A prospective cohort study of acute kidney injury and kidney outcomes, cardiovascular events, and death.
Acute kidney injury (AKI) has been reported to be associated with excess risks of death, kidney disease progression and cardiovascular events although previous studies have important limitations. To further examine this, we prospectively studied adults from four clinical centers surviving three months and more after hospitalization with or without AKI who were matched on center, pre-admission CKD status, and an integrated priority score based on age, prior cardiovascular disease or diabetes mellitus, preadmission estimated glomerular filtration rate (eGFR) and treatment in the intensive care unit during the index hospitalization between December 2009-February 2015, with follow-up through November 2018. All participants had assessments of kidney function before (eGFR) and at three months and annually (eGFR and proteinuria) after the index hospitalization. Associations of AKI with outcomes were examined after accounting for pre-admission and three-month post-discharge factors. Among 769 AKI (73% Stage 1, 14% Stage 2, 13% Stage 3) and 769 matched non-AKI adults, AKI was associated with higher adjusted rates of incident CKD (adjusted hazard ratio 3.98, 95% confidence interval 2.51-6.31), CKD progression (2.37,1.28-4.39), heart failure events (1.68, 1.22-2.31) and all-cause death (1.78, 1.24-2.56). AKI was not associated with major atherosclerotic cardiovascular events in multivariable analysis (0.95, 0.70-1.28). After accounting for degree of kidney function recovery and proteinuria at three months after discharge, the associations of AKI with heart failure (1.13, 0.80-1.61) and death (1.29, 0.84-1.98) were attenuated and no longer significant. Thus, assessing kidney function recovery and proteinuria status three months after AKI provides important prognostic information for long-term clinical outcomes.


Increased fat oxidation and regulation of metabolic genes with ultraendurance exercise.
Regular endurance exercise stimulates muscle metabolic capacity, but effects of very prolonged endurance exercise are largely unknown. This study examined muscle substrate availability and utilization during prolonged endurance exercise, and associated metabolic genes. Data were obtained from 11 competitors of a 4- to 5-day, almost continuous ultraendurance race (seven males, four females; age: 36 +/- 11 years; cycling Vo(2peak): males 57.4 +/- 5.9, females 48.1 +/- 4.0 mL kg(-1) min(-1)). Before and after the race muscle biopsies were obtained from vastus lateralis, respiratory gases were sampled during cycling at 25 and 50% peak aerobic power output, venous samples were obtained, and fat mass was estimated by bioimpedance under standardized conditions. After the race fat mass was decreased by 1.6 +/- 0.4 kg (11%; P < 0.01). Respiratory exchange ratio at the 25 and 50% workloads decreased (P < 0.01) from 0.83 +/- 0.06 and 0.93 +/- 0.03 before, to 0.71 +/- 0.01 and 0.85 +/- 0.02, respectively, after the race. Plasma fatty acids were 3.5 times higher (from 298 +/- 74 to 1407 +/- 118 micromol L(-1); P < 0.01). Muscle glycogen content fell 50% (from 554 +/- 28 to 270 +/- 25 nmol kg(-1) d.w.; n = 7, P < 0.01), whereas the decline in muscle triacylglycerol (from 32 +/- 5 to 22 +/- 3 mmol kg(-1) d.w.; P = 0.14) was not statistically significant. After the race, muscle mRNA content of lipoprotein lipase and glycogen synthase increased (P < 0.05) 3.9- and 1.7-fold, respectively, while forkhead homolog in rhabdomyosarcoma, pyruvate dehydrogenase kinase 4 and vascular endothelial growth factor mRNA tended (P < 0.10) to be higher, whereas muscle peroxisome proliferator-activated receptor gamma co-activator-1beta mRNA tended to be lower (P = 0.06). Very prolonged exercise markedly increases plasma fatty acid availability and fat utilization during exercise. Exercise-induced regulation of genes encoding proteins involved in fatty acid recruitment and oxidation may contribute to these changes.


High yield fabrication of low threshold single-mode GaAs/AlGaAs semiconductor ring lasers using metallic etch masks.
We demonstrate a novel high yield fabrication process for single-mode ridge-waveguide GaAs/AlGaAs ring lasers with significantly lower threshold currents than previously reported for similar devices. In this fabrication process, the ridge waveguide structure is patterned using a metallic etch mask, which survives ensuing fabrication steps to form a continuous metallic cover over the entire resonator structure. This metallic cover improves the uniformity of electrical contact between the resonator structure and the metallic biasing layer deposited at the conclusion of the fabrication process. This leads to optimum electrical pumping of the fabricated devices. This fabrication process also allows for the passivation of the ridge-waveguide device sidewalls and separation of the metallic biasing layer from the optical mode.


Synthesis of Bioinspired Carbohydrate Amphiphiles that Promote and Inhibit Biofilms.
The synthesis and characterization of a new class of bioinspired carbohydrate amphiphiles that modulate Pseudomonas aeruginosa biofilm formation are reported. The carbohydrate head is an enantiopure poly-amido-saccharide (PAS) prepared by a controlled anionic polymerization of β-lactam monomers derived from either glucose or galactose. The supramolecular assemblies formed by PAS amphiphiles are investigated in solution using fluorescence assays and dynamic light scattering. Dried samples are investigated using X-ray, infrared spectroscopy, and transmission electron microscopy. Additionally, the amphiphiles are evaluated for their ability to modulate biofilm formation by the Gram-negative bacterium Pseudomonas aeruginosa. Remarkably, from a library of eight amphiphiles, we identify a structure that promotes biofilm formation and two structures that inhibit biofilm formation. Using biological assays and electron microscopy, we relate the chemical structure of the amphiphiles to the observed activity. Materials that modulate the formation of biofilms by bacteria are important both as research tools for microbiologists to study the process of biofilm formation and for their potential to provide new drug candidates for treating biofilm-associated infections.


Electron-electron correlation in graphite: a combined angle-resolved photoemission and first-principles study.
The full three-dimensional dispersion of the pi bands, Fermi velocities, and effective masses are measured with angle-resolved photoemission spectroscopy and compared to first-principles calculations. The band structure by density-functional theory underestimates the slope of the bands and the trigonal warping effect. Including electron-electron correlation on the level of the GW approximation, however, yields remarkable improvement in the vicinity of the Fermi level. This demonstrates the breakdown of the independent electron picture in semimetallic graphite and points toward a pronounced role of electron correlation for the interpretation of transport experiments and double-resonant Raman scattering for a wide range of carbon based materials.


Exploring the chemical space for freeze-drying excipients.
Commonly, a limited number of generally accepted bulking agents and lyoprotectants are used for freeze-drying; predominantly mannitol, glycine, sucrose and trehalose. The purpose of this study was to combine a theoretical approach using molecular descriptors with a large scale experimental screening to evaluate the suitability of a broad range of excipients for freeze-drying. A large selection of sugars, polyols and amino acids was characterized by modulated differential scanning calorimetry (mDSC) and X-ray powder diffraction (XRPD) after well-plate based freeze-drying. The calculated molecular descriptors were investigated with both hierarchical cluster analysis and principal component analysis. A clear clustering of the excipients according to the size-related and weight-related descriptors was observed; however other relevant descriptors could also be identified. From a practical perspective, a trend was observed with regard to a higher likelihood for amorphisation and a higher glass transition temperature of the maximally freeze-concentrated solution with increasing molecular size. A translation of the molecular descriptors on pharmaceutical performance was more successful for lyoprotectants than for bulking agents. Additionally, in the course of the experimental screening, several new potential bulking agents and lyoprotectants were identified.


SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe.
The aim of this study was to develop, validate, and illustrate an updated prediction model (SCORE2) to estimate 10-year fatal and non-fatal cardiovascular disease (CVD) risk in individuals without previous CVD or diabetes aged 40-69 years in Europe. We derived risk prediction models using individual-participant data from 45 cohorts in 13 countries (677 684 individuals, 30 121 CVD events). We used sex-specific and competing risk-adjusted models, including age, smoking status, systolic blood pressure, and total- and HDL-cholesterol. We defined four risk regions in Europe according to country-specific CVD mortality, recalibrating models to each region using expected incidences and risk factor distributions. Region-specific incidence was estimated using CVD mortality and incidence data on 10 776 466 individuals. For external validation, we analysed data from 25 additional cohorts in 15 European countries (1 133 181 individuals, 43 492 CVD events). After applying the derived risk prediction models to external validation cohorts, C-indices ranged from 0.67 (0.65-0.68) to 0.81 (0.76-0.86). Predicted CVD risk varied several-fold across European regions. For example, the estimated 10-year CVD risk for a 50-year-old smoker, with a systolic blood pressure of 140 mmHg, total cholesterol of 5.5 mmol/L, and HDL-cholesterol of 1.3 mmol/L, ranged from 5.9% for men in low-risk countries to 14.0% for men in very high-risk countries, and from 4.2% for women in low-risk countries to 13.7% for women in very high-risk countries. SCORE2-a new algorithm derived, calibrated, and validated to predict 10-year risk of first-onset CVD in European populations-enhances the identification of individuals at higher risk of developing CVD across Europe.


Approaches for the successful isolation and cell culture of American Rickettsia species.
Rickettsia are intracellular vector-borne bacteria, which are the etiologic agent of severe infections that could inflict death to their host. The intracellular behaviour of Rickettsia makes the study of its genetics, proteomics and cellular processes very difficult. Hence, isolation remains an important experimental technique that permits the obtention of important yields of bacteria, useful for a broad range of experiments. Isolation of Rickettsia using passages in animals or embryonated eggs has been described for long time; however, it was until the 1990s that faster and more feasible approaches for cell culture were developed. Current isolation approaches are mainly based on shell vial culture, that varies according to the media, atmosphere or temperature conditions. These variations have allowed the establishment of isolates from different pathogenic and non-pathogenic Rickettsia species, using arthropod, animal or human samples. Purification method of bacteria has also witnessed changes alongside the quantification of its load in the resulting isolates, from the laborious and time consuming plaque assays, to the routinary use of real-time polymerase chain reaction (qPCR), which is faster and more accurate. This review discusses various approaches that have been used for the isolation and purification of different Rickettsia species along with the mention of some successful examples. It indicated that a successful strategy for the isolation of Rickettsia requires a careful selection of media, cell lines and culture conditions which now are not as time consuming as used to be.


A Three-arm Randomized Clinical Trial Comparing Continuous Femoral Plus Single-injection Sciatic Peripheral Nerve Blocks versus Periarticular Injection with Ropivacaine or Liposomal Bupivacaine for Patients Undergoing Total Knee Arthroplasty.
Multimodal analgesia is standard practice for total knee arthroplasty; however, the role of regional techniques in improved perioperative outcomes remains unknown. The authors hypothesized that peripheral nerve blockade would result in lower pain scores and opioid consumption than two competing periarticular injection solutions. This three-arm, nonblinded trial randomized 165 adults undergoing unilateral primary total knee arthroplasty to receive (1) femoral catheter plus sciatic nerve blocks, (2) ropivacaine-based periarticular injection, or (3) liposomal bupivacaine-based periarticular injection. Primary outcome was maximal pain during postoperative day 1 (0 to 10, numerical pain rating scale) in intention-to-treat analysis. Additional outcomes included pain scores and opioid consumption for postoperative days 0 to 2 and 3 months. One hundred fifty-seven study patients received peripheral nerve block (n = 50), ropivacaine (n = 55), or liposomal bupivacaine (n = 52) and reported median maximal pain scores on postoperative day 1 of 3, 4, and 4.5 and on postoperative day 0 of 1, 4, and 5, respectively (average pain scores for postoperative day 0: 0.6, 1.7, and 2.4 and postoperative day 1: 2.5, 3.5, and 3.7). Postoperative day 1 median maximal pain scores were significantly lower for peripheral nerve blockade compared to liposomal bupivacaine-based periarticular injection (P = 0.016; Hodges-Lehmann median difference [95% CI] = -1 [-2 to 0]). After postanesthesia care unit discharge, postoperative day 0 median maximal and average pain scores were significantly lower for peripheral nerve block compared to both periarticular injections (ropivacaine: maximal -2 [-3 to -1]; P < 0.001; average -0.8 [-1.3 to -0.2]; P = 0.003; and liposomal bupivacaine: maximal -3 [-4 to -2]; P < 0.001; average -1.4 [-2.0 to -0.8]; P < 0.001). Ropivacaine-based periarticular injections provide pain control comparable on postoperative days 1 and 2 to a femoral catheter and single-injection sciatic nerve block. This study did not demonstrate an advantage of liposomal bupivacaine over ropivacaine in periarticular injections for total knee arthroplasty.


The Protocol of Fixed Reconstruction for Severely Worn Teeth Combined with Anterior Deep Bite.
Full mouth reconstruction is one of the most effective methods to restore severe worn teeth that have suffered reduced vertical dimension. Although the use of the overlay splint restoration for a trial period allowing the patient to adapt to an increased vertical dimension is the recognized method, the specific protocol from the transitional splint to the fixed reconstruction is yet to be established. This case report describes a 50-year-old female patient who has severely worn teeth combined with an anterior deep bite and chewing pain. The protocol of the treatment process is described.


Antenatal interpersonal sensitivity is more strongly associated than perinatal depressive symptoms with postnatal mother-infant interaction quality.
Maternal mental health has enduring effects on children's life chances and is a substantial cost driver for child health, education and social services. A key linking mechanism is the quality of mother-infant interaction. A body of work associates maternal depressive symptoms across the antenatal and postnatal (perinatal) period with less-than-optimal mother-infant interaction. Our study aims to build on previous research in the field through exploring the association of a maternal personality trait, interpersonal sensitivity, measured in early pregnancy, with subsequent mother-infant interaction quality. We analysed data from the Avon Longitudinal Study of Parents and Children (ALSPAC) to examine the association between antenatal interpersonal sensitivity and postnatal mother-infant interaction quality in the context of perinatal depressive symptoms. Interpersonal sensitivity was measured during early pregnancy and depressive symptoms in the antenatal year and across the first 21 months of the postnatal period. In a subsample of the ALSPAC, mother-infant interaction was measured at 12 months postnatal through a standard observation. For the subsample that had complete data at all time points (n = 706), hierarchical regression examined the contribution of interpersonal sensitivity to variance in mother-infant interaction quality. Perinatal depressive symptoms predicted little variance in mother-infant interaction. Antenatal interpersonal sensitivity explained a greater proportion of variance in mother-infant interaction quality. The personality trait, interpersonal sensitivity, measured in early pregnancy, is a more robust indicator of subsequent mother-infant-interaction quality than perinatal depressive symptoms, thus affording enhanced opportunity to identify vulnerable mother-infant relationships for targeted early intervention.


Intracranial migration of Eucoleus (Capillaria) boehmi in a dog.
A 4-year-old, spayed-female great Dane was referred for surgical treatment of a suspected meningioma, diagnosed on magnetic resonance imaging 10 days prior to presentation. The suspected meningioma was removed via image-guided stereotactic craniotomy. Histopathological diagnosis was severe, locally extensive, chronic meningoencephalitis with an intralesional nematode egg. The egg was morphologically consistent with Eucoleus boehmi, and aberrant migration into the cranial cavity was the presumed cause of this lesion. Three faecal samples were collected and revealed 4+ E. boehmi eggs. Treatment involved 110 mg/kg fenbendazole (Panacur, Intervet) orally twice daily for 14 days. Nematodes including E. boehmi are a previously un-recognised source of intracranial disease in dogs, and should be considered as a differential for mass-like lesions visualised by magnetic resonance imaging.


