The involvement of limbic structures in typical and atypical absence epilepsy.
Typical and atypical seizures of absence epilepsy are thought to be generated by a rhythmogenic interplay between the cortex and the thalamus. However, the question remains as to which other subcortical and extrathalamic structures are involved in the pathophysiology of typical and atypical absence epilepsy. Limbic structures are not thought to be involved in typical absence seizures, since in animal models and human patients there is no evidence for the occurrence of spike-and-wave discharges of absence seizures in the limbic regions. However, there are a number of observations from animal models of absence epilepsy that point to a possibly important link between absence seizure mechanisms and limbic structures. Atypical absence seizures are distinct in many ways from typical absence seizures although they bear considerable clinical, EEG, and pharmacological resemblance to typical absence seizures. The differences between typical and atypical seizures of absence epilepsy appear to be circuitry dependent. While both typical and atypical absence seizures involve the cortico-thalamo-cortical circuitry, they each engage different neuronal networks within that circuitry. This review examines the involvement of limbic structures in typical and atypical absence seizures, shows that limbic circuitry forms an integral component of the absence epilepsy network and concludes that further knowledge of this component is important for understanding the complex relationships involved in absence epilepsy.


Sympathoadrenal Neurochemistry and early weaning of swine.
Three litters of pigs were weaned at 21 days of age, and 3 others were left with the sow. Pigs were killed at 21, 23, 28, or 39 days of age. Weaned pigs exhibited anxiety, gastrointestinal dysfunction, and decreased rate of body weight gain. Plasma glucose or liver glycogen concentrations were not decreased by weaning. Adrenal gland weights and tyrosine hydroxylase (EC 1.14.3a), dopamine beta-hydroxylase (EC 220.127.116.11), phenethanolamine-N-methyl transferase (EC 2.1.1), and monoamine oxidase (EC 126.96.36.199) activities were increased after weaning. Adrenal catecholamine and cortisol levels and dopa decarboxylase (EC 22.214.171.124) and catechol-o-methyl transferase (EC 188.8.131.52) activities were not significantly altered, although some increases were indicated. Cranial cervical ganglionic choline acetyltransferase (EC 184.108.40.206) and tyrosine hydroxylase activities were increased after weaning. Weaning of swine at 21 days of age is a stressful experience, and many effects persist for at least 18 days; however, growth was no longer impaired 18 days after weaning.


A retrospective study on the causes for evisceration at Tilganga Eye Centre.
Evisceration is one of destructive surgery of eye after which a patient loses his hope of restoration of sight forever. To identify the major causes of evisceration at a tertiary eye centre of Nepal. This is hospital based retrospective study of patients presented at Tilganga eye centre, Kathmandu, Nepal over a period of two years (10 Nov 2004 to 10 Nov 2006). Out of 2,31,976 total OPD patients, 71 patients who had evisceration with or without implant were selected and finally, only 67 patients record were enrolled for study as data were insufficient in the remaining records to fi ll up the study format. Data processing and analysis done using computer SPSS 11.5. A total of 67 cases, with age ranging from 1.5 years to 85 years, out of which 33 male and 34 were female. Evisceration was performed most commonly due to trauma and it's subsequent sequele in 37 cases (55.2% of total cases), who were within the age group of 30 - 59 years (p = 0.033) and predominantly male 25 cases(p = 0.001). Most of the patients presented from outside Kathmandu valley, with visual acuity of no perception of light. Evisceration without implant was most common surgical procedure, with trauma being the leading cause for it and most of the trauma was seen in active, potential and young male patients. So prevention of ocular injuries together with early treatment protocol is best way to decrease the rate of evisceration due to ocular trauma. To prevent ocular injuries news paper, television and health education may play an important role.


Toward a loss of functional diversity in stream fish assemblages under climate change.
The assessment of climate change impacts on biodiversity has so far been biased toward the taxonomic identification of the species likely either to benefit from climate modifications or to experience overall declines. There have still been few studies intended to correlate the characteristics of species to their sensitivity to climate change, even though it is now recognized that functional trait-based approaches are promising tools for addressing challenges related to global changes. In this study, two functional indices (originality and uniqueness) were first measured for 35 fish species occurring in French streams. They were then combined to projections of range shifts in response to climate change derived from species distribution models. We set out to investigate: (1) the relationship between the degrees of originality and uniqueness of fish species, and their projected response to future climate change; and (2) the consequences of individual responses of species for the functional diversity of fish assemblages. After accounting for phylogenetic relatedness among species, we have demonstrated that the two indices used measure two complementary facets of the position of fish species in a functional space. We have also rejected the hypothesis that the most original and/or less redundant species would necessarily experience the greatest declines in habitat suitability as a result of climate change. However, individual species range shifts could lead simultaneously both to a severe decline in the functional diversity of fish assemblages, and to an increase in the functional similarity among assemblages, supporting the hypothesis that disturbance favors communities with combination of common traits and biotic homogenization as well. Our findings therefore emphasize the importance of going beyond the simple taxonomic description of diversity to provide a better assessment of the likely future effects of environmental changes on biodiversity, thus helping to design more effective conservation and management measures.


Activation of cytotoxic activity of human blood lymphocytes by tumor-promoting compounds.
Three categories of tumor promoters and chemically related but inactive substances were tested for their effect on the cytotoxic activity of human blood lymphocytes against K562 and Daudi targets. Lymphocytes incubated overnight in the presence of phorbol esters 12-O-tetradecanoylphorbol-13-acetate and phorbol-12,13-dibutyrate [P(Bu)2] had enhanced function. Incubation with 4-alpha-phorbol-12,13-didecanoate was without effect. Enhancing activity was also exerted by the indole alkaloids, teleocidin and lyngbyatoxin A, and the polyacetates, aplysiatoxin and debromoaplysiatoxin, but not by dihydroteleocidin. Only the tumor-promoting compounds activated the cytotoxic potential. The substances acted in a dose-dependent manner with optimal activity at characteristic concentrations. Overnight incubation of lymphocytes at 4 degrees did not change their spontaneous cytotoxicity but abolished the enhancing effect of P(Bu)2. Thus, P(Bu)2-induced activation occurred only on metabolically active cells. The activation did not require DNA synthesis. Similar to controls, the P(Bu)2-treated cells required divalent cations and an intact cytoskeleton in order to perform their lytic function. Experiments with the various metabolic inhibitors indicate that phorbol ester treatment does not induce an alternative cytotoxic mechanism since, as with untreated lymphocytes, P(Bu)2-activated cells require contact with the target and intact secretory functions. The enhanced cytolytic potential was not due to induction of alpha-interferon (IFN-alpha) production, as shown by the fact that the effect was not abolished by addition of anti-IFN antibodies during the P(Bu)2 treatment of lymphocytes or during the cytotoxic assay. However, the presence of antiserum against IFN reduced the cytotoxic potential of control cells, suggesting that endogenous IFN production contributes to the maintenance of lytic function in cultured cells. If this mechanism is counteracted by addition of anti-IFN serum, the phorbol esters can provide an alternative activation signal. When P(Bu)2-activated lymphocytes were subsequently treated with IFN-alpha or IFN-gamma, their lytic capacity was further increased. These results indicate that P(Bu)2 and IFN activate cytotoxic potential through different pathways.


Cloning, DNA sequencing, and characterization of a nifD-homologous gene from the archaeon Methanosarcina barkeri 227 which resembles nifD1 from the eubacterium Clostridium pasteurianum.
L. Sibold, M. Henriquet, O. Possot, and J.-P. Aubert (Res. Microbiol. 142:5-12, 1991) cloned and sequenced two nifH-homologous open reading frames (ORFs) from Methanosarcina barkeri 227. Phylogenetic analysis of the deduced amino acid sequences of the nifH ORFs from M. barkeri showed that nifH1 clusters with nifH genes from alternative nitrogenases, while nifH2 clusters with nifH1 from the gram-positive eubacterium Clostridium pasteurianum. The N-terminal sequence of the purified nitrogenase component 2 (the nifH gene product) from M. barkeri was identical with that predicted for nifH2, and dot blot analysis of RNA transcripts indicated that nifH2 (and nifDK2) was expressed in M. barkeri when grown diazotrophically in Mo-containing medium. To obtain nifD2 from M. barkeri, a 4.7-kbp BamHI fragment of M. barkeri DNA was cloned which contained at least five ORFs, including nifH2, ORF105, and ORF125 (previously described by Sibold et al.), as well as nifD2 and part of nifK2. ORFnifD2 is 1,596 bp long and encodes 532 amino acid residues, while the nifK2 fragment is 135 bp long. The deduced amino acid sequences for nifD2 and the nifK2 fragment from M. barkeri cluster most closely with the corresponding nifDK1 gene products from C. pasteurianum. The predicted M. barkeri nifD2 product contains a 50-amino acid insert near the C terminus which has previously been found only in the clostridial nifD1 product. Previous biochemical and sequencing evidence indicates that the C. pasteurianum nitrogenase is the most divergent of known eubacterial Mo-nitrogenases, most likely representing a distinct nif gene family, which now also contains M. barkeri as a member. The similarity between the methanogen and clostridial nif sequences is especially intriguing in light of the recent findings of sequence similarities between gene products from archaea and from low-G+C gram-positive eubacteria for glutamate dehydrogenase, glutamine synthetase I, and heat shock protein 70. It is not clear whether this similarity is due to horizontal gene transfer or to the resemblance of the M. barkeri and C. pasteurianum nitrogenase sequences to an ancestral nitrogenase.


Comparison between the Effectiveness of Manual Acupuncture and Laser Acupuncture at EX-B3 Weiwanxiashu in a Rat Model of Type 2 Diabetes.
Diabetes mellitus (DM) is a chronic metabolic disease characterized by increased blood sugar levels. The current management of DM to date has a target of controlling blood glucose, but the therapy cannot be separated from long-term drug side effects. Acupuncture can be an option as an adjunct therapy for DM. The purpose of this study was to compare the effectiveness between manual acupuncture and laser acupuncture. This study was a randomized control experimental study with a pretest and posttest design using 24 male Sprague-Dawley rats divided into 4 groups: a normal group, a diabetes group, an acupuncture group, and a laser group. Manual acupuncture and laser acupuncture were performed 6 times in two weeks. Fasting blood glucose (FBG) levels, the cell density of Langerhans islets, and side effects were assessed and compared among the 4 groups. The highest mean cell density of Langerhans islets was found in the laser and acupuncture group, and the lowest was found in the diabetes group. In the post hoc analysis, the normal, acupuncture, and the laser groups had a significantly higher mean cell density than the diabetes group. The lowest mean FBG level was in the laser group, followed by the acupuncture group, and the highest was in the diabetes group, but this difference was not significant. There were no serious side effects from the use of manual acupuncture or laser acupuncture. Both manual acupuncture and laser acupuncture can improve the histological findings of Langerhans islets in type 2 diabetic rats, and both are safe to use.


