/day) to twice-daily furosemide (1, 2, 4, 8 mg/kg/day). For all doses of the second study, 11 dogs received a first day of treatment, followed by a 3 day washout and resumed daily treatment for 10 days (until Day 14). Blood and urine were collected to measure urinary torasemide excretion and plasma torasemide concentrations and daily diuresis and natriuresis. Torasemide PK was linear. After rapid absorption (Tmax 0.5-1 h), 61% of the bioavailable torasemide was eliminated unchanged in urine. Diuresis and natriuresis observed with torasemide were similar to the ones obtained after furosemide (daily dose-ratios: 1/20 to 1/10). The average diuresis increased from baseline (220 ± 53 mL/day for 10 kg dogs) to 730 ±120 mL after the first torasemide administration and up to 1150 ± 252 mL after 10 administrations at the highest dose. At higher doses (≥0.3 mg/kg/day), daily diureses after 10 diuretic treatment-days were higher than Day 1 and variable between dogs; in contrast, diureses remained constant over time and less variable for doses up to 0.2 mg/kg/day. Natriuresis peaked after the first day and decreased dramatically after the 2nd treatment-day then stabilized to a value close to baseline, except for 0.4 mg/kg/day. Urinary torasemide excretion predicted pharmacodynamics better than plasma concentrations. The decrease in natriuresis observed was successfully modeled using a resistance mechanism; this is likely due to a reabsorption of sodium which did not seem however to affect the volume of urine excreted. For a daily target diuresis of 460 mL/dog/day in severe pulmonary oedema (net fluid loss 240 mL/dog/day), a computed dose of 0.26 mg/kg/day (3.5 mg/kg/day furosemide-equivalent) was selected for clinical studies. Due to high inter-individual variability in diureses at doses ≥0.3 mg/kg, higher doses should be limited to 3-5 days to avoid supra-clinical effects in high responders.


Phylogeography and Antigenic Diversity of Low-Pathogenic Avian Influenza H13 and H16 Viruses.
Low-pathogenic avian influenza viruses (LPAIVs) are genetically highly variable and have diversified into multiple evolutionary lineages that are primarily associated with wild-bird reservoirs. Antigenic variation has been described for mammalian influenza viruses and for highly pathogenic avian influenza viruses that circulate in poultry, but much less is known about antigenic variation of LPAIVs. In this study, we focused on H13 and H16 LPAIVs that circulate globally in gulls. We investigated the evolutionary history and intercontinental gene flow based on the hemagglutinin (HA) gene and used representative viruses from genetically distinct lineages to determine their antigenic properties by hemagglutination inhibition assays. For H13, at least three distinct genetic clades were evident, while for H16, at least two distinct genetic clades were evident. Twenty and ten events of intercontinental gene flow were identified for H13 and H16 viruses, respectively. At least two antigenic variants of H13 and at least one antigenic variant of H16 were identified. Amino acid positions in the HA protein that may be involved in the antigenic variation were inferred, and some of the positions were located near the receptor binding site of the HA protein, as they are in the HA protein of mammalian influenza A viruses. These findings suggest independent circulation of H13 and H16 subtypes in gull populations, as antigenic patterns do not overlap, and they contribute to the understanding of the genetic and antigenic variation of LPAIVs naturally circulating in wild birds.IMPORTANCE Wild birds play a major role in the epidemiology of low-pathogenic avian influenza viruses (LPAIVs), which are occasionally transmitted-directly or indirectly-from them to other species, including domestic animals, wild mammals, and humans, where they can cause subclinical to fatal disease. Despite a multitude of genetic studies, the antigenic variation of LPAIVs in wild birds is poorly understood. Here, we investigated the evolutionary history, intercontinental gene flow, and antigenic variation among H13 and H16 LPAIVs. The circulation of subtypes H13 and H16 seems to be maintained by a narrower host range, in particular gulls, than the majority of LPAIV subtypes and may therefore serve as a model for evolution and epidemiology of H1 to H12 LPAIVs in wild birds. The findings suggest that H13 and H16 LPAIVs circulate independently of each other and emphasize the need to investigate within-clade antigenic variation of LPAIVs in wild birds.


Does different wording of a global oral health question provide different results?
Focusing on 70-year-old adults in Sweden and guided by the conceptual framework of International Classification of Impairments, Disabilities and Handicaps (ICIDH), the purpose of this study was to examine the extent to which socio-demographic characteristics, self-reported oral disease and social/psychological/physical oral health outcome variables are associated with two global measures of self-assessed satisfaction with oral health in Swedish 70-year-olds and if there is a degree of discordance between these global questions. It has become an important task to create a simple way to measure self-perceived oral health. In these attempts to find practical ways to measure health, the 'global oral health question' is a possible tool to measure self-rated oral health, but there is limited knowledge about how important the wording of this question is. In 2012, a questionnaire was mailed to all persons born in 1942 in two Swedish counties, Örebro (T) and Östergötland (E). The total population of 70-year-olds amounted to 7889. Bivariate analyses were conducted by cross-tabulation and Chi-square statistics. Multivariate analyses were conducted using binary multiple logistic regression. The two global oral health question of 70-year-olds in Sweden was mainly explained by the number of teeth (OR=5.6 and 5.2), chewing capacity (OR=6.9 and 4.2), satisfaction with dental appearance (OR=19.8 and 17.3) and Oral Impact on Daily Performance (OIDP) (OR=3.5 and 3.9). Regardless of the wording, it seems that the concept of a global oral health question has the same main determinants.


Metabolic hallmarks for purine nucleotide biosynthesis in small-cell lung carcinoma.
Small-cell lung cancer (SCLC) has a poor prognosis, emphasizing the necessity for developing new therapies. The de novo synthesis pathway of purine nucleotides, which is involved in the malignant growth of SCLC, has emerged as a novel therapeutic target. Purine nucleotides are supplied by two pathways: de novo and salvage. However, the role of the salvage pathway in SCLC and the differences in utilization and crosstalk between the two pathways remain largely unclear. Here, we found that deletion of the HPRT1 gene, which codes for the rate-limiting enzyme of the purine salvage pathway, significantly suppressed tumor growth in vivo in several SCLC cells. We also demonstrated that HPRT1 expression confers resistance to lemetrexol (LMX), an inhibitor of the purine de novo pathway. Interestingly, HPRT1-knockout had less effect on SCLC SBC-5 cells, which are more sensitive to LMX than other SCLC cell lines, suggesting that a preference for either the purine de novo or salvage pathway occurs in SCLC. Furthermore, metabolome analysis of HPRT1-knockout cells revealed increased intermediates in the pentose phosphate pathway and elevated metabolic flux in the purine de novo pathway, indicating compensated metabolism between the de novo and salvage pathways in purine nucleotide biosynthesis. These results suggest that HPRT1 has therapeutic implications in SCLC and provide fundamental insights into the regulation of purine nucleotide biosynthesis. Implications: SCLC tumors preferentially utilize either the de novo or salvage pathway in purine nucleotide biosynthesis, and HPRT1 has therapeutic implications in SCLC.


Non-pharmacological interventions for adult ADHD: a systematic review.
Attention-deficit/hyperactivity disorder (ADHD) is a common developmental disorder, often persisting into adulthood. Whilst medication is first-line treatment for ADHD, there is a need for evidence-based non-pharmacological treatment options for adults with ADHD who are either still experiencing significant symptoms or for those who have made the informed choice not to start medication. We systematically searched PsycINFO, MEDLINE (Ovid), EMBASE, CINAHL and CENTRAL for randomised controlled trials of non-pharmacological treatments for ADHD in adults. After screening of titles and abstracts, full text articles were reviewed, data extracted and bias assessed using a study proforma. There were 32 eligible studies with the largest number of studies assessing cognitive behavioural therapy (CBT). CBT consisted of either group, internet or individual therapy. The majority found an improvement in ADHD symptoms with CBT treatment. Additionally, mindfulness and cognitive remediation have evidence as effective interventions for the core symptoms of ADHD and there is evidence for the use of group dialectical behavioural therapy and hypnotherapy. However, evidence for these is weaker due to small numbers of participants and limitations due to the lack of suitable control conditions, and a high risk of bias.