Identification of the mutation causing progressive retinal atrophy in Old Danish Pointing Dog.
Progressive retinal atrophy (PRA) is a common cause of blindness in many dog breeds. It is most often inherited as a simple Mendelian trait, but great genetic heterogeneity has been demonstrated both within and between breeds. In many breeds the genetic cause of the disease is not known, and until now, the Old Danish Pointing Dog (ODP) has been one of those breeds. ODP is one of the oldest dog breeds in Europe. Seventy years ago the breed almost vanished, but today a population still exists, primarily in Denmark but with some dogs in Germany and Sweden. PRA has been diagnosed in ODP since the late 1990s. It resembles late onset PRA in other dog breeds, and it is inherited as an autosomal recessive trait. In the present study, we performed whole-genome sequencing and identified a single base insertion (c.3149_3150insC) in exon 1 of C17H2orf71. This is the same mutation previously found to cause PRA in Gordon Setters and Irish Setters, and it was later found in Tibetan Terrier, Standard Poodle and the Polski Owczarek Nizinny. The presence of the mutation in such a diverse range of breeds indicates an origin preceding creation of modern dog breeds. Hence, we screened 262 dogs from 44 different breeds plus four crossbred dogs, and can subsequently add Miniature Poodle and another polish sheepdog, the Polski Owczarek Podhalanski, to the list of affected breeds.


Pipeline Embolization Device with or without Adjunctive Coil Embolization: Analysis of Complications from the IntrePED Registry.
Flow diversion to treat cerebral aneurysms has revolutionized neurointerventional surgery. Because the addition of coils potentially increases the time and complexity of endovascular procedures, we sought to determine whether adjunctive coil use is associated with an increase in complications. Patients in the International Retrospective Study of Pipeline Embolization Device registry were divided into those treated with the Pipeline Embolization Device alone (n = 689 patients; n = 797 aneurysms; mean aneurysm size, 10.3 ± 7.6 mm) versus those treated with the Pipeline Embolization Device and concurrent coil embolization (n = 104 patients; n = 109 aneurysms; mean aneurysm size, 13.6 ± 7.8 mm). Patient demographics and aneurysm characteristics were examined. Rates of neurologic morbidity and mortality were compared between groups. The Pipeline Embolization Device with versus without coiling required a significantly longer procedure time (135.8 ± 63.9 versus 96.7 ± 46.2 min; P < .0001) and resulted in higher neurological morbidity (12.5% versus 7.8%; P = .13). These data suggest that either strategy represents an acceptable risk profile in the treatment of complex cerebral aneurysms and warrants further investigation.


Endocytic mechanisms responsible for uptake of GPI-linked diphtheria toxin receptor.
We have here used diphtheria toxin as a tool to investigate the type of endocytosis used by a glycosylphosphatidylinositol-linked molecule, a glycosylphosphatidylinositol-linked version of the diphtheria toxin receptor that is able to mediate intoxication. The receptor is expressed in HeLa cells where clathrin-dependent endocytosis can be blocked by overexpression of mutant dynamin. Diphtheria toxin intoxicates cells by first binding to cell-surface receptors, then the toxin is endocytosed, and upon exposure to low endosomal pH, the toxin enters the cytosol where it inhibits protein synthesis. Inhibition of protein synthesis by the toxin can therefore be used to probe the entry of the glycosylphosphatidylinositol-linked receptor into an acidic compartment. Furthermore, degradation of the toxin can be used as an indicator of entry into the endosomal/lysosomal compartment. The data show that although expression of mutant dynamin inhibits intoxication mediated via the wild-type receptors, mutant dynamin does not affect intoxication or endocytosis and degradation of diphtheria toxin bound to the glycosylphosphatidylinositol-linked receptor. Confocal microscopy demonstrated that diphtheria toxin is transported to vesicles containing EEA1, a marker for early endosomes. Biochemical and ultrastructural studies of the HeLa cells used reveal that they have very low levels of caveolin-1 and that they contain very few if any caveolae at the cell surface. Furthermore, the endocytic uptake of diphtheria toxin bound to the glycosylphosphatidylinositol-linked receptor was not reduced by methyl-beta-cyclodextrin or by nystatin which both disrupt caveolar structure and functions. Thus, uptake of a glycosylphosphatidylinositol-linked protein, in this case the diphtheria toxin receptor, into the endosomal/lysosomal system can occur independently of both caveolae and clathrin-coated vesicles.


Comparison between deep brain stimulation and magnetic resonance-guided focused ultrasound in the treatment of essential tremor: a systematic review and pooled analysis of functional outcomes.
The current gold standard surgical treatment for medication-resistant essential tremor (ET) is deep brain stimulation (DBS). However, recent advances in technologies have led to the development of incisionless techniques, such as magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy. The authors perform a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement to compare unilateral MRgFUS thalamotomy to unilateral and bilateral DBS in the treatment of ET in terms of tremor severity and quality of life improvement. PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials and SCOPUS databases were searched. 45 eligible articles, published between 1990 and 2019, were retrieved. 1202 patients were treated with DBS and 477 were treated with MRgFUS thalamotomy. Postoperative tremor improvement was greater following DBS than MRgFUS thalamotomy (p<0.001). A subgroup analysis was carried out stratifying by treatment laterality: bilateral DBS was significantly superior to both MRgFUS and unilateral DBS (p<0.001), but no significant difference was recorded between MRgFUS and unilateral DBS (p<0.198). Postoperative quality of life improvement was significantly greater following MRgFUS thalamotomy than DBS (p<0.001). Complications were differently distributed among the two groups (p<0.001). Persistent complications were significantly more common in the MRgFUS group (p=0.042). While bilateral DBS proves superior to unilateral MRgFUS thalamotomy in the treatment of ET, a subgroup analysis suggests that treatment laterality is the most significant determinant of tremor improvement, thus highlighting the importance of future investigations on bilateral staged MRgFUS thalamotomy.


Sympatric parallel diversification of major oak clades in the Americas and the origins of Mexican species diversity.
Oaks (Quercus, Fagaceae) are the dominant tree genus of North America in species number and biomass, and Mexico is a global center of oak diversity. Understanding the origins of oak diversity is key to understanding biodiversity of northern temperate forests. A phylogenetic study of biogeography, niche evolution and diversification patterns in Quercus was performed using 300 samples, 146 species. Next-generation sequencing data were generated using the restriction-site associated DNA (RAD-seq) method. A time-calibrated maximum likelihood phylogeny was inferred and analyzed with bioclimatic, soils, and leaf habit data to reconstruct the biogeographic and evolutionary history of the American oaks. Our highly resolved phylogeny demonstrates sympatric parallel diversification in climatic niche, leaf habit, and diversification rates. The two major American oak clades arose in what is now the boreal zone and radiated, in parallel, from eastern North America into Mexico and Central America. Oaks adapted rapidly to niche transitions. The Mexican oaks are particularly numerous, not because Mexico is a center of origin, but because of high rates of lineage diversification associated with high rates of evolution along moisture gradients and between the evergreen and deciduous leaf habits. Sympatric parallel diversification in the oaks has shaped the diversity of North American forests.