[Description of the medical care of younger patients (<65 years) with colorectal cancer in Schleswig-Holstein--are diagnostics and therapy compliant with the actual S3-guidelines?].
The Guideline Colorectal Cancer has been existed since 1999. In 2004, a revision was published in form of the S3-guideline (number of the AWMF registry: 021/007). In this study we aimed to evaluate whether diagnostics and therapy of colorectal cancer of younger patients (<65 years) in Schleswig-Holstein (SH) were in accordance with the guideline or not. Therefore patients from a molecular genetic research project ("popgen") were asked to complete a questionnaire regarding their medical care. Data from the self-administered questionnaire and from the routine data set of the epidemiological cancer registry SH were available for 245 patients (mean age: 56.9 years; 48.6% were females). Nearly 54% of the patients had a tumour located in the colon and 42.9% in the rectum. Most patients (65.7%) experienced locally progressing tumours (T3/T4). Positive lymph nodes were diagnosed in 41% of the patients, distant metastases in less than 1%. About 88% had a coloscopy, 62.4% an X-ray of the lung, and 78.7% a sonography of the abdomen in the course of the preoperative diagnostics. Of all patients, 97.1% have been operated. An adjuvant radiation was received by 31.7% and adjuvant chemotherapy was given to 36.3% of the patients. In order to assess medical care, reference values were defined for specific phrasings from the S3-guideline (e.g., "always indicated": > 95%). According to the data from the patients' questionnaires and according to the S3-guideline, quality indicators of the preoperative diagnostics in SH were beneath the assumed reference values. But the data on therapy procedures indicated a good or at least satisfactory medical care.


Ceramic-metal composites for heat exchangers in concentrated solar power plants.
The efficiency of generating electricity from heat using concentrated solar power plants (which use mirrors or lenses to concentrate sunlight in order to drive heat engines, usually involving turbines) may be appreciably increased by operating with higher turbine inlet temperatures, but this would require improved heat exchanger materials. By operating turbines with inlet temperatures above 1,023 kelvin using closed-cycle high-pressure supercritical carbon dioxide (sCO2) recompression cycles, instead of using conventional (such as subcritical steam Rankine) cycles with inlet temperatures below 823 kelvin1-3, the relative heat-to-electricity conversion efficiency may be increased by more than 20 per cent. The resulting reduction in the cost of dispatchable electricity from concentrated solar power plants (coupled with thermal energy storage4-6) would be an important step towards direct competition with fossil-fuel-based plants and a large reduction in greenhouse gas emissions7. However, the inlet temperatures of closed-cycle high-pressure sCO2 turbine systems are limited8 by the thermomechanical performance of the compact, metal-alloy-based, printed-circuit-type heat exchangers used to transfer heat to sCO2. Here we present a robust composite of ceramic (zirconium carbide, ZrC) and the refractory metal tungsten (W) for use in printed-circuit-type heat exchangers at temperatures above 1,023 kelvin9. This composite has attractive high-temperature thermal, mechanical and chemical properties and can be processed in a cost-effective manner. We fabricated ZrC/W-based heat exchanger plates with tunable channel patterns by the shape-and-size-preserving chemical conversion of porous tungsten carbide plates. The dense ZrC/W-based composites exhibited failure strengths of over 350 megapascals at 1,073 kelvin, and thermal conductivity values two to three times greater than those of iron- or nickel-based alloys at this temperature. Corrosion resistance to sCO2 at 1,023 kelvin and 20 megapascals was achieved10 by bonding a copper layer to the composite surface and adding 50 parts per million carbon monoxide to sCO2. Techno-economic analyses indicate that ZrC/W-based heat exchangers can strongly outperform nickel-superalloy-based printed-circuit heat exchangers at lower cost.


Cofactor requirements and reconstitution of microcin B17 synthetase: a multienzyme complex that catalyzes the formation of oxazoles and thiazoles in the antibiotic microcin B17.
In the maturation of the Escherichia coli antibiotic Microcin B17 (MccB17), the McbA prepro-antibiotic is modified post-translationally by the multimeric microcin synthetase complex (composed of the McbB, -C, and -D proteins), which cyclizes four cysteines and four serines to thiazoles and oxazoles, respectively. Herein, we report the purification of individual subunits of MccB17 synthetase as fusions to maltose binding protein (MBP), and the in vitro reconstitution of heterocyclization activity. Preliminary characterization of each subunit reveals McbB to be a zinc-containing protein that may catalyze the initial cyclodehydration step, and McbC to contain flavin, consistent with an anticipated role for a dehydrogenase. We have previously demonstrated that McbD is a regulated ATPase/GTPase that may function as a conformational switch. Photolabeling experiments with the McbA propeptide now identify McbD as the initial site of substrate recognition. Heterocyclization activity was reconstituted only by combining all three subunits, demonstrating that each protein is required for heterocycle formation. Titration assays indicate that the subunits bind to each other with at least micromolar affinities, although McbD affords activity only after the MBP tag is proteolytically removed. Subunit competition assays with an McbDD147A mutant, which yields a catalytically deficient synthetase in vivo, show it to be defective in complex formation, whereas the McbBC181A/C184A double mutant, which is also inactive, competitively inhibits reconstitution by native McbB. Addition of the HtpG chaperone (originally shown to copurify with MccB17 synthetase), does not stimulate synthetase reconstitution or heterocyclization activity in vitro. A model for synthetase activity is proposed.


Human tooth culture: a study model for reparative dentinogenesis and direct pulp capping materials biocompatibility.
In a previous work, based on an in vitro entire tooth culture model of human immature third molars, we demonstrated that perivascular progenitor cells can proliferate and migrate to the injury site after pulp exposure. In this work, we investigated the differentiation of cells after direct capping with biomaterials classically used in restorative dentistry. Histological staining after direct pulp capping with Calcium Hydroxide XR(R) or MTA revealed early and progressive mineralized foci formation containing BrdU-labeled sequestered cells. The molecular characterization of the matrix and the sequestered cells by immunohistochemistry (Collagene type I, Dentin sialoprotein, and Nestin) clearly demonstrates that these areas share common characteristics of the mineralized matrix of reparative dentin formed by odontoblast-like cells. This reproduces some features of the pulp responses after applying these materials in vivo and demonstrates that the entire tooth culture model reproduces a part of the early steps of dentin regeneration in vivo. Its future development may be useful in studying the effects of biomaterials on this process.


[Treatment of patients with gastrointestinal stromal tumour with imatinib mesylate].
Gastrointestinal stromal tumour (GIST) is the most frequent mesenchymal tumour type of the digestive tract. Between 30 and 40% of patients have high-risk, malignant GIST with poor prognosis after surgery. Imatinib mesylate is a recently introduced KIT tyrosine kinase inhibitor with effect on metastatic GIST. We report our experience with imatinib mesylate in the treatment of GIST. Nine patients diagnosed with GIST have received imatinib mesylate since August 2001. Eight patients had metastatic disease, one patient received adjuvant treatment. The patients were evaluated according to standard protocols for clinical performance, effect of treatment, and adverse effects. Tumour tissue was analysed for mutational status in KIT and PDGFRA. All patients with metastatic disease had palliative benefit; three had partial response and the remaining stable disease. The single patient receiving adjuvant treatment had no sign of recurrence. Side effects were mainly mild diarrhoea, nausea and vomiting. Seven patients had mutations in KIT exon 11, one in KIT exon 9, and one in PDGFRA exon 12. The results demonstrate that imatinib mesylate is an effective drug that can stabilise and reduce disease in patients with advanced GIST.


Blood urea nitrogen is independently associated with renal outcomes in Japanese patients with stage 3-5 chronic kidney disease: a prospective observational study.
Blood urea nitrogen (BUN) is one of the substances that affects the calculated serum osmolality (cSosm). A previous study demonstrated that BUN and cSosm were independently associated with the development of chronic kidney disease (CKD) in patients with preserved kidney function. In advanced CKD stages, there is a concomitant increase in cSosm and BUN levels. However, it remains unclear whether BUN or cSosm levels are related to renal outcomes in patients with moderate to severe kidney dysfunction. The aim of this study was to clarify whether the BUN or cSosm level is associated with kidney disease progression in patients with advanced CKD. In this prospective study, we enrolled 459 patients with CKD (stages 3-5). The composite renal endpoint was end-stage renal disease (ESRD) or death, and ESRD alone was added as an alternative outcome. A Cox proportional hazards model was utilized to determine the risk factors for a poor renal outcome. We adjusted for covariates including estimated glomerular filtration rate (eGFR). The cSosm (mOsm/kg) was calculated using the following formula: (2 × sodium) + (BUN/2.8) + (glucose/18). During a median follow-up of 25.8 months, the renal endpoint was observed in 210 patients. Multivariable Cox analysis determined the hazard ratio (HR) [95% confidence interval (CI)] for the composite renal outcome in the second, third, and fourth BUN quartiles were 1.36 (0.72-2.58), 1.87 (0.95-3.66), and 2.66 (1.23-5.76) (P for trend < 0.01), respectively compared with the first BUN quartile. Conversely, by multivariable Cox analysis, the HRs (95% CIs) for poor outcomes in the second, third, and fourth cSosm quartiles, compared with the first cSosm quartile, were 1.13 (0.69-1.87), 0.95 (0.58-1.55), and 1.26 (0.78-2.03), respectively (P for trend = 0.39). In addition, with regard to the renal outcome of ESRD alone, higher BUN quartiles had a significantly increased risk for the outcome, but cSosm levels were not associated with the outcome. Higher BUN levels, but not cSosm levels, were associated with adverse renal outcomes independent of the eGFR, suggesting that BUN may be a useful marker for predicting kidney disease progression.