Ultrafast nonlinear optical response of photoconductive ZnO films with fluorine nanoparticles.
The absorptive and refractive third order nonlinear optical properties exhibited by a ZnO thin solid film with fluorine nanoparticles were studied with picosecond and femtosecond pulses using different techniques. We were able to evaluate the photoconductivity of the material and the quenching of the induced birefringence observed in the presence of two-photon absorption. The samples were prepared by a chemical spray deposition technique. In order to investigate the different contributions of the third order nonlinearities of the film, we analyzed the vectorial self-diffraction effect and the optical Kerr transmittance observed in the sample. A dominantly absorptive nonlinearity was measured at a 532 nm wavelength with 50 ps pulses, while nonlinear refraction was found to be negligible in this regime. On the other side, a pure electronic refractive third order nonlinearity without the contribution of nonlinear absorption was detected at 830 nm with 80 fs pulse duration. A quasi-instantaneous optical response and a strong enhancement in the ultrafast nonlinear refraction with the inhibition of the picosecond two-photon absorption mechanism were measured for the case of the femtosecond excitation.


Effects of Medhya Rasayana and Yogic practices in improvement of short-term memory among school-going children.
Excellent memory, extraordinary intelligence, great academic achievement, and successful career are the dreams of every individual in this era of competition and professionalism. A good memory power acts as a catalyst in all walks of life, be it academic success or maintenance of personal relationships. It is observed that an average man uses only 10% of his natural memory. Remaining 90% is left unused in a haphazard manner. As per the American psychologist Carl Emil Seashore, if one is alert and makes systematic attempts to awaken and use the natural memory properly, his/her natural memory would be activated creatively and would offer benefits of higher order. A comparative study was conducted comprising 90 subjects to know the efficacy of Medhya Rasayana and Yogic practices in short-term memory of school-going children. The study was conducted over a period of 3 months. It was an open, prospective, and randomized clinical study. The subjects of group A formed the control group and they were observed silently for 3 months without any intervention. The subjects in group B were administered with Choorna (powder) of four Medhya Rasayanas, Mandukaparni (Centella asiatica Linn.), Yashtimadhu (Glycyrrhiza glabra Linn.), Guduchi [Tinospora cordifolia (Willd.) Miers ex Hook. f. and Thoms.], and Sankhapushpi (Convolvulus pluricaulis Choisy), at a dose of 2 g twice daily with milk. Subjects belonging to group C were advocated regular Yogic practices of Asanas, Pranayama, and Dhyana. Further study revealed that among the three groups, group B treated with Medhya Rasayana showed highly significant and most effective changes with respect to objective parameters in the tests, i.e. (1) short-term memory test pictures and (2) serial recall effects test using memory scope. Among the three groups, group C treated with Yogic practices showed highly significant and most effective changes with respect to subjective and objective parameters in mini mental status scale i.e. test 3. The treatment is cost effective and devoid of side effects, which can be beneficial for the community. Mean increase after first follow-up in group B was higher as compared to group C. This shows that Medhya Rasayanas are quick in action and bring about improvement in memory faster when compared with Yogic practices. So, on the whole, group B can be considered to be the most efficient among the three groups.


Metabolic network topology reveals transcriptional regulatory signatures of type 2 diabetes.
Type 2 diabetes mellitus (T2DM) is a disorder characterized by both insulin resistance and impaired insulin secretion. Recent transcriptomics studies related to T2DM have revealed changes in expression of a large number of metabolic genes in a variety of tissues. Identification of the molecular mechanisms underlying these transcriptional changes and their impact on the cellular metabolic phenotype is a challenging task due to the complexity of transcriptional regulation and the highly interconnected nature of the metabolic network. In this study we integrate skeletal muscle gene expression datasets with human metabolic network reconstructions to identify key metabolic regulatory features of T2DM. These features include reporter metabolites--metabolites with significant collective transcriptional response in the associated enzyme-coding genes, and transcription factors with significant enrichment of binding sites in the promoter regions of these genes. In addition to metabolites from TCA cycle, oxidative phosphorylation, and lipid metabolism (known to be associated with T2DM), we identified several reporter metabolites representing novel biomarker candidates. For example, the highly connected metabolites NAD+/NADH and ATP/ADP were also identified as reporter metabolites that are potentially contributing to the widespread gene expression changes observed in T2DM. An algorithm based on the analysis of the promoter regions of the genes associated with reporter metabolites revealed a transcription factor regulatory network connecting several parts of metabolism. The identified transcription factors include members of the CREB, NRF1 and PPAR family, among others, and represent regulatory targets for further experimental analysis. Overall, our results provide a holistic picture of key metabolic and regulatory nodes potentially involved in the pathogenesis of T2DM.


A critical evaluation of the current state-of-the-art in quantitative imaging mass spectrometry.
Mass spectrometry imaging (MSI) has evolved into a valuable tool across many fields of chemistry, biology, and medicine. However, arguably its greatest disadvantage is the difficulty in acquiring quantitative data regarding the surface concentration of the analyte(s) of interest. These difficulties largely arise from the high dependence of the ion signal on the localized chemical and morphological environment and the difficulties associated with calibrating such signals. The development of quantitative MSI approaches would correspond to a giant leap forward for the field, particularly for the biomedical and pharmaceutical fields, and is thus a highly active area of current research. In this review, we outline the current progress being made in the development and application of quantitative MSI workflows with a focus on biomedical applications. Particular emphasis is placed on the various strategies used for both signal calibration and correcting for various ion suppression effects that are invariably present in any MSI study. In addition, the difficulties in validating quantitative-MSI data on a pixel-by-pixel basis are highlighted.


The Impact of Open versus Closed Catheter Access System of Central Venous Catheter on Infection Prevention in Critically Ill Patients: A Comparative Evaluation.
Use of Central Venous Catheters (CVC) can be associated with increased incidence of Catheter-Related Bloodstream Infections (CRBSIs). The present study assessed the impact of open versus closed catheter access system of CVC on infection prevention in critically sick patients admitted in the Intensive Care Unit (ICU). After obtaining ethical clearance and consent of relatives of the patients admitted in ICU of our institute, the present study was carried out as a randomized, prospective, double-blind trial with parallel group design (of 200 patients in each group). In study group (Group I), closed catheter access system (Luer access split septum) was used, while open access (three-way) system was used in the control group. Among clinical parameters, if any patient developed fever, his/her blood, urine, and tracheal secretions were sent for culture and sensitivity. Collected data were analyzed using descriptive and inferential statistics. Demographic profile was similar in both the groups. Significant clinical and statistical differences were observed in blood culture values (χ2 = 58.30, df = 1, p < 0.001) as well as Total Leukocyte Counts (TLC) on day 1, 4, and 8 (F2,260= 80.61, p < 0.001). However, no statistically significant (t390= 0.90, p = 0.367) difference was found in the duration of hospital stay among patients in both the groups despite significant differences in various clinical parameter. Luer access split septum connectors along with appropriate training of the nursing personals decrease CRBSI.