Polarization insensitive 25-Gbaud direct D(Q)PSK receiver based on polymer planar lightwave hybrid integration platform.
We report a direct DPSK receiver based on polymer planar lightwave circuit technology, which incorporates a 2x25 GHz photodiode (PD) array hybridly integrated via 45° mirrors. In this direct DPSK receiver, a half-wave plate and heating electrodes are implemented to eliminate the polarization-dependent frequency-shift (PDFS) of the delay-line interferometer (DLI). By applying a proper heating current, a residual PDFS of practically zero at 1550 nm and within ±125 MHz was achieved over the full C-band. Integrated with the PD array, the peak responsivity is ~0.14 A/W for orthogonal polarizations over the C-band. To characterize this direct receiver, we introduce an adapted common-mode rejection ratio (CMRR), which takes into account the unequal responsivities of the PDs, the uneven split of the input power by the DLI, the phase error and the extinction ratio of the DLI. The measured CMRR under DC condition is below -20 dB over the C-band.


Muscle mTORC1 suppression by IL-6 during cancer cachexia: a role for AMPK.
Although catabolic signaling has a well-established role in muscle wasting during cancer cachexia, the suppression of anabolic signaling also warrants further investigation. In cachectic tumor-bearing mice, circulating IL-6 levels are associated with suppressed muscle protein synthesis and mTORC1 signaling. We have found AMPK and IGF-I/insulin signaling, two well-known regulators of the mammalian target of rapamycin (mTOR), are altered with the progression of cachexia. How IL-6 can induce suppression of mTORC1 signaling remains to be established. The purpose of this study was to examine mTOR complex 1 (mTORC1) activation and regulation by IL-6 during cancer cachexia. IL-6 effects on mTOR activation were examined in Apc(Min/+) mouse skeletal muscle and C2C12 myotubes. Systemic IL-6 overexpression in Apc(Min/+) mice produced a dose-dependent suppression of mTOR signaling that corresponded to induction of STAT3 and AMPK phosphorylation. This result was also evident in IL-6-treated myotubes. Basal mTOR activation and mTOR responsiveness to glucose administration were suppressed in cachectic skeletal muscle. However, insulin induction of mTOR activity was maintained in IL-6-treated myotubes. Whereas IL-6 suppression of myotube mTOR activity was rescued by AMPK inhibition, inhibition of STAT3 signaling was not sufficient to rescue IL-6 suppression of mTOR activity. Last, treadmill exercise training was able to prevent IL-6-induced inhibition of mTOR signaling in Apc(Min/+) mice independently of activated STAT. In conclusion, we report dose-dependent suppression of mTOR activity by IL-6 and suppressed mTOR responsiveness to glucose administration in Apc(Min/+) mice. IL-6 suppression of mTOR activity was dependent on AMPK activation and independent of STAT signaling in myotubes.


Developmental cell death in dictyostelium does not require paracaspase.
Apoptotic cell death often requires caspases. Caspases are part of a family of related molecules including also paracaspases and metacaspases. Are molecules of this family generally involved in cell death? More specifically, do non-apoptotic caspase-independent types of cell death require paracaspases or metacaspases? Dictyostelium discoideum lends itself well to answering these questions because 1) it undergoes non-apoptotic developmental cell death of a vacuolar autophagic type and 2) it bears neither caspase nor metacaspase genes and apparently only one paracaspase gene. This only paracaspase gene can be inactivated by homologous recombination. Paracaspase-null clones were thus obtained in each of four distinct Dictyostelium strains. These clones were tested in two systems, developmental stalk cell death in vivo and vacuolar autophagic cell death in a monolayer system mimicking developmental cell death. Compared with parent cells, all of the paracaspase-null cells showed unaltered cell death in both test systems. In addition, paracaspase inactivation led to no alteration in development or interaction with a range of bacteria. Thus, in Dictyostelium, vacuolar programmed cell death in development and in a monolayer model in vitro would seem not to require paracaspase. To our knowledge, this is the first instance of developmental programmed cell death shown to be independent of any caspase, paracaspase or metacaspase. These results have implications as to the relationship in evolution between cell death and the caspase family.


Imaging dopamine receptors in humans with [11C]-(+)-PHNO: dissection of D3 signal and anatomy.
[(11)C]-(+)-PHNO is a D3 preferring PET radioligand which has recently opened the possibility of imaging D3 receptors in the human brain in vivo. This imaging tool allows characterisation of the distribution of D3 receptors in vivo and further investigation of their functional role. The specific [(11)C]-(+)-PHNO signal is a mixture of D3 and D2 components with the relative magnitude of each component determined by the regional receptor densities. An accurate and reproducible delineation of regions of interest (ROI) is therefore important for optimal analysis of human PET data. We present a set of anatomical guidelines for the delineation of D3 relevant ROIs including substantia nigra, hypothalamus, ventral pallidum/substantia innominata, ventral striatum, globus pallidus and thalamus. Delineation of these structures using this approach allowed for high intra- and inter-operator reproducibility. Subsequently we used a selective D3 antagonist to dissect the total [(11)C]-(+)-PHNO signal in each region into its D3 and D2 components and estimated the regional fraction of the D3 signal (f(PHNO)(D3)). In descending order of magnitude the following results for the f(PHNO)(D3) were obtained: hypothalamus=100%, substantia nigra=100%, ventral pallidum/substantia innominata=75%, globus pallidus=65%, thalamus=43%, ventral striatum=26% and precommissural-ventral putamen=6%. An automated approach for the delineation of these anatomical regions of interest was also developed and investigated in terms of its reproducibility and accuracy.


Pneumocystis carinii contains a functional cell-division-cycle Cdc2 homologue.
Pneumocystis carinii causes life-threatening pneumonia in immunocompromised patients. The inability to culture P. carinii has hampered basic investigations of the organism's life cycle, limiting the development of new therapies directed against it. Recent investigations indicate that P. carinii is a fungus phylogenetically related to other ascomycetes such as Schizosaccharomyces pombe. The cell cycles of S. pombe and homologous fungi are carefully regulated by cell-division-cycle molecules (cdc), particularly cell-division-cycle 2 (Cdc2), a serine-threonine kinase with essential activity at the G1 restriction point and for entry into mitosis. Antibodies to the proline-serine-threonine-alanine-isoleucine-arginine (PSTAIR) amino-acid sequence conserved in Cdc2 proteins specifically precipitated, from P. carinii extracts, a molecule with kinase activity consistent with a Cdc2-like protein. Cdc2 molecules exhibit differential activity throughout the life cycle of the organisms in which they occur. In accord with this, the P. carinii Cdc2 showed greater specific activity in P. carinii trophic forms (trophozoites) than in spore-case forms (cysts). In addition, complete genomic and complementary DNA (cDNA) sequences of P. carinii Cdc2 were cloned and found to be most closely homologus to the corresponding sequences of other pathogenic fungi. The function of P. carinii cdc2 cDNA was further documented through its ability to complement the DNA of mutant strains of S. pombe with temperature-sensitive deficiencies in Cdc2 activity. The P. carinii cdc2 cDNA restored normal Cdc2 function in these mutant strains of S. pombe, and promoted fungal proliferation. These studies represent the first molecular analysis of the cell-cycle-regulatory machinery in P. carinii. Further understanding of P. carinii's life cycle promises novel insights for preventing and treating the intractable infection it causes in immunocompromised patients.


Factors influencing sialocele or salivary fistula formation postparotidectomy.
Does the extent of parotidectomy or other patient or tumor characteristics influence the rate of sialocele/salivary fistula formation? All patients who underwent parotidectomy at the University of Wisconsin from 1994 to 2013 were considered. Patients who developed a sialocele/salivary fistula were identified. Extent of dissection, age, sex, body mass index (BMI), volume of specimen, and rate of malignancy were examined. Seventy of 771 patients (9.1%) developed a sialocele/salivary fistula. Sixty-seven fistulae (96%) developed within 1 month and all resolved by 6 months. Age, sex, pathology, and BMI were not increased in the sialocele group. Inferior and middle superficial parotidectomy had a significantly higher rate of sialocele than other extents of dissection. Volume of tissue removed was not significantly different between dissection groups. Sialocele/salivary fistula is common postparotidectomy and is more likely with inferior and middle superficial parotidectomy. © 2016 Wiley Periodicals, Inc. Head Neck 39: 387-391, 2017.