Placental site trophoblastic tumor presenting as subaponeurotic metastasis.
Cases of metastatic placental site trophoblastic tumor (PSTT) have a very poor prognosis because these tumors tend to be less sensitive to chemotherapy than other types of gestational trophoblastic disease. We describe the case of a 25-year-old woman who presented with occipital tumor and abnormal vaginal bleeding. Hysterectomy, bilateral salpingo-oophorectomy, and occipital tumor removal revealed a primary PSTT in the uterus, with ovarian and occipital subaponeurotic metastases. She received etoposide, methotrexate, actinomycin-D/cyclophosphamide, vincristine chemotherapy and had a complete clinical remission. Fifteen months later, she had a recurrent subaponeurotic occipital tumor invading the cranium and underwent tumor removal along with cranial bone followed by local irradiation. She was then treated with etoposide, cis-platinum/etoposide, methotrexate, actinomycin-D chemotherapy and again had a remission for 5 months. The patient, however, had a left parietal subaponeurotic tumor, invading the dura mater, and received local irradiation. Soon after, she developed left orbital bone metastasis, treated by local irradiation. These bone metastases responded to the radiation completely. However, multiple organ metastases were found, and she died of the disease. This represents the first case of PSTT with initial subaponeurotic metastasis in a living patient. New modalities of treatment for high-risk or metastatic PSTT need to be developed.


Cervicogenic Dizziness After Self-Manipulation of the Cervical Spine.
Patients with pre-existing cervical pathologies who experience dizziness and related neck pain are referred to as having cervicogenic dizziness. We describe a case of a 49-year-old female who presented with acute onset of vertigo and imbalance following self-manipulation of the cervical spine. Examination revealed a restricted cervical range of motion, muscle hypertonicity, and positive neurological signs. Radiographs demonstrated loss of normal cervical lordosis. The patient was diagnosed with cervicogenic dizziness and prescribed chiropractic treatments that included spinal manipulation, soft tissue release, and rehabilitative exercises. After four weeks of care, her symptoms had improved. At the six-month follow-up, the patient remained asymptomatic with a full cervical range of motion. This case highlights the risks associated with neck manipulation and the effectiveness of chiropractic treatment for cervicogenic dizziness. Patients should be counseled to seek evaluation and treatment from appropriate medical professionals for neck issues or dizziness/imbalance.


Do imagined and executed actions share the same neural substrate?
This paper addresses the issue of the functional correlates of motor imagery, using mental chronometry, monitoring the autonomic responses and measuring cerebral blood flow in humans. The timing of mentally simulated actions closely mimic actual movement times. Autonomic responses during motor imagery parallel the autonomic responses to actual exercise. Cerebral blood flow increases are observed in the motor cortices involved in the programming of actual movement (i.e. premotor cortex, anterior cingulate, inferior parietal lobule and cerebellum). These three sources of data provide converging support for the hypothesis that imagined and executed actions share, to some extent, the same central structures.


Promotion of Cyst Formation from a Renal Stem Cell Line Using Organ-Specific Extracellular Matrix Gel Format Culture System.
Researchers have long awaited the technology to develop an in vitro kidney model. Here, we establish a rapid fabricating technique for kidney-like tissues (cysts) using a combination of an organ-derived extracellular matrix (ECM) gel format culture system and a renal stem cell line (CHK-Q cells). CHK-Q cells, which are spontaneously immortalized from the renal stem cells of the Chinese hamster, formed renal cyst-like structures in a type-I collagen gel sandwich culture on day 1 of culture. The cysts fused together and expanded while maintaining three-dimensional structures. The expression of genes related to kidney development and maturation was increased compared with that in a traditional monolayer. Under the kidney-derived ECM (K-ECM) gel format culture system, cyst formation and maturation were induced rapidly. Gene expressions involved in cell polarities, especially for important material transporters (typical markers Slc5a1 and Kcnj1), were restored. K-ECM composition was an important trigger for CHK-Q cells to promote kidney-like tissue formation and maturation. We have established a renal cyst model which rapidly expressed mature kidney features via the combination of K-ECM gel format culture system and CHK-Q cells.


Interactions among morphotype, nutrition, and temperature impact fitness of an invasive fly.
Invasive animals depend on finding a balanced nutritional intake to colonize, survive, and reproduce in new environments. This can be especially challenging during situations of fluctuating cold temperatures and food scarcity, but phenotypic plasticity may offer an adaptive advantage during these periods. We examined how lifespan, fecundity, pre-oviposition periods, and body nutrient contents were affected by dietary protein and carbohydrate (P:C) ratios at variable low temperatures in two morphs (winter morphs WM and summer morphs SM) of an invasive fly, Drosophila suzukii. The experimental conditions simulated early spring after overwintering and autumn, crucial periods for survival. At lower temperatures, post-overwintering WM lived longer on carbohydrate-only diets and had higher fecundity on low-protein diets, but there was no difference in lifespan or fecundity among diets for SM. As temperatures increased, low-protein diets resulted in higher fecundity without compromising lifespan, while high-protein diets reduced lifespan and fecundity for both WM and SM. Both SM and WM receiving high-protein diets had lower sugar, lipid, and glycogen (but similar protein) body contents compared to flies receiving low-protein and carbohydrate-only diets. This suggests that flies spend energy excreting excess dietary protein, thereby affecting lifespan and fecundity. Despite having to recover from nutrient depletion after an overwintering period, WM exhibited longer lifespan and higher fecundity than SM in favorable diets and temperatures. WM exposed to favorable low-protein diet had higher body sugar, lipid, and protein body contents than SM, which is possibly linked to better performance. Although protein is essential for oogenesis, WM and SM flies receiving low-protein diets did not have shorter pre-oviposition periods compared to flies on carbohydrate-only diets. Finding adequate carbohydrate sources to compensate protein intake is essential for the successful persistence of D. suzukii WM and SM populations during suboptimal temperatures.


Near-complete de novo assembly of Tricholoma bakamatsutake chromosomes revealed the structural divergence and differentiation of Tricholoma genomes.
Tricholoma bakamatsutake, which is an edible ectomycorrhizal fungus associated with Fagaceae trees, may have diverged before the other species in Tricholoma section Caligata. We generated a highly contiguous whole-genome sequence for T. bakamatsutake SF-Tf05 isolated in an Oak (Quercus salicina) forest in Japan. The assembly of high-fidelity long reads, with a median read length of 12.3 kb, resulted in 13 chromosome-sized contigs comprising 142,068,211 bases with an average guanine and cytosine (GC) content of 43.94%. The 13 chromosomes were predicted to encode 11,060 genes. A contig (122,566 bases) presumably containing the whole circular mitochondrial genome was also recovered. The chromosome-wide comparison of T. bakamatsutake and Tricholoma matsutake (TMA_r1.0) indicated that the basic number of chromosomes (13) was conserved, but the structures of the corresponding chromosomes diverged, with multiple inversions and translocations. Gene conservation and cluster analyses revealed at least 3 phylogenetic clades in Tricholoma section Caligata. Specifically, all T. bakamatsutake strains belonged to the "bakamatsutake" clade, which is most proximal to the "caligatum" clade consisting of Tricholoma caligatum and Tricholoma fulvocastaneum. The constructed highly contiguous nearly telomere-to-telomere genome sequence of a T. bakamatsutake isolate will serve as a fundamental resource for future research on the evolution and differentiation of Tricholoma species.


Uncommon synchronous association between ovarian carcinoma and gastrointestinal stromal tumor: a case study and literature review.
The association of gastrointestinal stromal tumors (GIST) and other cancers is well known, but its synchronous occurrence with gynecological malignancies is very uncommon. Usually, the diagnosis is accidentally established. We describe a patient with GIST and concurrent ovarian cancer and discuss the clinical implications of this finding. A 64-year-old woman with a prior diagnosis of ovarian cancer developed a second recurrence after having undergone two operations and adjuvant chemotherapy. While tumor debulking was performed, a small, nonsuspicious lesion was removed from the greater curvature of the stomach. Histology revealed a GIST. The association of GIST and ovarian cancer is a rarity and its synchronicity may alter the oncological prognosis and therapy of the patient.


External validity of post-stroke interventional gait rehabilitation studies.
Gait rehabilitation is a major component of stroke rehabilitation, and is supported by extensive research. The objective of this review was to examine the external validity of intervention studies aimed at improving gait in individuals post-stroke. To that end, two aspects of these studies were assessed: subjects' exclusion criteria and the ecological validity of the intervention, as manifested by the intervention's technological complexity and delivery setting. Additionally, we examined whether the target population as inferred from the titles/abstracts is broader than the population actually represented by the reported samples. We systematically researched PubMed for intervention studies to improve gait post-stroke, working backwards from the beginning of 2014. Exclusion criteria, the technological complexity of the intervention (defined as either elaborate or simple), setting, and description of the target population in the titles/abstracts were recorded. Fifty-two studies were reviewed. The samples were exclusive, with recurrent stroke, co-morbidities, cognitive status, walking level, and residency being major reasons for exclusion. In one half of the studies, the intervention was elaborate. Descriptions of participants in the title/abstract in almost one half of the studies included only the diagnosis (stroke or comparable terms) and its stage (acute, subacute, and chronic). The external validity of a substantial number of intervention studies about rehabilitation of gait post-stroke appears to be limited by exclusivity of the samples as well as by deficiencies in ecological validity of the interventions. These limitations are not accurately reflected in the titles or abstracts of the studies.


The Association Between Rate and Severity of Exacerbations in Chronic Obstructive Pulmonary Disease: An Application of a Joint Frailty-Logistic Model.
Exacerbations are a hallmark of chronic obstructive pulmonary disease (COPD). Evidence suggests the presence of substantial between-individual variability (heterogeneity) in exacerbation rates. The question of whether individuals vary in their tendency towards experiencing severe (versus mild) exacerbations, or whether there is an association between exacerbation rate and severity, has not yet been studied. We used data from the MACRO Study, a 1-year randomized trial of the use of azithromycin for prevention of COPD exacerbations (United States and Canada, 2006-2010; n = 1,107, mean age = 65.2 years, 59.1% male). A parametric frailty model was combined with a logistic regression model, with bivariate random effects capturing heterogeneity in rate and severity. The average rate of exacerbation was 1.53 episodes/year, with 95% of subjects having a model-estimated rate of 0.47-4.22 episodes/year. The overall ratio of severe exacerbations to total exacerbations was 0.22, with 95% of subjects having a model-estimated ratio of 0.04-0.60. We did not confirm an association between exacerbation rate and severity (P = 0.099). A unified model, implemented in standard software, could estimate joint heterogeneity in COPD exacerbation rate and severity and can have applications in similar contexts where inference on event time and intensity is considered. We provide SAS code (SAS Institute, Inc., Cary, North Carolina) and a simulated data set to facilitate further uses of this method.