The roles of BDNF, pCREB and Wnt3a in the latent period preceding activation of progenitor cell mitosis in the adult dentate gyrus by fluoxetine.
The formation of new neurons continues into adult life in the dentate gyrus of the rat hippocampus, as in many other species. Neurogenesis itself turns out to be highly labile, and is regulated by a number of factors. One of these is the serotoninergic system: treatment with drugs (such as the SSRI fluoxetine) markedly stimulates mitosis in the progenitor cells of the dentate gyrus. But this process has one remarkable feature: it takes at least 14 days of continuous treatment to be effective. This is despite the fact that the pharmacological action of fluoxetine occurs within an hour or so of first administration. This paper explores the role of BDNF in this process, using the effect of a Trk antagonist (K252a) on the labelling of progenitor cells with the mitosis marker Ki67 and the associated expression of pCREB and Wnt3a. These experiments show that (i) Fluoxetine increased Ki67 counts, as well as pCREB and Wnt3a expression in the dentate gyrus. The action of fluoxetine on the progenitor cells and on pCREB (but not Wnt3a) depends upon Trk receptor activation, since it was prevented by icv infusion of K252a. (ii) These receptors are required for both the first 7 days of fluoxetine action, during which no apparent change in progenitor mitosis occurs, as well as the second 7 days. Increased pCREB was always associated with progenitor cell mitosis, but Wnt3a expression may be necessary but not sufficient for increased progenitor cell proliferation. These results shed new light on the action of fluoxetine on neurogenesis in the adult dentate gyrus, and have both clinical and experimental interest.


X-ray crystallography over the past decade for novel drug discovery - where are we heading next?
Macromolecular X-ray crystallography has been the primary methodology for determining the three-dimensional structures of proteins, nucleic acids and viruses. Structural information has paved the way for structure-guided drug discovery and laid the foundations for structural bioinformatics. However, X-ray crystallography still has a few fundamental limitations, some of which may be overcome and complemented using emerging methods and technologies in other areas of structural biology. This review describes how structural knowledge gained from X-ray crystallography has been used to advance other biophysical methods for structure determination (and vice versa). This article also covers current practices for integrating data generated by other biochemical and biophysical methods with those obtained from X-ray crystallography. Finally, the authors articulate their vision about how a combination of structural and biochemical/biophysical methods may improve our understanding of biological processes and interactions. X-ray crystallography has been, and will continue to serve as, the central source of experimental structural biology data used in the discovery of new drugs. However, other structural biology techniques are useful not only to overcome the major limitation of X-ray crystallography, but also to provide complementary structural data that is useful in drug discovery. The use of recent advancements in biochemical, spectroscopy and bioinformatics methods may revolutionize drug discovery, albeit only when these data are combined and analyzed with effective data management systems. Accurate and complete data management is crucial for developing experimental procedures that are robust and reproducible.


A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts.
In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations. Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n = 929) and the Rotterdam Study (n = 182) from the Netherlands, and the CARDS Trial (n = 254) from the UK were genotyped for rs11212617 and tested for an association with both HbA(1c) reduction and treatment success, defined as the ability to reach the treatment target of an HbA(1c) ≤ 7 % (53 mmol/mol). Finally, a meta-analysis including data from literature was performed. In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95% CI 1.03, 1.58, p = 0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95% CI 0.87, 2.39, p = 0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49, p = 0.016 and OR 1.25, 95% CI 1.33, 1.38, p = 7.8 × 10(-6), respectively). A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK. This is the first robustly replicated common susceptibility locus found to be associated with metformin treatment response.


Autistic traits and autism spectrum disorders: the clinical validity of two measures presuming a continuum of social communication skills.
Research indicates that autism is the extreme end of a continuously distributed trait. The Social Responsiveness Scale (SRS) and the Social and Communication Disorders Checklist (SCDC) aim to assess autistic traits. The objective of this study was to compare their clinical validity. The SRS showed sensitivities of .74 to .80 and specificities of .69 to 1.00 for autism. Sensitivities were .85 to .90 and specificities .28 to.82 for the SCDC. Correlations with the ADI-R, ADOS and SCQ were higher for the SRS than for the SCDC. The SCDC seems superior to the SRS to screen for unspecific social and communicative deficits including autism. The SRS appears more suitable than the SCDC in clinical settings and for specific autism screening.


Phase I trial of escalating doses of paclitaxel plus doxorubicin and dexrazoxane in patients with advanced breast cancer.
To determine the maximum-tolerable dose (MTD) of paclitaxel given as a 3-hour intravenous (IV) infusion that could be used in conjunction with doxorubicin and dexrazoxane, and to determine the effect of dexrazoxane on the pharmacokinetics of paclitaxel and doxorubicin. Twenty-five patients with advanced breast cancer received dexrazoxane (600 mg/m2 by IV infusion over 15 minutes), followed 15 minutes later by doxorubicin (60 mg/m2 IV), followed 15 minutes later by paclitaxel (150 or 175 mg/m2 by IV infusion over 3 hours) in cohorts of three to six patients using a standard phase I design without (group A) and with (group B) granulocyte colony-stimulating factor (G-CSF). Treatment continued until there was a substantial decrease in the left ventricular ejection fraction (LVEF), congestive heart failure, progressive disease, or physician discretion to discontinue. The MTD of paclitaxel was 150 mg/m2, and adjunctive therapy with G-CSF was required to prevent febrile neutropenia. Dexrazoxane had no significant effect on the pharmacokinetics of paclitaxel or doxorubicin. After a median cumulative doxorubicin dose of 360 mg/m2 (range, 60 to 870 mg/m2), no patient developed congestive heart failure or had a decrease in LVEF below normal. An objective response occurred in all five patients with locally advanced breast cancer and in eight of 20 patients (40%; 95% confidence interval, 19% to 61%) with metastatic breast cancer. When combined with doxorubicin (60 mg/m2) and dexrazoxane (600 mg/m2), paclitaxel given as a 3-hour infusion had an MTD of 150 mg/m2, and G-CSF was required to prevent febrile neutropenia. Dexrazoxane had no effect on the pharmacokinetics of paclitaxel or doxorubicin. No patient in this trial had a decrease in the LVEF below normal, compared with about 20% to 50% of patients treated with doxorubicin and paclitaxel without dexrazoxane in other trials.


Blockade of the programmed death-1 pathway restores sarcoidosis CD4(+) T-cell proliferative capacity.
Effective therapeutic interventions for chronic, idiopathic lung diseases remain elusive. Normalized T-cell function is an important contributor to spontaneous resolution of pulmonary sarcoidosis. Up-regulation of inhibitor receptors, such as programmed death-1 (PD-1) and its ligand, PD-L1, are important inhibitors of T-cell function. To determine the effects of PD-1 pathway blockade on sarcoidosis CD4(+) T-cell proliferative capacity. Gene expression profiles of sarcoidosis and healthy control peripheral blood mononuclear cells were analyzed at baseline and follow-up. Flow cytometry was used to measure ex vivo expression of PD-1 and PD-L1 on systemic and bronchoalveolar lavage-derived cells of subjects with sarcoidosis and control subjects, as well as the effects of PD-1 pathway blockade on cellular proliferation after T-cell receptor stimulation. Immunohistochemistry analysis for PD-1/PD-L1 expression was conducted on sarcoidosis, malignant, and healthy control lung specimens. Microarray analysis demonstrates longitudinal increase in PDCD1 gene expression in sarcoidosis peripheral blood mononuclear cells. Immunohistochemistry analysis revealed increased PD-L1 expression within sarcoidosis granulomas and lung malignancy, but this was absent in healthy lungs. Increased numbers of sarcoidosis PD-1(+) CD4(+) T cells are present systemically, compared with healthy control subjects (P < 0.0001). Lymphocytes with reduced proliferative capacity exhibited increased proliferation with PD-1 pathway blockade. Longitudinal analysis of subjects with sarcoidosis revealed reduced PD-1(+) CD4(+) T cells with spontaneous clinical resolution but not with disease progression. Analogous to the effects in other chronic lung diseases, these findings demonstrate that the PD-1 pathway is an important contributor to sarcoidosis CD4(+) T-cell proliferative capacity and clinical outcome. Blockade of the PD-1 pathway may be a viable therapeutic target to optimize clinical outcomes.