Crop Rotation and Nematicides for Management of Mixed Populations of Meloidogyne spp. on Tobacco.
The effects of crop rotation and the nematicides 1,3-dichloropropene (1,3-D), ethoprop, and fenamiphos on the relative frequency of Meloidogyne incognita race 3, M. arenaria race 2, and M. javanica and tobacco yields on a sandy loam soil were determined. Cropping sequences altered the species composition and population densities of Meloidogyne spp. Meloidogyne arenaria and M. incognita predominated when cotton, corn, sorghum, or rye-fallow preceded tobacco. Meloidogyne javanica and M. arenaria predominated when tobacco preceded tobacco. Sorghum, cotton, corn, or rye-fallow preceding tobacco enhanced yields compared to tobacco preceding tobacco in plots containing mixtures of Meloidogyne species. Sorghum supported minimal reproduction of any Meloidogyne spp. Application of 1,3-D increased tobacco yields and reduced root galling when compared to untreated controls. Both fenamiphos and ethoprop treatments were less effective than 1,3-D in controlling Meloidogyne spp. or increasing yields. A rotation crop x nematicide interaction was not observed. In continuous tobacco, use of the M. incognita-resistant tobacco cv. Coker 176 increased tobacco yields when compared to the M. incognita-susceptible cv. Coker 319 when 1,3-D was not applied.


Joint Torques and Patellofemoral Force During Single-Leg Assisted and Unassisted Cycling.
Unassisted single-leg cycling should be replaced by assisted single-leg cycling, given that this last approach has potential to mimic joint kinetics and kinematics from double-leg cycling. However, there is need to test if assisting devices during pedaling effectively replicate joint forces and torque from double-leg cycling. To compare double-leg, single-leg assisted, and unassisted cycling in terms of lower-limb kinetics and kinematics. Cross-sectional crossover. Laboratory. 14 healthy nonathletes. Two double-leg cycling trials (240 ± 23 W) and 2 single-leg trials (120 ± 11 W) at 90 rpm were performed for 2 min using a bicycle attached to a cycle trainer. Measurements of pedal force and joint kinematics of participants' right lower limb were performed during double- and single-leg trials. For the single-leg assisted trial, a custom-made adaptor was used to attach 10 kg of weight to the contralateral crank. Peak hip, knee, and ankle torques (flexors and extensors) along with knee-flexion angle and peak patellofemoral compressive force. Reduced peak hip-extensor torque (10%) and increased peak knee-flexor torque (157%) were observed at the single-leg assisted cycling compared with the double-leg cycling. No differences were found for peak patellofemoral compressive force or knee-flexion angle comparing double-leg with single-leg assisted cycling. However, single-leg unassisted cycling resulted in larger peak patellofemoral compressive force (28%) and lower knee-flexion angle (3%) than double-leg cycling. These results suggest that although single-leg assisted cycling differs for joint torques, it replicates knee loads from double-leg cycling.


Tau triage decisions mediated by the chaperone network.
The pathological accumulation of the microtubule-binding protein tau is linked to an increasing number of neurodegenerative conditions associated with aging, though the mechanisms by which tau accumulates in disease are unclear. In this review, we will summarize our previous research assessing the mechanism of action, as well as the therapeutic potential of Hsp90 inhibition for the treatment of tauopathies. Specifically, we describe the development of a high-throughput screening approach to identify and rank compounds, and demonstrate the selective elimination of aberrant p-tau species in the brain following treatment with an Hsp90 inhibitor. Additionally, we identify CHIP as an essential component of the Hsp90 chaperone complex that mediates tau degradation, and present evidence to suggest that CHIP functions to identify and sequester neurotoxic tau species. Finally, we discuss recent data identifying an additional mechanism by which CHIP modulates protein triage decisions involving Hsp90. Specifically, CHIP indirectly regulates Hsp90 chaperone activity by modulating steady-state levels of the Hsp90 deacetylase, HDAC6, thus influencing both the acetylation state and function of Hsp90. Thus future research directions will focus on the manipulation of this network to promote degradation of pathogenic tau species in disease.


Q-T interval prolongation in cirrhosis: prevalence, relationship with severity, and etiology of the disease and possible pathogenetic factors.
Prolonged Q-T interval predicts severe arrhythmias and sudden death, and has been shown to occur in alcoholic liver disease and cirrhotic patients who are candidates for liver transplantation. This study first evaluated the prevalence of prolonged Q-T interval in a large population of unselected patients with cirrhosis, and assessed the relationship between abnormal Q-T, etiology, and severity of liver disease and mortality of patients. Possible causes of Q-T abnormality were also explored. Ninety-four patients with cirrhosis without overt heart disease and 37 control subjects with mild chronic active hepatitis were enrolled. Rate-corrected Q-T interval (Q-Tc) was assessed along with routine liver tests, Child-Pugh score, serum bile salts, electrolytes and creatinine, plasma renin activity, aldosterone, norepinephrine, atrial natriuretic factor and, gonadal hormones. Q-Tc was longer in patients with cirrhosis than in controls (440.3 +/- 3.2 vs. 393.6 +/- 3.7 ms; P < .001) and prolonged (> 440 ms) in 44 patients (46.8%) and 2 controls (5.4%; P < .001). Q-Tc length was not influenced by the etiology of cirrhosis and correlated with Child-Pugh score (r = .53; P < .001), liver tests such as prothrombin activity, and serum concentrations of albumin and bilirubin, plasma bile salts, and plasma norepinephrine. Multivariate analysis showed that only Child-Pugh score and plasma norepinephrine were independently correlated with Q-Tc duration. Over a median follow-up period of 19 months (range, 2-33 months), patients with Q-Tc longer than 440 ms had a significantly lower survival rate than those with normal Q-Tc. Q-T interval is frequently prolonged in patients with cirrhosis, regardless the etiology of the disease, worsens in parallel with the severity of the disease, and may have an important prognostic meaning. In addition to other undefined factors related to the severity of cirrhosis, sympathoadrenergic hyperactivity may play a pathogenetic role.


The interaction between the gelatin-binding domain of fibronectin and the attachment of Pasteuria penetrans endospores to nematode cuticle.
Pasteuria penetrans is a Gram-positive endospore-producing bacterium that is a parasite of root-knot nematodes. Attachment of endospores to the cuticle of the nematode is the first stage in the infection process. Western blot analysis with monoclonal and polyclonal antibodies that recognize the 30 kDa heparin-binding domain (HBD) and the 45 kDa gelatin-binding domain (GBD) fragments of human fibronectin (Fn) revealed a series of polypeptides of approximately 40, 45 and 55 kDa present in crude cuticle extracts of Meloidogyne javanica 2nd-stage juveniles. The results suggest that the structure of the nematode fibronectin is different to the fibronectins so far characterized. Pre-treatment of endospores of Pasteuria with either the HBD or the GBD was found to inhibit binding to the nematode cuticle. The larger GBD fragment was the most effective at blocking adhesion. Pre-treatment of the GBD fragment with gelatin prevented the GBD fragment from inhibiting endospore attachment to the nematode cuticle.


Resonator channel drop filters in a plasmon-polaritons metal.
Channel drop filters with ring/disk resonators in a plasmon-polaritons metal are studied. It shows that light can be efficiently dropped. Results obtained by the finite difference time domain method are consistent with those from the coupled mode theory. It also shows, without considering the loss of the metal, that the quality factor for the channel drop system can be very high. The quality factor decreases significantly if we take into account the loss, which also leads to a weak drop efficiency.