A scoping review to ascertain the parameters for an evidence synthesis of psychological interventions to improve work and wellbeing outcomes among employees with chronic pain.
Psychological interventions have mixed effects on improving employee outcomes, partly due to significant variability across studies and a lack of focus on mechanisms of action. This scoping review reports on the parameters of these interventions and examines intervention content to bring clarity to this heterogeneous topic area and direct future systematic review work. Six databases were searched (Cinahl, Cochrane, Embase, Medline, PsychINFO and Web of Science) from April 2010 to August 2020, and a grey literature search was undertaken. Screening was undertaken independently by two authors. The results summarised country, participant and employment characteristics, psychological interventions and work, health and wellbeing outcomes. 10% of the papers were analysed to determine the feasibility of coding intervention descriptions for theory and behaviour change technique (BCT) components. Database searches yielded 9341 titles, of which 91 studies were included. Most studies were conducted in Europe (78%) and included males and females (95%) ranging in age from 31-56.6 years although other demographic, and employment information was lacking. Musculoskeletal pain was common (87%). Psychological interventions commonly included cognitive behavioural therapy (30%) and education (28%). Most studies employed a randomised control trial design (64%). Over half contained a control group (54%). Interventions were delivered in mostly healthcare settings (72%) by health professionals. Multiple outcomes were often reported, many of which involved measuring sickness absence and return-to-work (62%) and pain and general health (53%). Within the feasibility analysis, most papers met the minimum criteria of containing one paragraph of intervention description, but none explicitly mentioned theory or BCTs. Psychological interventions for employees with chronic pain vary in their nature and implementation. We have shown scoping reviews can be used to assess the feasibility of applying tools from health psychology to identify the content of these interventions in future systematic review work to improve intervention development.


Performance of young calves fed soybean protein replacers.
In two 12-wk trials we evaluated soybean protein in calf milk replacers. In trial 1, twelve 5-day-old Holstein calves were allotted randomly to three milk replacers. The diets contained 26% crude protein. In trial 2, 18 calves were used and the diet contained 30% crude protein. In trial 1 period 1 (10 to 15 days), mean coefficients of apparent digestibility (%) for milk protein, soy protein concentrate, and full fat soy flour replacers were dry matter 92.0, 70.0, 71.0; protein 90.1, 56.6, 61.3; fat 88.9, 55.0, 53.2;; and ash 85.8, 62.5, 61.2. Average daily nitrogen retentions were 10.8, -1.24, and -.7 g. Results in period 2 (30 to 35 days) for digestibilities and nitrogen retention showed considerable improvement over those in period 1. In trial 2 period 1, mean coefficients of apparent digestibility (%) for milk protein, soy protein concentrate, and defatted soy flour replacers were dry matter 87.5, 66.6, 47.9; protein 80.5, 57.2, 28.5; fat 81.5, 55.9, 33.5; and ash 83.8, 58.9, 48.4. Average daily nitrogen retentions were 10.8, 2.9, and -3.6 g. Results in period 2 for digestibilities and nitrogen retention also showed considerable improvement. Calves are able to use soy based replacers more effectively with age.


De Novo Design of Peptidic Positive Allosteric Modulators Targeting TRPV1 with Analgesic Effects.
Transient receptor potential vanilloid 1 (TRPV1) ion channel is a nociceptor critically involved in pain sensation. Direct blockade of TRPV1 exhibits significant analgesic effects but also incurs severe side effects such as hyperthermia, causing failures of TRPV1 inhibitors in clinical trials. In order to selectively target TRPV1 channels that are actively involved in pain-sensing, peptidic positive allosteric modulators (PAMs) based on the high-resolution structure of the TRPV1 intracellular ankyrin-repeat like domain are de novo designed. The hotspot centric approach is optimized for protein design; its usage in Rosetta increases the success rate in protein binder design. It is demonstrated experimentally, with a combination of fluorescence resonance energy transfer (FRET) imaging, surface plasmon resonance, and patch-clamp recording, that the designed PAMs bind to TRPV1 with nanomolar affinity and allosterically enhance its response to ligand activation as it is designed. It is further demonstrated that the designed PAM exhibits long-lasting in vivo analgesic effects in rats without changing their body temperature, suggesting that they have potentials for developing into novel analgesics.


Collagen I promotes metastasis in pancreatic cancer by activating c-Jun NH(2)-terminal kinase 1 and up-regulating N-cadherin expression.
We have previously shown that N-cadherin expression is associated with tumor invasion, and that some cancer cells respond to specific extracellular matrix molecules by up-regulating N-cadherin. Pancreatic cancer is characterized by excessive deposition of type I collagen. Here, we show that human pancreatic cancer cells respond to collagen I, but not other matrices, by increasing motility and up-regulating mesenchymal markers, including N-cadherin. Both collagen I-mediated motility and metastasis in a mouse model for pancreatic cancer were inhibited by N-cadherin knockdown. Furthermore, inhibiting c-Jun NH(2)-terminal kinase (JNK) with chemical inhibitors or short hairpin RNA abrogated all collagen I-induced changes. We show that JNK1 is activated in response to collagen I, which increases tumorigenesis by up-regulating N-cadherin expression and by increasing motility.


Non-data-aided and universal cycle slip detection and correction for coherent communication systems.
We propose a simple non-data-aided (or unsupervised) and universal cycle slip detection and correction (CS-DC) technique based on locating the minimum of the sliding average of twice estimated phase noise. The CS-DC can be appended to any carrier phase estimation(CPE) technique and is modulation format independent. We analytically derive the probability density function of the CS detection metric and study how the sliding window length and detection threshold affects CS detection performance. Simulation results reveal significant cycle slips reduction for various modulation formats with a residual CS probability of 2 × 10-7 for single carrier system even in unrealistic highly nonlinear system setups. In addition, we show that a second stage of CS-DC with a different sliding window length can further reduce the cycle slip probability by at least an order of magnitude. We also show that CS-DC is tolerant to inter-channel nonlinearities and residue frequency offset effects. Overall, the proposed CS-DC technique can be used in conjunction to other CS reduction techniques to maximize the ability of CS mitigation in next generation optical transceivers.


Low rates of nucleoside reverse transcriptase inhibitor resistance in a well-monitored cohort in South Africa on antiretroviral therapy.
The emergence of complex HIV-1 drug resistance mutations has been linked to the duration of time patients are on a failing antiretroviral drug regimen. This study reports on resistance profiles in a closely monitored subtype C infected cohort. A total of 812 participants were enrolled into the CIPRA-SA 'safeguard the household' study, viral loads were determined at 12-weekly intervals for 96 weeks. Virological failure was defined as either a <1.5 log decrease in viral load at week 12 or two consecutive viral load measurements of >1,000 RNA copies/ml after week 24. Regimens prescribed were in line with the South African roll-out programme (stavudine, lamivudine, efavirenz or nevirapine). Viral RNA was extracted from patients with virological failure, and pol reverse-transcriptase PCR and sequence analysis were performed to determine drug-resistant mutations. Virological failure was observed in 83 participants on the first-line regimen during the study period, of which 61 (73%) had HIV-1 drug-resistant mutations. The M184V mutation was the most frequent (n=46; 65%), followed by K103N (46%) and Y181C (21%). Thymidine analogue mutations were infrequent (1%) and Q151M was not observed. Drug resistance profiles were less complex than has been previously reported in South Africa using the same antiretroviral drug regimens. These data suggest that frequent viral load monitoring limits the level and complexity of resistance observed in HIV-1 subtype C, preserving susceptibility to second-line options.


Restriction fragment analysis of the HLA class II region: application to tissue transplantation.
Southern blotting and hybridization with locus specific probes is a reliable method for the determination of HLA Class II specificities and in conjunction with several other techniques is providing valuable information on the nature of Class II polymorphisms in man. In terms of the identification of Class II specificities in transplantation however, the advanced nature of DR serology means that DR beta restriction fragment analysis is probably limited only to those situations where serological methods have been unsuccessful. Whether DQ and DP incompatibilities can evoke rejection responses in vivo remains to be fully ascertained although our preliminary data suggest that DQ mismatches probably have little effect upon graft outcome. Restriction fragment analysis is particularly attractive in that it enables reliable retrospective studies to be performed in conjunction with prolonged clinical follow up, and the technique will clearly continue to contribute significantly to our understanding of the importance of these molecules in transplantation.


Small Regulatory RNAs in the Enterobacterial Response to Envelope Damage and Oxidative Stress.
The ability of bacteria to thrive in diverse habitats and to adapt to ever-changing environmental conditions relies on the rapid and stringent modulation of gene expression. It has become evident in the past decade that small regulatory RNAs (sRNAs) are central components of networks controlling the bacterial responses to stress. Functioning at the posttranscriptional level, sRNAs base-pair with cognate mRNAs to alter translation, stability, or both to either repress or activate the targeted transcripts; the RNA chaperone Hfq participates in stabilizing sRNAs and in promoting pairing between target and sRNA. In particular, sRNAs act at the heart of crucial stress responses, including those dedicated to overcoming membrane damage and oxidative stress, discussed here. The bacterial cell envelope is the outermost protective barrier against the environment and thus is constantly monitored and remodeled. Here, we review the integration of sRNAs into the complex networks of several major envelope stress responses of Gram-negative bacteria, including the RpoE (σE), Cpx, and Rcs regulons. Oxidative stress, caused by bacterial respiratory activity or induced by toxic molecules, can lead to significant damage of cellular components. In Escherichia coli and related bacteria, sRNAs also contribute significantly to the function of the RpoS (σS)-dependent general stress response as well as the specific OxyR- and SoxR/S-mediated responses to oxidative damage. Their activities in gene regulation and crosstalk to other stress-induced regulons are highlighted.