Religion, clinicians, and the integration of complementary and alternative medicines.
The aim of this study was to compare religious characteristics of general internists, rheumatologists, naturopaths, and acupuncturists, as well as to examine associations between physicians' religious characteristics and their openness to integrating complementary and alternative medicine (CAM). The design involved a national mail survey. The subjects were internists, rheumatologists, naturopaths, and acupuncturists. Physician outcome measures were use of and attitudes toward six classes of CAM. Predictors were religious affiliation, intrinsic religiosity, spirituality, and religious traditionalism. There was a 65% response. Naturopaths and acupuncturists were three times as likely as internists and rheumatologists to report no religious affiliation (35% versus 12%, p < 0.001), but were more likely to describe themselves as very spiritual (51% versus 20%, p < 0.001) and to agree they try to carry religious beliefs into life's dealings (51% versus 44%, p < 0.01). Among physicians, increased spirituality and religiosity coincided with more personal use of CAM and willingness to integrate CAM into a treatment program. Current and future integrative medicine will be shaped in part by religious and spiritual characteristics of providers.


Malaria knowledge, attitudes and practices among migrants from malaria-endemic countries in Evrotas, Laconia, Greece, 2013.
Following re-emergence of malaria in Evrotas, Laconia, in 2009–12, a malaria-control programme was implemented in 2011–12 targeting migrants from malaria-endemic countries, including house-to-house active case detection, health education and distribution of mosquito protection items. In June 2013, we surveyed migrants in Evrotas to assess their malaria knowledge, attitudes and practices to guide prevention activities. We selected participants using simple random sampling and interviewed them, using structured questionnaires. We defined mosquito protection practices (MPPs) as the use of full-length clothes/topical repellent, mosquito screens, fans or air-conditioning, and insecticides. We calculated prevalence ratios (PRs) using Poisson regression and we allowed for clustering of participants in a residence. Of 654 migrants, we invited 132 and 130 participated (all men; 120 (92%) from Pakistan). Of the 130, 56 (43%) identified fever as a malaria symptom; those who were aware of this had higher level of education (PR: 3.2; 95% confidence interval (CI): 1.2–9.0). A total of 111 (85%) used insecticide-treated bednets and 95 (73%) used more than two MPPs. Poor housing conditions (warehouses/shacks: PR: 0.8; 95% CI: 0.6–0.9), were associated with use of up to two MPPs. Despite extensive interventions in Evrotas, the level of malaria awareness among migrants remained suboptimal and poor housing conditions hindered effective mosquito protection. We recommend culturally adapted health education and improvement of housing conditions to minimise the risk of new cases and re-establishment of malaria in Greece.


Social molecular pathways and the evolution of bee societies.
Bees provide an excellent model with which to study the neuronal and molecular modifications associated with the evolution of sociality because relatively closely related species differ profoundly in social behaviour, from solitary to highly social. The recent development of powerful genomic tools and resources has set the stage for studying the social behaviour of bees in molecular terms. We review 'ground plan' and 'genetic toolkit' models which hypothesize that discrete pathways or sets of genes that regulate fundamental behavioural and physiological processes in solitary species have been co-opted to regulate complex social behaviours in social species. We further develop these models and propose that these conserved pathways and genes may be incorporated into 'social pathways', which consist of relatively independent modules involved in social signal detection, integration and processing within the nervous and endocrine systems, and subsequent behavioural outputs. Modifications within modules or in their connections result in the evolution of novel behavioural patterns. We describe how the evolution of pheromonal regulation of social pathways may lead to the expression of behaviour under new social contexts, and review plasticity in circadian rhythms as an example for a social pathway with a modular structure.


A new measure of classifier performance for gene expression data.
One of the major aims of many microarray experiments is to build discriminatory diagnosis and prognosis models. A large number of supervised methods have been proposed in literature for microarray-based classification for this purpose. Model evaluation and comparison is a critical issue and, the most of the time, is based on the classification cost. This classification cost is based on the costs of false positives and false negative, that are generally unknown in diagnostics problems. This uncertainty may highly impact the evaluation and comparison of the classifiers. We propose a new measure of classifier performance that takes account of the uncertainty of the error. We represent the available knowledge about the costs by a distribution function defined on the ratio of the costs. The performance of a classifier is therefore computed over the set of all possible costs weighted by their probability distribution. Our method is tested on both artificial and real microarray data sets. We show that the performance of classifiers is very depending of the ratio of the classification costs. In many cases, the best classifier can be identified by our new measure whereas the classic error measures fail.


Guaranteed classification via regularized similarity learning.
Learning an appropriate (dis)similarity function from the available data is a central problem in machine learning, since the success of many machine learning algorithms critically depends on the choice of a similarity function to compare examples. Despite many approaches to similarity metric learning that have been proposed, there has been little theoretical study on the links between similarity metric learning and the classification performance of the resulting classifier. In this letter, we propose a regularized similarity learning formulation associated with general matrix norms and establish their generalization bounds. We show that the generalization error of the resulting linear classifier can be bounded by the derived generalization bound of similarity learning. This shows that a good generalization of the learned similarity function guarantees a good classification of the resulting linear classifier. Our results extend and improve those obtained by Bellet, Habrard, and Sebban (2012). Due to the techniques dependent on the notion of uniform stability (Bousquet & Elisseeff, 2002), the bound obtained there holds true only for the Frobenius matrix-norm regularization. Our techniques using the Rademacher complexity (Bartlett & Mendelson, 2002) and its related Khinchin-type inequality enable us to establish bounds for regularized similarity learning formulations associated with general matrix norms, including sparse L1-norm and mixed (2,1)-norm.


Efficient Autotransporter-Mediated Extracellular Secretion of a Heterologous Recombinant Protein by Escherichia coli.
The autotransporter protein secretion system has been used previously to target the secretion of heterologous proteins to the bacterial cell surface and the extracellular milieu at the laboratory scale. The platform is of particular interest for the production of "difficult" recombinant proteins that might cause toxic effects when produced intracellularly. One such protein is IrmA. IrmA is a vaccine candidate that is produced in inclusion bodies requiring refolding. Here, we describe the use and scale-up of the autotransporter system for the secretion of an industrially relevant protein (IrmA). A plasmid expressing IrmA was constructed such that the autotransporter platform could secrete IrmA into the culture supernatant fraction. The autotransporter platform was suitable for the production and purification of IrmA with comparable physical properties to the protein produced in the cytoplasm. The production of IrmA was translated to scale-up protein production conditions resulting in a yield of 29.3 mg/L of IrmA from the culture supernatant, which is consistent with yields of current industrial processes. IMPORTANCE Recombinant protein production is an essential component of the biotechnology sector. Here, we show that the autotransporter platform is a viable method for the recombinant production, secretion, and purification of a "difficult" to produce protein on an industrially relevant scale. Use of the autotransporter platform could reduce the number of downstream processing operations required, thus accelerating the development time and reducing costs for recombinant protein production.