Insulin-like growth factor-1 as a predictive biomarker for metastatic uveal melanoma in humans.
High expression levels of insulin-like growth factor-1 (IGF-1) receptor were associated with metastatic uveal melanoma (UM). The purpose of this study was to examine the potential of serum IGF-1 in early detection of liver metastasis. IGF-1 serum levels were analyzed using enzyme-linked immunosorbent assay for 118 subjects in three different groups: 55 disease-free (DF) UM patients who did not develop metastasis within 10 years of diagnosis; 22 metastatic patients; and 41 healthy subjects. Matched pairs univariate analysis was performed for sera of 19 metastatic patients 12 and 6 months before the diagnosis of metastasis and on the day of diagnosis, both as time groups and normalized levels per patient. IGF-1 levels were compared among groups by analysis of variance and Student t-test. Mean ± SD IGF-1 serum levels for the control, DF, and metastatic groups were 152.48 ± 49.76, 119.92 ± 60.66, and 96.99 ± 56.91 ng/mL, respectively (P < 0.001). Normalized changes in IGF-1 per metastatic patient from 6 months prior to the diagnosis of metastases compared to the day of diagnosis of metastases showed a decreasing trend. IGF-1 levels in 10-years' disease-free UM patients were significantly lower than those in healthy subjects and were even lower in metastatic patients. IGF-1 levels decreased toward the diagnosis of metastases. Therefore, serum IGF-1 level may be used as a predictive biomarker for metastatic UM when measured repeatedly.


Effects of Changes in Diabetes Pay-for-Performance Incentive Designs on Patient Risk Selection.
Taiwan's National Health Insurance (NHI) Program implemented a Diabetes Pay-for-Performance Program (P4P) based on process-of-care measures in 2001. In late 2006, that P4P program was reformed to also include achievement of intermediate health outcomes. This study examined how the change in design affected patient risk selection. Study populations were identified from a 2002 to 2003 period (Phase 1) and a 2007 to 2008 period (Phase 2), spanning pre- and postimplementation of reforms in the P4P incentive design. Phase 1 had 74,529 newly enrolled P4P patients and 215,572 non-P4P patients, and Phase 2 had 76,901 newly enrolled P4P patients and 299,573 non-P4P patients. Logistic regression models were used to estimate the effect of changes in design on P4P patient selection. Patients with greater disease severity and comorbidity were more likely to be excluded from the P4P program in both phases. Furthermore, the additional financial incentive for patients' intermediate outcomes moderately worsened patient risk selection. Policy makers need to carefully monitor the care of the diabetes patients with more severe and complex disease statuses after the changes of P4P financial incentive design.


Consistent signatures of selection from genomic analysis of pairs of temporal and spatial Plasmodium falciparum populations from The Gambia.
Genome sequences of 247 Plasmodium falciparum isolates collected in The Gambia in 2008 and 2014 were analysed to identify changes possibly related to the scale-up of antimalarial interventions that occurred during this period. Overall, there were 15 regions across the genomes with signatures of positive selection. Five of these were sweeps around known drug resistance and antigenic loci. Signatures at antigenic loci such as thrombospodin related adhesive protein (Pftrap) were most frequent in eastern Gambia, where parasite prevalence and transmission remain high. There was a strong temporal differentiation at a non-synonymous SNP in a cysteine desulfarase (Pfnfs) involved in iron-sulphur complex biogenesis. During the 7-year period, the frequency of the lysine variant at codon 65 (Pfnfs-Q65K) increased by 22% (10% to 32%) in the Greater Banjul area. Between 2014 and 2015, the frequency of this variant increased by 6% (20% to 26%) in eastern Gambia. IC50 for lumefantrine was significantly higher in Pfnfs-65K isolates. This is probably the first evidence of directional selection on Pfnfs or linked loci by lumefantrine. Given the declining malaria transmission, the consequent loss of population immunity, and sustained drug pressure, it is important to monitor Gambian P. falciparum populations for further signs of adaptation.


Acceptance and Commitment Therapy Preceded by Attention Bias Modification on Residual Symptoms in Depression: A 12-Month Follow-Up.
Depression is a highly recurrent disorder with limited treatment alternatives for reducing risk of subsequent episodes. Acceptance and commitment therapy (ACT) and attention bias modification (ABM) separately have shown some promise in reducing depressive symptoms. This study investigates (a) if group-based ACT had a greater impact in reducing residual symptoms of depression over a 12-month follow-up than a control condition, and (b) if preceding ACT with ABM produced added benefits. This multisite study consisted of two phases. In phase 1, participants with a history of depression, currently in remission (N = 244), were randomized to either receive 14 days of ABM or a control condition. In phase 2, a quasi- experimental design was adopted, and only phase-1 participants from the Sørlandet site (N = 124) next received an 8-week group-based ACT intervention. Self-reported and clinician-rated depression symptoms were assessed at baseline, immediately after phase 1 and at 1, 2, 6, and 12 months after the conclusion of phase 1. At 12-month follow-up, participants who received ACT exhibited fewer self-reported and clinician-rated depressive symptoms. There were no significant differences between ACT groups preceded by ABM or a control condition. There were no significant differences between ACT groups preceded by ABM or a control condition. Group-based ACT successfully decreased residual symptoms in depression over 12 months, suggesting some promise in preventing relapse.


Risk factors for UK Plasmodium falciparum cases.
An increasing proportion of malaria cases diagnosed in UK residents with a history of travel to malaria endemic areas are due to Plasmodium falciparum. In order to identify travellers at most risk of acquiring malaria a proportional hazards model was used to estimate the risk of acquiring malaria stratified by purpose of travel and age whilst adjusting for entomological inoculation rate (EIR) and duration of stay in endemic countries. Travellers visiting friends and relatives and business travellers were found to have significantly higher hazard of acquiring malaria (adjusted hazard ratio (HR) relative to that of holiday makers 7.4, 95% CI 6.4-8.5, p < 0. 0001 and HR 3.4, 95% CI 2.9-3.8, p < 0. 0001, respectively). All age-groups were at lower risk than children aged 0-15 years. These estimates of the increased risk for business travellers and those visiting friends and relatives should be used to inform programmes to improve awareness of the risks of malaria when travelling.


The salient characteristics of the central effects of acupuncture needling: limbic-paralimbic-neocortical network modulation.
Human and animal studies suggest that acupuncture produces many beneficial effects through the central nervous system. However, the neural substrates of acupuncture actions are not completely clear to date. fMRI studies at Hegu (LI4) and Zusanli (ST36) indicated that the limbic system may play an important role for acupuncture effects. To test if this finding applies to other major classical acupoints, fMRI was performed on 10 healthy adults during manual acupuncture at Taichong (LV3), Xingjian (LV2), Neiting (ST44), and a sham point on the dorsum of the left foot. Although certain differences could be observed between real and sham points, the hemodynamic response (BOLD signal changes) and psychophysical response (sensory experience) to acupuncture were generally similar for all four points. Acupuncture produced extensive deactivation of the limbic-paralimbic-neocortical system. Clusters of deactivated regions were seen in the medial prefrontal cortex (frontal pole, pregenual cingulate), the temporal lobe (amygdala, hippocampus, and parahippocampus) and the posterior medial cortex (precuneus, posterior cingulate). The sensorimotor cortices (somatosensory cortices, supplementary motor cortex), thalamus and occasional paralimbic structures such as the insula and anterior middle cingulate cortex showed activation. Our results provide additional evidence in support of previous reports that acupuncture modulates the limbic-paralimbic-neocortical network. We hypothesize that acupuncture may mediate its antipain, antianxiety, and other therapeutic effects via this intrinsic neural circuit that plays a central role in the affective and cognitive dimensions of pain as well as in the regulation and integration of emotion, memory processing, autonomic, endocrine, immunological, and sensorimotor functions.