The Role of Airway Inflammation and Bronchial Hyperresponsiveness in Athlete's Asthma.
Asthma is frequently reported in endurance athletes. The aim of the present study was to assess the long-term airway inflammatory response to endurance exercise in high-level athletes with and without asthma. In a cross-sectional design, 20 asthmatic athletes (10 swimmers and 10 cross-country skiers), 19 athletes without asthma (10 swimmers and 9 cross-country skiers), and 24 healthy nonathletes completed methacholine bronchial challenge, lung function tests, and sputum induction on two separate days. All athletes competed on a national or international level and exercised ≥10 h·wk. The nonathletes exercised ≤5 h·wk and reported no previous lung disease. Bronchial hyperresponsiveness (BHR) was defined as a methacholine provocation dose causing 20% decrease in the forced expiratory volume in 1 s of ≤8 μmol. BHR was present in 13 asthmatic athletes (62%), 11 healthy athletes (58%), and 8 healthy nonathletes (32%), and the prevalence differed among groups (P = 0.005). Sputum inflammatory and epithelial cell counts did not differ between groups and were within the normal range. Median (25th to 75th percentiles) sputum interleukin-8 was elevated in both asthmatic (378.4 [167.0-1123.4]) and healthy (340.2 [175.5-892.4]) athletes as compared with healthy nonathletes (216.6 [129.5-314.0], P = 0.02). No correlations were found between provocation dose causing 20% decrease and sputum cell counts. Independent of asthma diagnosis, a high occurrence of BHR and an increased sputum interleukin-8 were found in athletes as compared with nonathletes. Airway inflammation or epithelial damage was not related to BHR.


An inter-laboratory comparison demonstrates that [H]-NMR metabolite fingerprinting is a robust technique for collaborative plant metabolomic data collection.
In any metabolomics experiment, robustness and reproducibility of data collection is of vital importance. These become more important in collaborative studies where data is to be collected on multiple instruments. With minimisation of variance in sample preparation and instrument performance it is possible to elucidate even subtle differences in metabolite fingerprints due to genotype or biological treatment. In this paper we report on an inter laboratory comparison of plant derived samples by [(1)H]-NMR spectroscopy across five different sites and within those sites utilising instruments with different probes and magnetic field strengths of 9.4 T (400 MHz), 11.7 T (500 MHz) and 14.1 T (600 MHz). Whilst the focus of the study is on consistent data collection across laboratories, aspects of sample stability and the requirement for sample rotation within the NMR magnet are also discussed. Comparability of the datasets from participating laboratories was exceptionally good and the data were amenable to comparative analysis by multivariate statistics. Field strength differences can be adjusted for in the data pre-processing and multivariate analysis demonstrating that [(1)H]-NMR fingerprinting is the ideal technique for large scale plant metabolomics data collection requiring the participation of multiple laboratories.


Prospects for a complete molecular map of the human genome.
Linkage maps are limited by the number of recombinations that can be scored in human pedigrees to a resolution of ca. 1 centimorgan (relative distance between genes on a chromosome having a crossover value of 1%) which is estimated to be about 10 megabases. Molecular maps can be formed at any resolution down to the base sequence. To complement the linkage approach, the most useful molecular map would be one that helped to locate disease loci, by using restriction fragment length polymorphisms (RFLPS) and accurate localization of recombinations, and which then helped to find candidate genes in this region, by providing the positions of coding sequences. This paper discusses the appropriate form and scale of such a map, how it can be produced with methods now available, and the most efficient strategy for building the map, based on present knowledge of the organization of the human genome.


Cardiovascular disease and diabetes in people with severe mental illness position statement from the European Psychiatric Association (EPA), supported by the European Association for the Study of Diabetes (EASD) and the European Society of Cardiology (ESC).
People with severe mental illnesses, such as schizophrenia, depression or bipolar disorder, have worse physical health and reduced life expectancy compared to the general population. The excess cardiovascular mortality associated with schizophrenia and bipolar disorder is attributed in part to an increased risk of the modifiable coronary heart disease risk factors; obesity, smoking, diabetes, hypertension and dyslipidaemia. Antipsychotic medication and possibly other psychotropic medication like antidepressants can induce weight gain or worsen other metabolic cardiovascular risk factors. Patients may have limited access to general healthcare with less opportunity for cardiovascular risk screening and prevention than would be expected in a non-psychiatric population. The European Psychiatric Association (EPA), supported by the European Association for the Study of Diabetes (EASD) and the European Society of Cardiology (ESC) published this statement with the aim of improving the care of patients suffering from severe mental illness. The intention is to initiate cooperation and shared care between the different healthcare professionals and to increase the awareness of psychiatrists and primary care physicians caring for patients with severe mental illness to screen and treat cardiovascular risk factors and diabetes.


Using Serial and Discrete Digit Naming to Unravel Word Reading Processes.
During reading acquisition, word recognition is assumed to undergo a developmental shift from slow serial/sublexical processing of letter strings to fast parallel processing of whole word forms. This shift has been proposed to be detected by examining the size of the relationship between serial- and discrete-trial versions of word reading and rapid naming tasks. Specifically, a strong association between serial naming of symbols and single word reading suggests that words are processed serially, whereas a strong association between discrete naming of symbols and single word reading suggests that words are processed in parallel as wholes. In this study, 429 Grade 1, 3, and 5 English-speaking Canadian children were tested on serial and discrete digit naming and word reading. Across grades, single word reading was more strongly associated with discrete naming than with serial naming of digits, indicating that short high-frequency words are processed as whole units early in the development of reading ability in English. In contrast, serial naming was not a unique predictor of single word reading across grades, suggesting that within-word sequential processing was not required for the successful recognition for this set of words. Factor mixture analysis revealed that our participants could be clustered into two classes, namely beginning and more advanced readers. Serial naming uniquely predicted single word reading only among the first class of readers, indicating that novice readers rely on a serial strategy to decode words. Yet, a considerable proportion of Grade 1 students were assigned to the second class, evidently being able to process short high-frequency words as unitized symbols. We consider these findings together with those from previous studies to challenge the hypothesis of a binary distinction between serial/sublexical and parallel/lexical processing in word reading. We argue instead that sequential processing in word reading operates on a continuum, depending on the level of reading proficiency, the degree of orthographic transparency, and word-specific characteristics.


Elevated Secretion of Aldosterone Increases TG/HDL-C Ratio and Potentiates The Ox-LDL-Induced Dysfunction of HUVEC.
Atherosclerosis (AS) is one of the most common causes of human death and disability. This study is designed to investigate the roles of aldosterone (Aldo) and oxidized low-density lipoprotein (Ox-LDL) in this disease by clinical data and cell model. In this experimental study, clinical data were collected to investigate the Aldo role for the patients with primary aldosteronism or adrenal tumors. Cell viability assay, fluorescence-activated cell sorting (FACS) assay, apoptosis assay, cell aging analysis, and matrigel tube formation assay were performed to detect effects on human umbilical vein endothelial cells (HUVECs) treated with Aldo and/or Ox-LDL. Quantitative polymerase chain reaction (qPCR) and Western blot analysis were performed to figure out critical genes in the process of endothelial cells dysfunction induced by Aldo and/or Ox-LDL. We found that the Aldo level had a positive correlation with the TG/HDL-C ratio. Endothelial cell growth, angiogenesis, senescence, and apoptosis were significantly affected, and eNOS/Sirt1, the value of Bcl-2/Bax and Angiopoietin1/2 were significantly affected when cells were co-treated by Aldo and Ox-LDL. Elevated Aldo with high Ox-LDL together may accelerate the dysfunction of HUVEC, and the Ox-LDL, especially for those patients with high Aldo should be well controlled. The assessment of the role of Aldo may provide a theoretical basis for the effective prevention and investigation of a new treatment of AS.


Hemoglobinopathies: three illustrative case studies.
Three cases studies from the Regional Hemoglobinopathy Laboratory at St. Joseph's Hospital in Hamilton are presented. These cases demonstrate the diagnostic value of a comprehensive hemoglobinopathy screen, family studies, and appropriate clinical information in solving complex hemoglobinopathy problems. The first case is a 79-year-old woman found to have small amounts of an unknown hemoglobin migrating electrophoretically in the position of hemoglobin S. The second case describes a boy of Greek extraction with a thalassemic blood picture but otherwise normal hemoglobinopathy screen. The third case involves a 70-year-old man with a previously normal hemoglobinopathy screen who subsequently showed evidence of alpha thalassemia.


Treatment of Advanced Prostate Cancer.
The therapeutic landscape of prostate cancer has been transformed over the last decade by new therapeutics, advanced functional imaging, next-generation sequencing, and better use of existing therapies in early-stage disease. Until 2004, progression on androgen deprivation therapy for metastatic disease was treated with the addition of secondary hormonal manipulation; in the last decade, six systemic agents have been approved for the treatment of castration-resistant prostate cancer. We review clinical trials and survival benefit for these therapies and assess how the understanding of the disease shifted as these therapies were developed. We also discuss advances in noncastrate disease states, identification of biomarkers for prognosis and treatment selection, and opportunities in locoregional therapy to delay androgen deprivation therapy.


Hiatal hernia repair: prevention of mesh erosion and migration into the esophagogastric junction.
Erosion and migration into the esophagogastric lumen after laparoscopic hiatal hernia repair with mesh placement has been published. To present surgical maneuvers that seek to diminish the risk of this complication. We suggest mobilizing the hernia sac from the mediastinum and taking it down to the abdominal position with its blood supply intact in order to rotate it behind and around the abdominal esophagus. The purpose is to cover the on-lay mesh placed in "U" fashion to reinforce the crus suture. We have performed laparoscopic hiatal hernia repair in 173 patients (total group). Early postoperative complications were observed in 35 patients (27.1%) and one patient died (0.7%) due to a massive lung thromboembolism. One hundred twenty-nine patients were followed-up for a mean of 41+28months. Mesh placement was performed in 79 of these patients. The remnant sac was rotated behind the esophagus in order to cover the mesh surface. In this group, late complications were observed in five patients (2.9%). We have not observed mesh erosion or migration to the esophagogastric lumen. The proposed technique should be useful for preventing erosion and migration into the esophagus.