Heart rate and arterial blood pressure during exercise in patients with angina pectoris. Effects of training and of nitroglycerin.
In 29 patients with typical exertional angina pectoris, intra-arterial systolic blood pressure (SBP), heart rate (HR), and the rate-pressure product (RPP = HR X SBP X 10(-2) were continuously recorded during repeated bouts of leg or arm exercise. Development of chest pain was independent of the workload and occurred at a fairly constant value of RPP, of HR, and of SBP in each patient for a given type of exercise, but the pain threshold values for all three variables were consistently higher during arm exercise than during leg exercise. The reproducibility of the pain threshold values was assessed for leg exercise. The variation, based on individual coefficients of variation, ranged from 1.3% to 13% (group mean, about 6%). There was no significant difference between the SBP values obtained by the traditional, noninvasive cuff technique and the values during intra-arterial monitoring. In 25 patients a physical training program of an average of three months increased the maximal amount of work (watt X sec) performed before onset of pain by 100%. The most conspicuous effect of training on cardiac function was a 10% reduction of HR at a given workload, SBP being unchanged. Over-all, the data suggest that the increased exercise capacity caused by training could be accounted for by the reduction in the relation between RPP and external workload. The improvement in exercise capacity resulting from training was on the same level of magnitude as the 90% increase obtained in 11 untrained patients after administration of 0.25 to 0.50 mg of nitroglycerine sublingually prior to exercise. In contrast to the finding after training, nitroglycerin administered to subjects increased HR by 10%, but reduced SBP by 13%, RPP remaining unchanged. Therefore to explain the effect of nitroglycerin on exercise capacity additional economizing changes in myocardial performance (e.g., reduction of heart volume) are required.


Effects of a short-term rehabilitation program on airway inflammation in children with cystic fibrosis.
Respiratory therapy in cystic fibrosis (CF) consists of airway clearance, infection control, and reduction of airway inflammation. It is well recognized that physical activity as well as daily chest physiotherapy, enhance airway clearance. We investigated the effects of pulmonary rehabilitation, including physical activity and chest physiotherapy, on airway inflammation in children with CF. Eighteen children with stable CF (six females), aged 8.2-16.2 years, participating in a 3-week multidisciplinary inpatient rehabilitation program were recruited. Assessment at the beginning and the end of the program included clinical score, pulmonary function test, exhaled breath condensate (EBC) and sputum analysis. Sputum supernatant and EBC were analyzed for interleukin (IL)-1b, 6, 8, 10, 12, tumor necrosis factor-alpha (TNF-alpha) and LTB4. Median (IQR) symptom scores decreased from 19 [23] to 16 [21], P = 0.005. Vital capacity and FVC increased significantly (P < 0.05). However no difference was found for the total sputum cells and sputum as well as EBC cytokines between the two visits. Significant correlations were found for sputum IL-1 (+), IL-6 (-), and IL-8 (+) to total sputum cell count and neutrophils and for IL-8 to TNF-alpha. We have shown that a short-term inpatient rehabilitation for children with stable CF with intensive physical activity mainly improve subjective clinical symptoms and measures of lung function such as VC and FVC but does not influence airflow obstruction and airway inflammation as assessed by sputum and EBC analysis.


Reduced-impact logging and biodiversity conservation: a case study from Borneo.
A key driver of rain forest degradation is rampant commercial logging. Reduced-impact logging (RIL) techniques dramatically reduce residual damage to vegetation and soils, and they enhance the long-term economic viability of timber operations when compared to conventionally managed logging enterprises. Consequently, the application of RIL is increasing across the tropics, yet our knowledge of the potential for RIL also to reduce the negative impacts of logging on biodiversity is minimal. We compare the impacts of RIL on birds, leaf-litter ants, and dung beetles during a second logging rotation in Sabah, Borneo, with the impacts of conventional logging (CL) as well as with primary (unlogged) forest. Our study took place 1-8 years after the cessation of logging. The species richness and composition of RIL vs. CL forests were very similar for each taxonomic group. Both RIL and CL differed significantly from unlogged forests in terms of bird and ant species composition (although both retained a large number of the species found in unlogged forests), whereas the composition of dung beetle communities did not differ significantly among forest types. Our results show little difference in biodiversity between RIL and CL over the short-term. However, biodiversity benefits from RIL may accrue over longer time periods after the cessation of logging. We highlight a severe lack of studies investigating this possibility. Moreover, if RIL increases the economic value of selectively logged forests (e.g., via REDD+, a United Nations program: Reducing Emissions from Deforestation and Forest Degradation in Developing Countries), it could help prevent them from being converted to agricultural plantations, which results in a tremendous loss of biodiversity.


BRCA and beyond: a genome-first approach to familial breast cancer risk assessment.
Breast cancer affects around 12% of women in the Western world, but individual lifetime risks vary significantly within any population. Currently, familial cancer services assess and manage familial breast cancer risk based on the presence of a family history of the condition or the identification of high-risk breast cancer susceptibility alleles. This model of clinical care provides an accurate genetic risk assessment for only the minority of families referred to these services. With increasing access to technologies that interrogate human variation at the genome-wide level, it is envisaged that familial breast cancer risk assessments will in the future assume a genome-first approach. This review discusses and highlights the different components of familial breast cancer risk, which will need to be integrated to make this new model of clinical risk assessment possible.


On-target inhibition of tumor fermentative glycolysis as visualized by hyperpolarized pyruvate.
Many cancer cells display the Warburg effect, that is, enhanced glycolysis followed by fermentation (conversion of pyruvate to lactate). Recently, the molecular basis for these effects has started to be elucidated, and the up-regulation of the lactate dehydrogenase A (LDH-A) isoform of lactate dehydrogenase is felt to be a major molecular mediator of this phenomenon. Moreover, LDH-A expression in tumor tissue and LDH-A levels in blood portend a bad prognosis, and LDH-A blockade can lead to tumor growth inhibition in tumor transplant models. We have extended existing data (some of which were published during the time when we were carrying out our studies) in two important ways: 1) inhibition of LDH-A in a glycolytic lung cancer cell line results in reactive oxygen species-mediated apoptosis and increased sensitivity to the chemotherapeutic drug paclitaxel and 2) inhibition of fermentative glycolysis can also be accomplished by activation of the pyruvate dehydrogenase complex by the drug dichloroacetate, now undergoing clinical trials, and that this phenomenon can be monitored in vivo in a noninvasive real-time manner through magnetic resonance spectroscopy using hyperpolarized pyruvate. Collectively, these data suggest that in vivo effects of drugs that redirect the fate of pyruvate, and hence are aimed at reversing the Warburg effect, could be monitored through the use of hyperpolarized magnetic resonance spectroscopy, a method that is scalable to human use.


Antibiotic Discovery with Synthetic Fermentation: Library Assembly, Phenotypic Screening, and Mechanism of Action of β-Peptides Targeting Penicillin-Binding Proteins.
In analogy to biosynthetic pathways leading to bioactive natural products, synthetic fermentation generates mixtures of molecules from simple building blocks under aqueous, biocompatible conditions, allowing the resulting cultures to be directly screened for biological activity. In this work, a novel β-peptide antibiotic was successfully identified using the synthetic fermentation platform. Phenotypic screening was carried out in an initially random fashion, allowing simple identification of active cultures. Subsequent deconvolution, focused screening, and structure-activity relationship studies led to the identification of a potent antimicrobial peptide, showing strong selectivity for our model system Bacillus subtilis over human HEK293 cells. To determine the antibacterial mechanism of action, a peptide probe bearing a photoaffinity tag was readily synthesized through the use of appropriate synthetic fermentation building blocks and utilized for target identification using a quantitative mass spectrometry-based strategy. The chemoproteomic approach led to the identification of a number of bacterial membrane proteins as prospective targets. These findings were validated through binding affinity studies with penicillin-binding protein 4 using microscale thermophoresis, with the bioactive peptide showing a dissociation constant ( Kd) in the nanomolar range. Through these efforts, we provide a proof of concept for the synthetic fermentation approach presented here as a new strategy for the phenotypic discovery of novel bioactive compounds.