Gancidin W, a potential low-toxicity antimalarial agent isolated from an endophytic Streptomyces SUK10.
Endophytic Streptomyces strains are potential sources for novel bioactive molecules. In this study, the diketopiperazine gancidin W (GW) was isolated from the endophytic actinobacterial genus Streptomyces, SUK10, obtained from the bark of Shorea ovalis tree, and it was tested in vivo against Plasmodium berghei PZZ1/100. GW exhibited an inhibition rate of nearly 80% at 6.25 and 3.125 μg kg-1 body weight on day four using the 4-day suppression test method on male ICR strain mice. Comparing GW at both concentrations with quinine hydrochloride and normal saline as positive and negative controls, respectively, 50% of the mice treated with 3.125 μg kg-1 body weight managed to survive for more than 11 months after infection, which almost reached the life span of normal mice. Biochemical tests of selected enzymes and proteins in blood samples of mice treated with GW were also within normal levels; in addition, no abnormalities or injuries were found on internal vital organs. These findings indicated that this isolated bioactive compound from Streptomyces SUK10 exhibits very low toxicity and is a good candidate for potential use as an antimalarial agent in an animal model.


Imagiological methods for prediction of fetal pulmonary hypoplasia: a systematic review.
To compare the different imagiological methods for prediction of fetal pulmonary hypoplasia (PH) in general diseases and associated with preterm rupture of membranes (PROM), and congenital diaphragmatic hernia (CDH). According to PRISMA guidelines, all the literature on PH from 1988 to 2018 was reviewed. Twenty-nine articles were selected and analyzed for two- and three- dimensional-ultrasounds (2D and 3D-US) as predictors for the lethal outcome. Overall, the results identify a general gap correlating prenatal pulmonary measurements and survival at birth; discrepant predictive values for the same imagiological methods are explained by the group heterogeneity in terms of diseases and degree of severity, with the 2D measurements being more affected than 3D; 2D and 3D-US present equally predictive values for groups with 0% of survival. Regarding PROM, results demonstrate comparable accuracies for similar survival rates suggesting a useful predictive value of 2D-US in outcome estimation; they also identify ultrasonographic methods as a more accurate prognostic factor than gestational age at rupture, latency or amniotic fluid index. In CDH, consistent with previous studies, our review shows magnetic resonance imaging as a better survival predictor followed by the 3D and 2D methods, while 2D-LHR was the more precise prognosticator correlating prenatal PH, survival at birth, and the need for neonatal respiratory support. Ultrasonographic methods can be valuable predictors for lethal PH and should be validated for a broad set of diseases (e.g. PROM). For that, restricted studies for disease groups and correlating fetal PH with the needed of neonatal support, and survival at birth is critically recommended.


Adaptation and implementation of cognitive behavioral intervention for trauma in schools with American Indian youth.
American Indian adolescents experience higher rates of suicide and psychological distress than the overall U.S. adolescent population, and research suggests that these disparities are related to higher rates of violence and trauma exposure. Despite elevated risk, there is limited empirical information to guide culturally appropriate treatment of trauma and related symptoms. We report a pilot study of an adaptation to the Cognitive Behavioral Intervention for Trauma in Schools in a sample of 24 American Indian adolescents. Participants experienced significant decreases in anxiety and posttraumatic stress disorder symptoms, and avoidant coping strategies, as well as a marginally significant decrease in depression symptoms. Improvements in anxiety and depression were maintained 6 months postintervention; improvements in posttraumatic stress disorder and avoidant coping strategies were not.


Localization of the gene for coagulation factor XIII a-chain to chromosome 6 and identification of sites of synthesis.
Factor XIII, the clotting factor essential for covalent stabilization of the fibrin clot, is a heterodimer consisting of a2 and b2 subunits, with catalytic function residing in the a-chain. In order to address questions regarding sites of synthesis and chromosomal localization of the Factor XIII a-chain, cDNA was cloned from a lambda gt11 human placental cDNA library. Nucleotide and amino acid sequences were determined from the cDNA. Amino acid sequencing of purified platelet Factor XIII a-chains confirmed the authenticity of the lambda gt11 clone. The gene for Factor XIII a-chain was mapped uniquely to chromosome 6. Northern blot analysis of human placental and U937 (monocytelike) cell poly (A)+ mRNA showed a single approximately 4.0-kb message for the Factor XIII a-chain. These results provide conclusive evidence that the a-chain is synthesized by placenta and monocyte cell lines.


Dystonia.
Dystonia is usually a lifelong condition with persistent pain and disability. Focal dystonia affects a single part of the body; generalised dystonia can affect most or all of the body. It is more common in women, and some types of dystonia are more common in people of European Ashkenazi Jewish descent. We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments, surgical treatments, and physical treatments for focal, and for generalised dystonia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 13 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: acetylcholine receptor inhibitors, acupuncture, anticholinergic drugs, anticonvulsants, atypical antipsychotic drugs, benzodiazepines, biofeedback, botulinum toxin, chiropractic manipulation, deep brain stimulation of thalamus and globus pallidus, dopaminergic agonists and antagonists, gamma-aminobutyric acid (GABA) inhibitors, microvascular decompression, myectomy, occupational therapy, osteopathy, pallidotomy, physiotherapy, selective peripheral denervation, serotonergic agonists and antagonists, speech therapy, and thalamotomy.


Does route of administration affect the outcome of TNF antagonist therapy?
The tumor necrosis factor (TNF) antagonists are parenterally administered biologic response modifiers indicated for the management of rheumatoid arthritis. Although infliximab, etanercept, and adalimumab are all members of this class, they differ in route of administration and dosing regimen. In the USA and in Europe, infliximab, in combination with oral methotrexate, is administered intravenously, initially at a dose of 3 mg/kg at weeks 0, 2, and 6, then every 8 weeks thereafter. The US Food and Drug Administration (FDA) has further approved that the dosage can be increased to 10 mg/kg and the doses can be given as often as every 4 weeks to optimize patient outcome (information based on the US package insert dated June 2002). Etanercept and adalimumab are given subcutaneously and can be self-injected. The FDA-approved dose of etanercept is 25 mg twice weekly, and of adalimumab is 40 mg every 2 weeks with methotrexate, or 40 mg alone. Medication adherence, possibly the most important factor in maintaining the benefits of anti-TNF therapy, is influenced by the interaction between the patient and his or her healthcare team, the patient's attitude toward the disease and medication regimen, and the choice of therapy.


Critical requirement of SOS1 RAS-GEF function for mitochondrial dynamics, metabolism, and redox homeostasis.
SOS1 ablation causes specific defective phenotypes in MEFs including increased levels of intracellular ROS. We showed that the mitochondria-targeted antioxidant MitoTEMPO restores normal endogenous ROS levels, suggesting predominant involvement of mitochondria in generation of this defective SOS1-dependent phenotype. The absence of SOS1 caused specific alterations of mitochondrial shape, mass, and dynamics accompanied by higher percentage of dysfunctional mitochondria and lower rates of electron transport in comparison to WT or SOS2-KO counterparts. SOS1-deficient MEFs also exhibited specific alterations of respiratory complexes and their assembly into mitochondrial supercomplexes and consistently reduced rates of respiration, glycolysis, and ATP production, together with distinctive patterns of substrate preference for oxidative energy metabolism and dependence on glucose for survival. RASless cells showed defective respiratory/metabolic phenotypes reminiscent of those of SOS1-deficient MEFs, suggesting that the mitochondrial defects of these cells are mechanistically linked to the absence of SOS1-GEF activity on cellular RAS targets. Our observations provide a direct mechanistic link between SOS1 and control of cellular oxidative stress and suggest that SOS1-mediated RAS activation is required for correct mitochondrial dynamics and function.