Effectiveness and safety of 30 mg versus 40 mg stavudine regimens: a cohort study among HIV-infected adults initiating HAART in South Africa.
As stavudine remains an important and widely prescribed drug in resource-limited settings, the effect of a reduced dose of stavudine (from 40 mg to 30 mg) on outcomes of highly active antiretroviral therapy (HAART) remains an important public health question. We analyzed prospectively collected data from the Themba Lethu Clinic in Johannesburg, South Africa. We assessed the relationship between stavudine dose and six- and/or 12-month outcomes of stavudine substitution, failure to suppress viral load to below 400 copies/ml, development of peripheral neuropathy, lipoatrophy and hyperlactatemia/lactic acidosis. Since individuals with a baseline weight of less than 60 kg were expected to have received the same dose of stavudine throughout the study period, analysis was restricted to individuals who weighed 60 kg or more at baseline. Data were analyzed using logistic regression. Between 1 April 2004 and 30 September 2009, 3910 patients were initiated on antiretroviral therapy (ART) with a recorded stavudine dose and were included in the analysis. Of these, 2445 (62.5%) received a 40 mg stavudine dose while 1565 (37.5%) received 30 mg. In multivariate analysis, patients receiving a 40 mg dose were more likely to discontinue stavudine use (adjusted odds ratio, OR 1.71; 95% confidence limits, CI 1.13-2.57) than those receiving 30 mg by 12 months on ART. Additionally, patients receiving 40 mg doses of stavudine were more likely to report peripheral neuropathy (OR 3.12; 95% CI 1.86-5.25), lipoatrophy (OR 11.8; 95% CI 3.2-43.8) and hyperlactatemia/lactic acidosis (OR 8.37; 95% CI 3.83-18.29) in the same time period. Failure to suppress HIV viral load within 12 months of HAART initiation was somewhat more common among those given 40 mg doses (OR 1.62; 95% CI 0.88, 2.97) although this result lacked precision. Sensitivity analyses accounting for death and loss to follow up generally supported these estimates. Lower stavudine dosage is associated with fewer reports of several stavudine-associated adverse events and also a lower risk of stavudine discontinuation within the first year on ART.


Effects of xylitol impregnated toothbrushes on periodontal status and microbial flora in orthodontic patients.
To investigate whether the use of xylitol-impregnated toothbrushes affects periodontal condition and microbial flora in orthodontic patients with poor oral hygiene. Forty-four patients with baseline mean Turesky plaque index scores ≥1.5 were randomly divided into two groups. Half received xylitol-containing toothbrushes and the other half, xylitol-free toothbrushes. The periodontal measurements and saliva samples were taken at baseline (T0), 1 month later (T1), and 3 months after brushing (T2) to evaluate periodontal health and microflora changes. Periodontal status was assessed with plaque index (PI), gingival index (GI), and bleeding on probing (BOP) scores. Data were statistically analyzed with Mann-Whitney U and Friedman tests. All periodontal parameters significantly decreased from T0 to T1 and from T0 to T2 in both groups. The PI and GI scores reduced significantly in the control group, while BOP scores reduced in both groups between T1 and T2. Intergroup comparisons showed significant differences for BOP, PI, and GI at T0, T1, and T2 times, respectively. For microbial parameters, there were no statistically significant differences within groups from T0 to T1. Total bacterial counts significantly decreased in the xylitol group between T1 and T2. Decreases in Streptococcus mutans and total bacteria were significant in both groups from T0 to T2. No significant differences were found between the groups in microbial flora at any time. A 3-month use of xylitol-containing toothbrushes showed almost the same changes and provided no positive effects on periodontal and microbial parameters compared to the control group.


Wear particle release at the interface of dental implant components: Effects of different material combinations. An in vitro study.
Particle generation from implant components caused by frictional wear affect the surrounding peri-implant tissues. The objective of this study was to evaluate the effect of combining implant and abutment materials on wear and particle release in a dynamical loading setup. A customized dynamical loading machine was used to subject two implant materials (Titanium and Titanium- Zirconium alloy) paired with two different abutment materials (Titanium and Zirconia) to a cyclic loading set of 240.000 cycles (simulating 1 year of clinical use). The implant and abutment complex was immersed in corrosive liquid to collect particle debris and measure the release of corroded ions. Scanning electron microscopy was used to analyze signs of wear on the components after testing and evaluate the size and composition of particle debris. Wear signs were evident in all material couplings. Particle debris was found on top, inside the implants, and on the abutment heads. The particle size ranged between 0.6 and 16.9 µm, with larger particles composed of Ti. Smaller-sized particles were found in the container liquid ranging from 0.253 to 1.7 µm compared to inside the implants ranging from 3.25 to 95.3 µm. Larger particles were found inside Tizr implants compared to Ti implants. Low levels of ions released due to corrosion were found when measuring content in surrounding liquid. Particle generation is evident when subjecting dental implant and abutment couplings in a dynamic loading setup. Internally connected implants hinder the release of larger particles to surrounding container liquid.


Osh proteins regulate COPII-mediated vesicular transport of ceramide from the endoplasmic reticulum in budding yeast.
Lipids synthesized at the endoplasmic reticulum (ER) are delivered to the Golgi by vesicular and non-vesicular pathways. ER-to-Golgi transport is crucial for maintaining the different membrane lipid composition and identities of organelles. Despite their importance, mechanisms regulating transport remain elusive. Here we report that in yeast coat protein complex II (COPII) vesicle-mediated transport of ceramide from the ER to the Golgi requires oxysterol-binding protein homologs, Osh proteins, which have been implicated in lipid homeostasis. Because Osh proteins are not required to transport proteins to the Golgi, these results indicate a specific requirement for the Osh proteins in the transport of ceramide. In addition, we provide evidence that Osh proteins play a negative role in COPII vesicle biogenesis. Together, our data suggest that ceramide transport and sphingolipid levels between the ER and Golgi are maintained by two distinct functions of Osh proteins, which negatively regulate COPII vesicle formation and positively control a later stage, presumably fusion of ceramide-enriched vesicles with Golgi compartments.


Reduction of sodium intake is a prerequisite for preventing and curing high blood pressure in hypertensive patients - second part: guidelines.
In the last decade many guidelines and report have been published about the optimal restriction of sodium intake for blood pressure control which deserve to be discussed in the medical community at large. The list includes i. the 2005 Dietary Guidelines of the Department of Health and Human Services and US Department of Agriculture; ii. The 2010 Dietary Guidelines for Americans; iii. The 2011 Presidential Statement of American Heart Association; iiii. The 2012 WHO guidelines on sodium intake in adults and children, v. The 2013 Report of the Institute of Medicine of the National Academies of the United States. All of them support the efficacy and feasibility of sodium restriction for blood pressure control.


Protection provided against the initial responses to cold immersion by a partial coverage wet suit.
The protection provided against the initial responses to cold water immersion by a partial coverage wet suit was assessed. Eighteen subjects performed three 2-min immersions into water at 5 degrees C. During each immersion, the subjects wore either: a) cotton overall, b) trunk and arms "wet" immersion suit, or c) "dry" immersion suit. Results showed that the dry suit provided significantly (p less than 0.05) greater protection against the initial cardiac and ventilatory responses to immersion than either the wet suit or cotton overall assemblies. The responses recorded in the wet suit were similar to, and in some cases did not differ from, the cotton overall. We conclude that immersion suit design and tests should consider all of the responses associated with accidental cold water immersion and not just those resulting in a fall in core temperature.


A 12,000-rad porcine radiation hybrid (IMNpRH2) panel refines the conserved synteny between SSC12 and HSA17.
Reverse or bidirectional Zoo-FISH suggests that synteny between porcine chromosome 12 (SSC12) and human chromosome 17 (HSA17) is completely conserved. The construction of a high-resolution radiation hybrid (RH) map for SSC12 provides a unique opportunity to determine whether chromosomal synteny is reflected at the molecular level by comparative gene mapping of SSC12 and HSA17. We report an initial, high-resolution RH map of SSC12 on the 12,000-rad IMNpRH2 panel using CarthaGene software. This map contains a total of 320 markers, including 20 microsatellites and 300 ESTs/genes, covering approximately 4836.9 cR12,000. The markers were ordered in 16 linkage groups at LOD 6.0 using framework markers previously mapped on the IMpRH7000-rad SSC12 and porcine genetic maps. Ten linkage groups ordered more than 10 markers, with the largest containing 101 STSs. The resolution of the current RH map is approximately 15.3 kb/cR on SSC12, a significant improvement over the second-generation EST SSC12 RH7000-rad map of 103 ESTs and 15 framework markers covering approximately 2287.2 cR7000. Compared to HSA17, six distinct segments were identified, revealing macro-rearrangements within the apparently complete synteny between SSC12 and HSA17. Further analysis of the order of 245 genes (ESTs) on HSA17 and SSC12 also revealed several micro-rearrangements within a synteny segment. A high-resolution SSC12 RH12,000-rad map will be useful in fine-mapping QTL and as a scaffold for sequencing this chromosome.


Development and evaluation of a simple calorimeter for the measurement of resting metabolism.
1. A simple calorimeter based on the measurement of oxygen uptake has been developed. 2. A respiratory simulator was used to evaluate oxygen uptake at different flow rates. A known concentration of mixed gases flows into the calorimeter via the respiratory simulator. Oxygen concentration and flow rate were measured and stored to memory for further analysis. 3. Results indicate that large errors occur at low flow rates, but that the error is less than 5% under normal conditions. 4. This device can be used to measure oxygen uptake under resting conditions.


Point-of-care ultrasonography in the allergy and immunology clinic.
To summarize evidence supporting the use of point-of-care ultrasonography as a clinical tool for allergists and immunologists. Cochrane Library, Medline, EMBASE, and Scopus databases were searched for articles published before December 18, 2018. We included any retrospective or prospective study that evaluated ultrasonography in allergy and immunology and epinephrine autoinjector (EAI) needle length. The standard EAI needle length may be inadequate for intramuscular delivery of epinephrine, particularly for women, at risk of anaphylaxis. In patients who weigh less than 15 kg, the lengths of commercially available EAIs may be too long, risking inadvertent intraosseous injection and resultant complications. Ultrasonography can be routinely used in the allergy clinic to guide needle length and angle for subcutaneous allergen immunotherapy injections to minimize systemic adverse effects. Point-of-care ultrasonography can be a useful tool to enhance patient care and safety in an allergy clinic. Ideally, all patients prescribed EAIs should have ultrasonographic measurement of the skin to muscle distance and skin to bone distance to assist in identifying patients at risk of subcutaneous or intraosseous injection in anaphylaxis and those at risk of intramuscular injection during subcutaneous allergen immunotherapy injections.