Detection of mercury and other undetermined materials in skin biopsies of endemic pemphigus foliaceus.
A novel variant of endemic pemphigus foliaceus (EPF) was described among individuals in an area surrounding El Bagre, Colombia, South America. The population in this rural mining community is exposed to high environmental levels of mercury, used for gold extraction, as well as other minerals, metalloids, and trace elements (e.g., quartz, rutile, granite, magnetite, and almenite) and ultraviolet radiation. Fifty control subjects and fifty EPF patients in the endemic area were examined for the presence of mercury in skin biopsies and hair, using autometallographic and mass spectroscopic analyses, respectively. Simultaneously, serum levels of IgE were measured, and cutaneous tests for hypersensitivity reactions were performed. Using autometallography, mercuric sulfides/selenides were detected in 14 of 51 skin biopsies distributed similarly in the control and patient groups. However, significantly higher serum IgE levels and mercury concentrations in hair, urine, and nails were found in patients compared with controls. Microscopic analysis revealed mercuric sulfides/selenides concentrated within and around the sweat gland epithelium, as well as in dendritic cells. Five skin biopsies from EPF patients and five from controls that tested positive for the presence of mercuric sulfides/selenides by autometallography were randomly selected for electron microscopic analysis. This analysis revealed a mixed electron-dense and electron-light material closely associated with desmosomes in patients. However, there were intracellular vesicles containing an amalgam of electron-dense and electron-light materials only in the EPF patients. Thus, EPF-affected individuals are exposed to high levels of environmental mercuric sulfides/selenides and other elements. This is the first study reporting mercuric sulfides/selenides in skin biopsies from people living in a focus of EPF, and these compounds may play a role in the pathogenesis of autoimmunity.


Peste des Petits Ruminants at the Wildlife-Livestock Interface in the Northern Albertine Rift and Nile Basin, East Africa.
In the recent past, peste des petits ruminants (PPR) emerged in East Africa causing outbreaks in small livestock across different countries, with evidences of spillover to wildlife. In order to understand better PPR at the wildlife-livestock interface, we investigated patterns of peste des petits ruminants virus (PPRV) exposure, disease outbreaks, and viral sequences in the northern Albertine Rift. PPRV antibodies indicated a widespread exposure in apparently healthy wildlife from South Sudan (2013) and Uganda (2015, 2017). African buffaloes and Uganda kobs <1-year-old from Queen Elizabeth National Park (2015) had antibodies against PPRV N-antigen and local serosurvey captured a subsequent spread of PPRV in livestock. Outbreaks with PPR-like syndrome in sheep and goats were recorded around the Greater Virunga Landscape in Kasese (2016), Kisoro and Kabale (2017) from western Uganda, and in North Kivu (2017) from eastern Democratic Republic of the Congo (DRC). This landscape would not be considered typical for PPR persistence as it is a mixed forest-savannah ecosystem with mostly sedentary livestock. PPRV sequences from DRC (2017) were identical to strains from Burundi (2018) and confirmed a transboundary spread of PPRV. Our results indicate an epidemiological linkage between epizootic cycles in livestock and exposure in wildlife, denoting the importance of PPR surveillance on wild artiodactyls for both conservation and eradication programs.


Neural correlates of memorized associations and cued movements in archistriatum of the domestic chick.
The archistriatum mediates a neural pathway from the medial part of intermediate hyperstriatum ventrale (in the dorsal pallium) to the lobus parolfactorius (in the medial striatum), thus is possibly involved in memory formation in the domestic chick. To elucidate the functional roles, we examined single neuron activities from archistriatum in unconstrained chicks during execution of a GO/NOGO task. In this task, a brief motor sound was given as initial cue, and immediately followed by presentation of a coloured bead. Chick was required to recall the memorized associations between the colour and reward, and pecked at the bead to gain food after a delay (GO trials) or stayed not pecking (NOGO trials). The ventral part of intermediate archistriatum proved to contain a group of neurons that selectively responded to the reward-associated colours before the reward was actually presented, possibly coding the memorized associations. Another group of neurons fired during the reward period, thus could code aspects of the food reward. Yet another group of neurons started to fire immediately on the cue sound and prior to the cued movements nonselectively in both GO and NOGO trials, thus could be involved in the sensori-motor link between the sound and the targeted body movements. It is concluded that even a subregion of archistriatum contains diverse neural codes for memorized associations and food rewards, and neural codes of movements cued by sounds, suggesting that archistriatum is a complex of different functional systems, possibly corresponding to striatum, limbic amygdala, and prefrontal cortex in mammals.


Alveolar macrophages are sentinels of murine pulmonary homeostasis following inhaled antigen challenge.
Alveolar macrophages are sentinels of the pulmonary mucosa and central to maintaining immunological homeostasis. However, their role in governing the response to allergen is not fully understood. Inappropriate responses to the inhaled environment manifest as asthma. We utilized a mechanistic IL-13-driven model and a house dust mite allergen mucosal sensitization model of allergic airway disease to investigate the role of alveolar macrophages in regulating pulmonary inflammation. IL-13-dependent eosinophilic and Th2 inflammation was enhanced in mice depleted of alveolar macrophages using clodronate liposomes. Similarly, depletion of alveolar macrophages during house dust mite sensitization or established disease resulted in augmented Th2 immunity and increased allergen-specific IgG1 and IgE. Clodronate treatment also delayed the resolution of tissue inflammation following cessation of allergen challenge. Strikingly, tissue interstitial macrophages were elevated in alveolar macrophage-deficient mice identifying a new homeostatic relationship between different macrophage subtypes. A novel role for the macrophage-derived immunoregulatory cytokine IL-27 was identified in modulating Th2 inflammation following mucosal allergen exposure. In summary, alveolar macrophages are critical regulators of Th2 immunity and their dysregulation promotes an inflammatory environment with exacerbation of allergen-induced airway pathology. Manipulating IL-27 may provide a novel therapeutic strategy for the treatment of asthma.


[Current indications for reimplantation of the upper extremity].
In the last decades there has been a great development in microsurgery that has enabled successful replantation of totally severed parts. Nowadays, the important issue is to decide which segments should be replanted, in order to achieve a good functional result. In this paper we study the indications and contraindications of replantation, based in our experience and we present a review of the recent literature. We consider the following aspects: general condition and age of the patient, mechanism of lesion, amputation level, ischemic time and also economic aspects. We conclude that replantation should be attempted in thumb and multiple digits amputations, in amputations at the palm, wrist and forearm, in single digit amputations distal to the flexor superficialis insertion and in any case in children.


MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5' end resection.
Appropriate repair of DNA lesions and the inhibition of DNA repair activities at telomeres are crucial to prevent genomic instability. By fuelling the generation of genetic alterations and by compromising cell viability, genomic instability is a driving force in cancer and ageing. Here we identify MAD2L2 (also known as MAD2B or REV7) through functional genetic screening as a novel factor controlling DNA repair activities at mammalian telomeres. We show that MAD2L2 accumulates at uncapped telomeres and promotes non-homologous end-joining (NHEJ)-mediated fusion of deprotected chromosome ends and genomic instability. MAD2L2 depletion causes elongated 3' telomeric overhangs, indicating that MAD2L2 inhibits 5' end resection. End resection blocks NHEJ while committing to homology-directed repair, and is under the control of 53BP1, RIF1 and PTIP. Consistent with MAD2L2 promoting NHEJ-mediated telomere fusion by inhibiting 5' end resection, knockdown of the nucleases CTIP or EXO1 partially restores telomere-driven genomic instability in MAD2L2-depleted cells. Control of DNA repair by MAD2L2 is not limited to telomeres. MAD2L2 also accumulates and inhibits end resection at irradiation-induced DNA double-strand breaks and promotes end-joining of DNA double-strand breaks in several settings, including during immunoglobulin class switch recombination. These activities of MAD2L2 depend on ATM kinase activity, RNF8, RNF168, 53BP1 and RIF1, but not on PTIP, REV1 and REV3, the latter two acting with MAD2L2 in translesion synthesis. Together, our data establish MAD2L2 as a crucial contributor to the control of DNA repair activity by 53BP1 that promotes NHEJ by inhibiting 5' end resection downstream of RIF1.


FZD10-Gα13 signalling axis points to a role of FZD10 in CNS angiogenesis.
Among the 10 Frizzled (FZD) isoforms belonging to the Class F of G protein-coupled receptors (GPCRs), FZD10 remains the most enigmatic. FZD10 shows homology to FZD4 and FZD9 and was previously implicated in both β-catenin-dependent and -independent signalling. In normal tissue, FZD10 levels are generally very low; however, its upregulation in synovial carcinoma has attracted some attention for therapy. Our findings identify FZD10 as a receptor interacting with and signalling through the heterotrimeric G protein Gα13 but not Gα12, Gαi1, GαoA, Gαs, or Gαq. Stimulation with the FZD agonist WNT induced the dissociation of the Gα13 protein from FZD10, and led to global Gα12/13-dependent cell changes assessed by dynamic mass redistribution measurements. Furthermore, we show that FZD10 mediates Gα12/13 activation-dependent induction of YAP/TAZ transcriptional activity. In addition, we show a distinct expression of FZD10 in embryonic CNS endothelial cells at E11.5-E14.5. Given the well-known importance of Gα13 signalling for the development of the vascular system, the selective expression of FZD10 in brain vascular endothelial cells points at a potential role of FZD10-Gα13 signalling in CNS angiogenesis.


Decreased Brain Neurokinin-1 Receptor Availability in Chronic Tennis Elbow.
Substance P is released in painful and inflammatory conditions, affecting both peripheral processes and the central nervous system neurokinin 1 (NK1) receptor. There is a paucity of data on human brain alterations in NK1 expression, how this system may be affected by treatment, and interactions between central and peripheral tissue alterations. Ten subjects with chronic tennis elbow (lateral epicondylosis) were selected out of a larger (n = 120) randomized controlled trial evaluating graded exercise as a treatment for chronic tennis elbow (lateral epicondylosis). These ten subjects were examined by positron emission tomography (PET) with the NK1-specific radioligand 11C-GR205171 before, and eight patients were followed up after treatment with graded exercise. Brain binding in the ten patients before treatment, reflecting NK1-receptor availability (NK1-RA), was compared to that of 18 healthy subjects and, longitudinally, to the eight of the original ten patients that agreed to a second PET examination after treatment. Before treatment, patients had significantly lower NK1-RA in the insula, vmPFC, postcentral gyrus, anterior cingulate, caudate, putamen, amygdala and the midbrain but not the thalamus and cerebellum, with the largest difference in the insula contralateral to the injured elbow. No significant correlations between brain NK1-RA and pain, functional severity, or peripheral NK1-RA in the affected limb were observed. In the eight patients examined after treatment, pain ratings decreased in everyone, but there were no significant changes in NK1-RA. These findings indicate a role for the substance P (SP) / NK1 receptor system in musculoskeletal pain and tissue healing. As neither clinical parameters nor successful treatment response was reflected in brain NK1-RA after treatment, this may reflect the diverse function of the SP/NK1 system in CNS and peripheral tissue, or a change too small or slow to capture over the three-month treatment.


Climate change and population health in Africa: where are the scientists?
Despite a growing awareness of Africans' vulnerability to climate change, there is relatively little empirical evidence published about the effects of climate on population health in Africa. This review brings together some of the generalised predictions about the potential continent-wide effects of climate change with examples of the relatively few locally documented population studies in which climate change and health interact. Although ecologically determined diseases such as malaria are obvious candidates for susceptibility to climate change, wider health effects also need to be considered, particularly among populations where adequacy of food and water supplies may already be marginal.


Salmonellosis cases caused by a rare Salmonella Enteritidis PT6c associated with travel to Bulgaria, June-July 2008.
In June 2008 an outbreak of gastroenteritis was registered in Sunny Beach resort situated on the Black Sea coast in Bulgaria, affecting 14 employees of a hotel, five of whom tested positive for Salmonella Enteritidis. During June-July 2008 four sporadic S. Enteritidis cases were also reported and two of them were foreign tourists. In the same period S. Enteritidis cases connected with travel to Bulgaria were reported to the European Centre for Disease Prevention and Control (ECDC) from Finland, United Kingdom, Sweden, Germany and Norway. We describe a study performed to find out relatedness between Bulgarian and Finnish S. Enteritidis isolates using phage typing (PT) and pulse-field gel electrophoresis (PFGE). Fifteen S. Enteritidis isolates from Bulgaria and 195 from Finland (including 28 from travellers to Bulgaria) were phage typed. Within Bulgarian isolates four different PTs were found and PT6c with eight strains was predominant. Nineteen out of 28 strains isolated from the Finns visiting Bulgaria belonged also to PT6c. PFGE typing (with one enzyme) of all S. Enteritidis PT6c strains (8 Bulgarian and 19 Finnish isolates) showed indistinguishable PFGE profile. The typing results thus demonstrated a link between Bulgarian and Finnish S. Enteritidis isolates. We conclude that S. Enteritidis PT6c was the cause of salmonella outbreak in Sunny Beach and was exported to Finland, and likely to the United Kingdom, Norway, Sweden and Germany.


Genetic analysis of the additional sex combs locus of Drosophila melanogaster.
Additional sex combs (Asx) is a member of the Polycomb group of genes, which are thought to be required for maintenance of chromatin structure. To better understand the function of Asx, we have isolated nine new alleles, each of which acts like a gain of function mutation. Asx is required for normal determination of segment identity. AsxP1 shows an unusual phenotype in that anterior and posterior homeotic transformations are seen in the same individuals, suggesting that AsxP1 might upset chromatin structure in a way that makes both activation and repression of homeotic genes more difficult. Analysis of embryonic and adult phenotypes of Asx alleles suggests that Asx is required zygotically for determination of segment number and polarity. The expression pattern of even-skipped is altered in Asx mutant embryos, suggesting that Asx is required for normal expression of this gene. We have transposon-tagged the Asx gene, and can thus begin molecular analysis of its function.


Distinct evolutionary patterns of brain and body size during adaptive radiation.
Morphological traits are often genetically and/or phenotypically correlated with each other and such covariation can have an important influence on the evolution of individual traits. The strong positive relationship between brain size and body size in vertebrates has attracted a lot of interest, and much debate has surrounded the study of the factors responsible for the allometric relationship between these two traits. Here, we use comparative analyses of the Tanganyikan cichlid adaptive radiation to investigate the patterns of evolution for brain size and body size separately. We found that body size exhibited recent bursts of rapid evolution, a pattern that is consistent with divergence linked to ecological specialization. Brain weight on the other hand, showed no bursts of divergence but rather evolved in a gradual manner. Our results thus show that even highly genetically correlated traits can present markedly different patterns of evolution, hence interpreting patterns of evolution of traits from correlations in extant taxa can be misleading. Furthermore, our results suggest, contrary to expectations from theory, that brain size does not play a key role during adaptive radiation.