Strategies to Integrate Genomic Medicine into Clinical Care: Evidence from the IGNITE Network.
The complexity of genomic medicine can be streamlined by implementing some form of clinical decision support (CDS) to guide clinicians in how to use and interpret personalized data; however, it is not yet clear which strategies are best suited for this purpose. In this study, we used implementation science to identify common strategies for applying provider-based CDS interventions across six genomic medicine clinical research projects funded by an NIH consortium. Each project's strategies were elicited via a structured survey derived from a typology of implementation strategies, the Expert Recommendations for Implementing Change (ERIC), and follow-up interviews guided by both implementation strategy reporting criteria and a planning framework, RE-AIM, to obtain more detail about implementation strategies and desired outcomes. We found that, on average, the three pharmacogenomics implementation projects used more strategies than the disease-focused projects. Overall, projects had four implementation strategies in common; however, operationalization of each differed in accordance with each study's implementation outcomes. These four common strategies may be important for precision medicine program implementation, and pharmacogenomics may require more integration into clinical care. Understanding how and why these strategies were successfully employed could be useful for others implementing genomic or precision medicine programs in different contexts.


Two distinct types of blood vessels in clear cell renal cell carcinoma have contrasting prognostic implications.
Intratumoral microvascular density (MVD) has been controversial as an indicator of prognosis in clear cell renal cell carcinoma (CCRCC). Classification of the intratumoral blood vessels based on differential expressions of blood vessel markers has not been correlated with patient prognosis in CCRCC. In this study, we aimed to evaluate the association of different categories of blood vessels with the patients' outcomes. Seventy-eight CCRCC patients who underwent nephrectomy alone were enrolled. Paraffin-embedded CCRCC tissues, together with 16 nonmalignant kidney cortex tissues, were used in tissue microarray analyses and conventional section analyses. The characteristics of intratumoral blood vessels were identified by multiple blood vessel markers and pericyte markers. A computerized image analysis program was used to quantitatively calculate the vascular density. Two distinct types of microvessels were identified in CCRCC: undifferentiated (CD31(+)/CD34(-)) and differentiated (CD34(+)) vessels. A higher undifferentiated MVD significantly correlated with higher tumor grades and shorter patient survival. In contrast, a higher differentiated MVD significantly correlated with lower tumor grade and longer survival. Multivariate analyses showed that undifferentiated MVD was an independent prognostic factor for patient survival. An inverse correlation between undifferentiated MVD and differentiated MVD was also identified in CCRCC. This is the first report showing distinct types of vasculature in CCRCC correlated with contrasting prognoses. A refined classification of CCRCC based on vasculature is therefore important for evaluating prognosis, and it may also have therapeutic implications.


Changes in Gas Composition during Low Flow Anaesthesia without Nitrous Oxide.
Low flow anaesthesia utilising Oxygen (O2) and Nitrous Oxide (N2O) mixture carries a risk of hypoxia, but avoiding N2O results in increased analgesic and volatile anaesthetic agent requirement. This study attempted to find the lowest Fraction of inspired Oxygen (FiO2) levels achieved with a mixture of 300 mL/min each of O2 and medical air over two hours and to compare the overall analgesic requirement and cost while using similar flows of N2O and O2, respectively. A prospective observational study was conducted between March 2015 and June 2016 at the Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India. Patients of American Society of Anaesthesiologists (ASA) Grade 1 and 2 undergoing surgery under general anaesthesia with an endotracheal tube were included in the study, in two groups of 40 each. In the initial ten minutes following induction of anaesthesia, both groups received high Fresh Gas Flows (FGF) of 3 L/min each (Group O: medical air and oxygen; Group N: N2O and oxygen), following which the FGF rates were reduced to 300 ml/min each. Any value of FiO2 lesser than 0.3 during the duration of anaesthesia was considered to render the technique unsafe for clinical use. SPSS software version 20.0 was used to generate data and figures. The lowest FiO2 recorded was 0.33 in Group O and 0.3 in Group N which occurred at the end of two hours. Mean analgesic requirement was significantly higher in Group O compared to Group N (151.85 μg, 124.85 μg; p-value=0.004) with a 62% increase in the cost incurred. The use of medical air and oxygen in flows of 300 ml/min each following initial high flows of 3 L/min appears to be a safe technique. However, this combination was associated with an increase in the cost of anaesthesia and in the need for additional intra-operative analgesia.


Regional differences between people who inject drugs in an HIV prevention trial integrating treatment and prevention (HPTN 074): a baseline analysis.
People who inject drugs (PWID) experience high HIV incidence and face significant barriers to engagement in HIV care and substance use treatment. Strategies for HIV treatment as prevention and substance use treatment present unique challenges in PWID that may vary regionally. Understanding differences in the risk structure for HIV transmission and disease progression among PWID is essential in developing and effectively targeting intervention strategies of HIV treatment as prevention. We present a baseline analysis of HIV Prevention Trials Network (HPTN) 074, a two-arm, randomized controlled trial among PWID in Indonesia (n = 258), Ukraine (n = 457) and Vietnam (n = 439). HPTN 074 was designed to determine the feasibility, barriers and uptake of an integrated intervention combining health systems navigation and psychosocial counselling for the early engagement of antiretroviral therapy (ART) and substance use treatment for PWID living with HIV. Discordant PWID networks were enrolled, consisting of an HIV-positive index and their HIV-negative network injection partner(s). Among the enrolled cohort of 1154 participants (502 index participants and 652 network partners), we examine regional differences in the baseline risk structure, including sociodemographics, HIV and substance use treatment history, and injection and sexual risk behaviours. The majority of participants were male (87%), with 82% of the enrolled females coming from Ukraine. The overall mean age was 34 (IQR: 30, 38). Most commonly injected substances included illegally manufactured methadone in Ukraine (84.2%), and heroin in Indonesia (81.8%) and Vietnam (99.5%). Injection network sizes varied by region: median number of people with whom participants self-reported injecting drugs was 3 (IQR: 2, 5) in Indonesia, 5 (IQR: 3, 10) in Ukraine and 3 (IQR: 2, 4) in Vietnam. Hazardous alcohol use, assessed using the Alcohol Use Disorders Identification Test - Alcohol Consumption Questions (AUDIT-C), was prominent in Ukraine (54.7%) and Vietnam (26.4%). Reported sexual risk behaviours in the past month, including having two or more sex partners and giving/receiving money or drugs in exchange for sex, were uncommon among all participants and regions. While regional differences in risk structure exist, PWID particularly in Ukraine need immediate attention for risk reduction strategies. Substantial regional differences in risk structure will require flexible, tailored treatment as prevention interventions for distinct PWID populations.


Serum and Gingival Fluid Antibodies as Adjuncts in the Diagnosis of Actinobacillus actinomycetemcomitans Associated Periodontal Disease.
Serum antibody titers to Actinobacillus actinomycetemcomitans were measured in 200 subjects by an enzyme-lined immunosorbent assay (ELISA) using whole microorganisms as antigen. Comparisons were made between titers found in periodontally normal subjects and titers in subjects with localized juvenile periodontitis (LJP), postlocalized juvenile periodontitis, generalized juvenile periodontitis or adult periodontitis. It was found that titers to all three serotypes of A. actinomycetemcomitans were elevated in LJP patients' sera, while serum antibody levels in other diseased groups were not significantly elevated to any of the serotypes. Patient sera were also examined for serum antibody to oral Haemophili previously shown to cross-react with A. actinomycetemcomitans. Similar antibody titers were found in both normal subjects and in patients with various forms of periodontal disease to Haemophilus aphrophilus, H. influenzae and H. parainfluenzae. The A. actinomycetemcomitans antibodies which were elevated in LJP patients could not be correlated with antibody titers to cross-reacting Haemophili, suggesting that these antibodies are A. actinomycetemcomitansspecific. Serum antibody responses in six of the LJP patients were assessed to autologous strains of A. actinomycetemcomitans. Each patient was found to be infected with only a single serotype of A. actinomycetemcomitans, and specific antibodies to the infecting serotype were found in the patients' sera. In families, the LJP patients had significantly elevated IgG, IgA and IgM serum antibody titers to A actinomycetemcomitans, while the IgG and IgA antibody titers in periodontally normal siblings were at levels comparable to those found in normal subjects. However, IgM serum antibodies were elevated in the periodontally normal siblings of LJP patients suggesting that the formation of IgM antibodies to A. actinomycetemcomitans may precede the clinical appearance of localized juvenile periodontitis. Gingival crevicular fluid and serum antibody levels to A. actinomycetemcomitans were compared in LJP patients. Comparable titers of IgG, IgA and IgM antibodies were found in serum and gingival fluid in most subjects; however, gingival fluid samples sometimes showed higher titers than serum, likely resulting from local antibody synthesis. The value of serum antibody determinations to A. actinomycetemcomitans in the diagnosis of Actinobacillus-associated periodontitis was also assessed. The predictive value of a positive test (significantly elevated anti-A actinomycetemcomitans IgG) was 86%, while the specificity was 89%. These results suggest that the measurement of serum or gingival crevicular fluid antibodies to A. actinomycetemcomitans may be valuable in the diagnosis of Actinobacillusassociated periodontal disease.


Role of expressive behaviour for robots that learn from people.
Robotics has traditionally focused on developing intelligent machines that can manipulate and interact with objects. The promise of personal robots, however, challenges researchers to develop socially intelligent robots that can collaborate with people to do things. In the future, robots are envisioned to assist people with a wide range of activities such as domestic chores, helping elders to live independently longer, serving a therapeutic role to help children with autism, assisting people undergoing physical rehabilitation and much more. Many of these activities shall require robots to learn new tasks, skills and individual preferences while 'on the job' from people with little expertise in the underlying technology. This paper identifies four key challenges in developing social robots that can learn from natural interpersonal interaction. The author highlights the important role that expressive behaviour plays in this process, drawing on examples from the past 8 years of her research group, the Personal Robots Group at the MIT Media Lab.


[Churg-Strauss syndrome: diagnostic and therapeutic challenge - a case report].
This report describes the Churg-Strauss syndrome (CSS) in a 23-year-old asthmatic man treated with a leukotriene antagonists-montelukast. The Churg-Strauss syndrome is now defined as one of the ANCA-associated vasculitis and is characterised by eosinophilia, asthma, chronic sinusitis, cardiomyopathy, pulmonary infiltrates, cutaneous vasculitis, gastrointestinal complaints and a muliplex neuropathy. The pathogenesis is not clear, but it has been reported in patients treated with leukotriene antagonists. We describe a case of CSS with severe pulmonary and cardiovascular complications.


Indoor radon measurements in the New York Capital District.
Radon-222 concentrations have been measured in 21 "energy-efficient" homes and 14 conventional homes in the New York Capital District. Usual concentrations are averaged over six-month or 12-month periods using solid-state track detectors. Full-year averages are available for 23 of the homes, and the winter-to-summer variations have been observed. In a number of cases, 222Rn emanations from various construction materials and soil samples have been measured and correlations sought with indoor 222Rn. Two major patterns emerge. The living areas of the energy-efficient homes without heat-storage masses have median radon concentrations that are 1.6 times those for conventional homes, and the energy-efficient homes with heat-storage masses have four to five times the 222Rn of conventional homes.


Stimulation of neuropeptide Y gene expression by brain-derived neurotrophic factor requires both the phospholipase Cgamma and Shc binding sites on its receptor, TrkB.
In PC12 cells, it has been previously reported that nerve growth factor stimulates neuropeptide Y (NPY) gene expression. In the current study we examined the signalling pathways involved in this effect by transiently expressing in PC12 cells the receptor (TrkB) for the related neurotrophin, brain-derived neurotrophic factor (BDNF). BDNF caused a 3-fold induction of luciferase expression from a transiently co-transfected plasmid possessing the firefly luciferase gene under the control of the NPY promoter. This effect of BDNF was completely blocked by either a Y484F mutation in TrkB (which blocks high-affinity Shc binding to TrkB) or by a Y785F substitution [which blocks the binding, phosphorylation and activation of phospholipase Cgamma (PLCgamma)]. Activation of the NPY promoter by neurotrophin-3 in PC12 cells overexpressing TrkC was also completely blocked by a naturally occurring kinase insert which prevents the high-affinity binding of Shc and PLCgamma. NPY promoter activation by BDNF was blocked by PD98059, suggesting a role for mitogen-activated protein kinase (MAP kinase). Stimulation of NPY gene expression by PMA, but not by BDNF, was blocked by Ro-31-8220, a protein kinase C inhibitor, excluding a role for this serine/threonine protein kinase in the effect of BDNF. In addition, BDNF did not cause an elevation in cytosolic Ca2+ concentration. Taken together, our results suggest that stimulation of the NPY promoter by BDNF requires the simultaneous activation of two distinct pathways; one involves Shc and MAP kinase, and the other appears to be PLCgamma-independent but requires an intact tyrosine-785 on TrkB and so may involve an effector of TrkB signalling that remains to be identified.


Building and implementing an institutional registry for a data-driven national neurosurgical practice: experience from a multisite medical center.
In an era when healthcare "value" remains a much-emphasized concept, measuring and reporting the quality of neurosurgical care and costs remains a challenge for large multisite health systems. Ensuring cohesion in outcomes across multiple sites is important to the development of a holistic competitive marketing strategy that seeks to promote "brand" performance characterized by a superior quality of patient care. This requires mechanisms for data collection and development of a single uniform outcomes measurement system site wide. Operationalizing a true multidisciplinary effort in this space requires intersection of a vast array of information technology and administrative resources along with the neurosurgeons who provide subject-matter expertise relevant to patient care. To measure neurosurgical quality and safety as well as improve payor contract negotiations, a practice analytics dashboard was created to allow summary visualization of operational indicators such as case volumes, quality outcomes, and relative value units and financial indicators such as total hospital costs and charges in order to provide a comprehensive overview of the "value" of surgical care. The current version of the dashboard summarizes these metrics by site, surgeon, and procedure for nearly 30,000 neurosurgical procedures that have been logged into the Mayo Clinic Enterprise Neurosurgery Registry since transition to the Epic electronic health record (EHR) system. In this article, the authors sought to review their experience in launching this EHR-linked data-driven neurosurgical practice initiative across a large, national multisite academic medical center.


Topological correlations of structural and functional networks in patients with traumatic brain injury.
Despite an increasing amount of specific correlation studies between structural and functional connectivity, there is still a need for combined studies, especially in pathological conditions. Impairments of brain white matter (WM) and diffuse axonal injuries are commonly suspected to be responsible for the disconnection hypothesis in traumatic brain injury (TBI) patients. Moreover, our previous research on TBI patients shows a strong relationship between abnormalities in topological organization of brain networks and behavioral deficits. In this study, we combined task-related functional connectivity (using event-related fMRI) with structural connectivity (derived from fiber tractography using diffusion MRI data) estimates in the same participants (17 adults with TBI and 16 controls), allowing for direct comparison between graph metrics of the different imaging modalities. Connectivity matrices were computed covering the switching motor network, which includes the basal ganglia, anterior cingulate cortex/supplementary motor area, and anterior insula/inferior frontal gyrus. The edges constituting this network consisted of the partial correlations between the fMRI time series from each node of the switching motor network. The interregional anatomical connections between the switching-related areas were determined using the fiber tractography results. We found that graph metrics and hubs obtained showed no agreement in both groups. The topological properties of brain functional networks could not be solely accounted for by the properties of the underlying structural networks. However, combining complementary information from both imaging modalities could improve accuracy in prediction of switching performance. Direct comparison between functional task-related and anatomical structural connectivity, presented here for the first time in TBI patients, links two powerful approaches to map the patterns of brain connectivity that may underlie behavioral deficits in brain-injured patients.


The Arousal-motor Hypothesis of Dopamine Function: Evidence that Dopamine Facilitates Reward Seeking in Part by Maintaining Arousal.
Dopamine facilitates approach to reward via its actions on dopamine receptors in the nucleus accumbens. For example, blocking either D1 or D2 dopamine receptors in the accumbens reduces the proportion of reward-predictive cues to which rats respond with cued approach. Recent evidence indicates that accumbens dopamine also promotes wakefulness and arousal, but the relationship between dopamine's roles in arousal and reward seeking remains unexplored. Here, we show that the ability of systemic or intra-accumbens injections of the D1 antagonist SCH23390 to reduce cued approach to reward depends on the animal's state of arousal. Handling the animal, a manipulation known to increase arousal, was sufficient to reverse the behavioral effects of the antagonist. In addition, SCH23390 reduced spontaneous locomotion and increased time spent in sleep postures, both consistent with reduced arousal, but also increased time spent immobile in postures inconsistent with sleep. In contrast, the ability of the D2 antagonist haloperidol to reduce cued approach was not reversible by handling. Haloperidol reduced spontaneous locomotion but did not increase sleep postures, instead increasing immobility in non-sleep postures. We place these results in the context of the extensive literature on dopamine's contributions to behavior, and propose the arousal-motor hypothesis. This novel synthesis, which proposes that two main functions of dopamine are to promote arousal and facilitate motor behavior, accounts both for our findings and many previous behavioral observations that have led to disparate and conflicting conclusions.


Nonrandom factors in modern human morphological diversification: a study of craniofacial variation in southern South american populations.
The causes of craniofacial variation among human populations have been the subject of controversy. In this work, we studied aboriginal populations from southern South America, the last continental region peopled by humans and with a wide range of ecological conditions. Because of these characteristics, southern South America provides a unique opportunity to study the relative importance of random and nonrandom factors in human diversification. Previous craniometric studies recognized remarkable differences among populations from this region, usually resorting to random factors as the main explanation. In contrast, here we suggest, using tests based on quantitative genetic models, that: (1) the rate of craniofacial divergence among these populations is too high and (2) the patterns of variation within and between populations are too different to be explained by genetic drift alone. In addition, the among-sample craniofacial variation is correlated with climate and diet but not with mtDNA variation. We suggest that the influence of nonrandom factors (e.g., plasticity, selection) on human craniofacial diversification in regions with large ecological variation is more important than generally acknowledged and capable to generate large craniofacial divergence in a short period of time. These results bring nonrandom factors into focus for the interpretation of human craniofacial variation.


Roles for APIS and the 20S proteasome in adenovirus E1A-dependent transcription.
We have determined distinct roles for different proteasome complexes in adenovirus (Ad) E1A-dependent transcription. We show that the 19S ATPase, S8, as a component of 19S ATPase proteins independent of 20S (APIS), binds specifically to the E1A transactivation domain, conserved region 3 (CR3). Recruitment of APIS to CR3 enhances the ability of E1A to stimulate transcription from viral early gene promoters during Ad infection of human cells. The ability of CR3 to stimulate transcription in yeast is similarly dependent on the functional integrity of yeast APIS components, Sug1 and Sug2. The 20S proteasome is also recruited to CR3 independently of APIS and the 26S proteasome. Chromatin immunoprecipitation reveals that E1A, S8 and the 20S proteasome are recruited to both Ad early region gene promoters and early region gene sequences during Ad infection, suggesting their requirement in both transcriptional initiation and elongation. We also demonstrate that E1A CR3 transactivation and degradation sequences functionally overlap and that proteasome inhibitors repress E1A transcription. Taken together, these data demonstrate distinct roles for APIS and the 20S proteasome in E1A-dependent transactivation.


Temporal weighting of binaural information at low frequencies: Discrimination of dynamic interaural time and level differences.
The importance of sound onsets in binaural hearing has been addressed in many studies, particularly at high frequencies, where the onset of the envelope may carry much of the useful binaural information. Some studies suggest that sound onsets might play a similar role in the processing of binaural cues [e.g., fine-structure interaural time differences (ITD)] at low frequencies. This study measured listeners' sensitivity to ITD and interaural level differences (ILD) present in early (i.e., onset) and late parts of 80-ms pure tones of 250-, 500-, and 1000-Hz frequency. Following previous studies, tones carried static interaural cues or dynamic cues that peaked at sound onset and diminished to zero at sound offset or vice versa. Although better thresholds were observed in static than dynamic conditions overall, ITD discrimination was especially impaired, regardless of frequency, when cues were not available at sound onset. Results for ILD followed a similar pattern at 1000 Hz; at lower frequencies, ILD thresholds did not differ significantly between dynamic-cue conditions. The results support the "onset" hypothesis of Houtgast and Plomp [(1968). J. Acoust. Soc. Am. 44, 807-812] for ITD discrimination, but not necessarily ILD discrimination, in low-frequency pure tones.