Politics and technology in health information systems development: a discourse analysis of conflicts addressed in a systems design group.
Different types of disagreements must be managed during the development of health information systems. This study examines the antagonisms discussed during the design of an information system for 175,000 users in a public health context. Discourse analysis methods were used for data collection and analysis. Three hundred and twenty-six conflict events were identified from four design meetings and divided into 16 categories. There were no differences regarding the types of conflicts that the different participants brought into the design discussions. Instead, conflict occurrence was primarily affected by the agendas that set the stage for examinations and debates. The results indicate that the selection of design method and the structure used for the meetings are important factors for the manner in which conflicts are brought into consideration during health information system design. Further studies comparing participatory and non-participatory information system design practices in health service settings are warranted.


Readmission of trauma patients in a nonacademic Level II trauma center.
Readmission of trauma patients has been identified as a quality indicator for trauma care. Few if any studies on this topic can be found from a nonacademic trauma center. The objectives of the study were to determine the rate, cause, and preventability for readmission and to identify predictors of readmission in a nonacademic trauma center. Cases registered from 2007 to 2009 were identified from trauma registry. A retrospective chart review of 98 readmission trauma patients was done to elicit the complications and outcomes. Criteria were selected to elicit preventability of readmissions.Predictors for readmission were identified by using a logistic regression analysis. Of 4,986 patients, 98 (1.96%) required readmission due to wound (23.47%), abdominal (16.33%), thromboembolic (4.08%),central nervous system (21.43%), hematoma (5.10%), and pulmonary (7.14%) complications. Among all readmission cases,surgery was performed in 38.78%, days to readmission was 19.44 ± 8.80, and six patients experienced a readmission chain.Penetrating injury, Injury Severity Score 25, and hospital length of stay were predictors of readmission. 90.82% of the trauma readmissions were trauma related and 15% were potentially preventable readmissions. Fifty-three percent of the readmissions occurred before a follow-up appointment. The incidence of readmissions was similar to published data from academic trauma centers, but the reason for readmission and the need for surgery at readmission were very different. Potentially preventable readmissions have not been well addressed in literature. Therefore, further multicenter studies that include nonacademic trauma centers are needed to analyze this complicated problem.


Genetic variability of serotonin pathway associated with schizophrenia onset, progression, and treatment.
Schizophrenia (SZ) onset and treatment outcome have important genetic components, however individual genes do not have strong effects on SZ phenotype. Therefore, it is important to use the pathway-based approach and study metabolic and signaling pathways, such as dopaminergic and serotonergic. Serotonin pathway has an important role in brain signaling, nevertheless, its role in SZ is not as thoroughly examined as that of dopamine pathway. In this study, we reviewed serotonin pathway genes and genetic variations associated with SZ, including variations at DNA, RNA, and epigenetic level. We obtained 30 serotonin pathway genes from Kyoto encyclopedia of genes and genomes and used these genes for the literature review. We extracted 20 protein coding serotonin pathway genes with genetic variations associated with SZ onset, development, and treatment from 31 research papers. Genes associated with SZ are present on all levels of serotonin pathway: serotonin synthesis, transport, receptor binding, intracellular signaling, and reuptake; however, regulatory genes are poorly researched. We summarized common challenges of genetic association studies and presented some solutions. The analysis of reported serotonin pathway-SZ associations revealed lack of information about certain serotonin pathway genes potentially associated with SZ. Furthermore, it is becoming clear that interactions among serotonin pathway genes and their regulators may bring further knowledge about their involvement in SZ.


Top-down phenomics of Arabidopsis thaliana: metabolic profiling by one- and two-dimensional nuclear magnetic resonance spectroscopy and transcriptome analysis of albino mutants.
Elucidating the function of each gene in a genome is important for understanding the whole organism. We previously constructed 4000 disruptant mutants of Arabidopsis by insertion of Ds transposons. Here, we describe a top-down phenomics approach based on metabolic profiling that uses one-dimensional 1H and two-dimensional 1H,13C NMR analyses and transcriptome analysis of albino mutant lines of Arabidopsis. One-dimensional 1H NMR metabolic fingerprinting revealed global metabolic changes in the albino mutants, notably a decrease in aromatic metabolites and changes in aliphatic metabolites. NMR measurements of plants fed with 13C6-glucose showed that the albino lines had dramatically different 13C-labeling patterns and increased levels of several amino acids, especially Asn and Gln. Microarray analysis of one of the albino lines revealed a unique expression profile and showed that changes in the expression of genes encoding metabolic enzymes did not correspond with changes in the levels of metabolites. Collectively, these results suggest that albino mutants lose the normal carbon/nitrogen balance, presumably mainly through lack of photosynthesis. Our study offers an idea of how much the metabolite network is affected by chloroplast function in plants and shows the effectiveness of NMR-based metabolic analysis for metabolite profiling. On the basis of these findings, we propose that future investigations of plant systems biology combine transcriptomic, metabolomic, and phenomic analyses of gene disruptant lines.


Gemcitabine depletes regulatory T-cells in human and mice and enhances triggering of vaccine-specific cytotoxic T-cells.
Particle-mediated epidermal delivery (PMED) is a potent genetic vaccination method. However, a recent report found PMED only poorly and infrequently triggered antigen-specific cytotoxic T-cells in cancer patients. Here, we show that injection of the chemotherapeutic drug Gemcitabine in mice results in improvement of the efficacy of subsequent PMED vaccination against NY-ESO-1. We found in mice and in cancer patients that administration of Gemcitabine induces a transient reduction in the percentage of regulatory T-cells among CD4-positive cells. The higher relative sensitivity of regulatory T-cells compared to other CD4-positive T-cells toward cytostatic drugs can be linked to the higher frequency of proliferating cells in the regulatory compartment compared to the nonregulatory CD4-compartment in healthy people and cancer patients. Thus, by affecting regulatory T-cells more than other lymphocyte subsets, chemotherapeutic agents can create a transient hyperimmunoreactive window. Such a window would provide an ideal timepoint to administer a vaccine expected to induce a therapeutically relevant anticancer cytotoxic T-cell response.


Dietary linolenic acid is inversely associated with plasma triacylglycerol: the National Heart, Lung, and Blood Institute Family Heart Study.
Dietary intake of linolenic acid is associated with a decreased risk of cardiovascular disease mortality. However, the mechanisms by which dietary linolenic acid affects cardiovascular disease risk are not clearly understood. We examined the association between dietary linolenic acid and plasma triacylglycerol concentrations. In a cross-sectional design, we studied 4440 white subjects (2036 men and 2404 women) aged 25-93 y who participated in the National Heart, Lung, and Blood Institute Family Heart Study. We used generalized linear models to estimate adjusted mean triacylglycerol concentrations according to categories of total dietary linolenic acid (alpha- and gamma-linolenic acid) intake. The mean dietary linolenic acid intakes were 0.81 and 0.69 g/d for the men and the women, respectively. High consumption of dietary linolenic acid was associated with young age; high intakes of energy, fat, carbohydrates, fruit, vegetables, and fish; low HDL cholesterol; current smoking; and frequent consumption of creamy salad dressing. High consumption of dietary linolenic acid was also associated with low plasma triacylglycerol concentrations. From the lowest to the highest quintile of linolenic acid intake, the multivariate-adjusted mean triacylglycerol concentrations were 1.75 (95% CI: 1.65, 1.85), 1.74 (1.66, 1.82), 1.69 (1.61, 1.77), 1.66 (1.58, 1.74), and 1.54 (1.44, 1.64) mmol/L, respectively (P for linear trend = 0.007). When linolenic acid was used as a continuous variable, the corresponding regression coefficient was -0.2811 (-0.4922, -0.07001). Consumption of total linolenic acid is inversely related to plasma triacylglycerol concentrations in both white men and white women. This suggests a pathway by which dietary linolenic acid might reduce cardiovascular disease risk.