Cortical projections to the two retinotopic maps of primate pulvinar are distinct.
Comprised of at least five distinct nuclei, the pulvinar complex of primates includes two large visually driven nuclei; one in the dorsal (lateral) pulvinar and one in the ventral (inferior) pulvinar, that contain similar retinotopic representations of the contralateral visual hemifield. Both nuclei also appear to have similar connections with areas of visual cortex. Here we determined the cortical connections of these two nuclei in galagos, members of the stepsirrhine primate radiation, to see if the nuclei differed in ways that could support differences in function. Injections of different retrograde tracers in each nucleus produced similar patterns of labeled neurons, predominately in layer 6 of V1, V2, V3, MT, regions of temporal cortex, and other visual areas. More complete labeling of neurons with a modified rabies virus identified these neurons as pyramidal cells with apical dendrites extending into superficial cortical layers. Importantly, the distributions of cortical neurons projecting to each of the two nuclei were highly overlapping, but formed separate populations. Sparse populations of double-labeled neurons were found in both V1 and V2 but were very low in number (<0.1%). Finally, the labeled cortical neurons were predominately in layer 6, and layer 5 neurons were labeled only in extrastriate areas. Terminations of pulvinar projections to area 17 was largely in superficial cortical layers, especially layer 1.


Targeting the Programmed Cell Death-1 Pathway in Genitourinary Tumors: Current Progress and Future Perspectives.
Immune checkpoint inhibitors have revolutionized the treatment of many malignancies with over a dozen new United States Food and Drug Administration (FDA) approvals in the past six years. Due to the combination of potent treatment success and potentially deadly adverse effects from immune checkpoint inhibitors, gathering prognostic and predictive information about FDA-indicated tumors is prudent. PD-L1 expression is a poor prognostic factor and predictive of better responses from both PD-1 and PD-L1 inhibitors in a variety of tumor types including Renal Cell Carcinoma (RCC) and urothelial carcinoma. Each FDAapproved PD-1/PD-L1 drug is paired with a PD-L1 Immunohistochemistry (IHC) assay. The majority of PD-1/PDL1 inhibitor clinical trials use proprietary IHC antibodies with undefined validation data. Thus, there is need for improved knowledge and application of PD-1/PD-L1 IHC biomarkers. There is a wealth of recent publications using antibody clones to characterize tumor PD-1/PD-L1 expression profiles. PD-1 is expressed on lymphocytes. PD-L1 is expressed on both tumor cells and immune cells. IHC staining appears in membranous fashion. A cutoff of at least 5% tumor cell PD-L1 staining for positivity has worked for most studies. Caution should be observed when employing tissue microarray techniques. RCC has been the most studied of the genitourinary malignancies for PD-L1 expression. The atezolizumab- approved IHC assay is unique in that only immune cell staining is quantified for the use of this assay in urothelial carcinoma. With familiarity of the current FDA guidelines, published medical literature, and general immunohistochemical considerations, the use of immune checkpoint biomarkers can continue to flourish.


Protein-primed DNA replication: a transition between two modes of priming by a unique DNA polymerase.
Phage phi29 from Bacillus subtilis is a paradigm of the protein-primed replication mechanism, in which a single-subunit DNA polymerase is involved in both the specific protein-primed initiation step and normal DNA elongation. To start phi29 DNA replication, the viral DNA polymerase must interact with a free molecule of the viral terminal protein (TP), to prime DNA synthesis once at each phi29 DNA end. The results shown in this paper demonstrate that the DNA polymerase-primer TP heterodimer is not dissociated immediately after initiation. On the contrary, there is a transition stage in which the DNA polymerase synthesizes a five nucleotide-long DNA molecule while complexed with the primer TP, undergoes some structural change during replication of nucleotides 6-9, and finally dissociates from the primer protein when nucleotide 10 is inserted onto the nascent DNA chain. This behaviour probably reflects the polymerase requirement for a DNA primer of a minimum length to efficiently catalyze DNA elongation. The significance of such a limiting transition stage is supported by the finding of abortive replication products consisting of the primer TP linked up to eight nucleotides, detected during in vitro replication of phi29 TP-DNA particularly under conditions that decrease the strand-displacement capacity of phi29 DNA polymerase.


Bayesian DNA copy number analysis.
Some diseases, like tumors, can be related to chromosomal aberrations, leading to changes of DNA copy number. The copy number of an aberrant genome can be represented as a piecewise constant function, since it can exhibit regions of deletions or gains. Instead, in a healthy cell the copy number is two because we inherit one copy of each chromosome from each our parents. Bayesian Piecewise Constant Regression (BPCR) is a Bayesian regression method for data that are noisy observations of a piecewise constant function. The method estimates the unknown segment number, the endpoints of the segments and the value of the segment levels of the underlying piecewise constant function. The Bayesian Regression Curve (BRC) estimates the same data with a smoothing curve. However, in the original formulation, some estimators failed to properly determine the corresponding parameters. For example, the boundary estimator did not take into account the dependency among the boundaries and succeeded in estimating more than one breakpoint at the same position, losing segments. We derived an improved version of the BPCR (called mBPCR) and BRC, changing the segment number estimator and the boundary estimator to enhance the fitting procedure. We also proposed an alternative estimator of the variance of the segment levels, which is useful in case of data with high noise. Using artificial data, we compared the original and the modified version of BPCR and BRC with other regression methods, showing that our improved version of BPCR generally outperformed all the others. Similar results were also observed on real data. We propose an improved method for DNA copy number estimation, mBPCR, which performed very well compared to previously published algorithms. In particular, mBPCR was more powerful in the detection of the true position of the breakpoints and of small aberrations in very noisy data. Hence, from a biological point of view, our method can be very useful, for example, to find targets of genomic aberrations in clinical cancer samples.


On the property of measurements with the PTW microLion chamber in continuous beams.
The performance of liquid ionization chambers, which may prove to be useful tools in the field of radiation dosimetry, is based on several chamber and liquid specific characteristics. The present work investigates the performance of the PTW microLion liquid ionization chamber with respect to recombination losses and perturbations from ambient electric fields at various dose rates in continuous beams. In the investigation, experiments were performed using two microLion chambers, containing isooctane (C(8)H(18)) and tetramethylsilane [Si(CH(3))(4)] as the sensitive media, and a NACP-02 monitor chamber. An initial activity of approximately 250 GBq (18)F was employed as the radiation source in the experiments. The initial dose rate in each measurement series was estimated to 1.0 Gy min(-1) by Monte Carlo simulations and the measurements were carried out during the decay of the radioactive source. In the investigation of general recombination losses, employing the two-dose-rate method for continuous beams, the liquid ionization chambers were operated at polarizing voltages 25, 50, 100, 150, 200, and 300 V. Furthermore, measurements were also performed at 500 V polarizing voltage in the investigation of the sensitivity of the microLion chamber to ambient electric fields. The measurement results from the liquid ionization chambers, corrected for general recombination losses according to the two-dose-rate method for continuous beams, had a good agreement with the signal to dose linearity from the NACP-02 monitor chamber for general collection efficiencies above 70%. The results also displayed an agreement with the theoretical collection efficiencies according to the Greening theory, except for the liquid ionization chamber containing isooctane operated at 25 V. At lower dose rates, perturbations from ambient electric fields were found in the microLion chamber measurement results. Due to the perturbations, measurement results below an estimated dose rate of 0.2 Gy min(-1) were excluded from the present investigation of the general collection efficiency. The perturbations were found to be more pronounced when the chamber polarizing voltage was increased. By using the two-dose-rate method for continuous beams, comparable corrected ionization currents from experiments in low and medium energy photon beams can be achieved. However, the valid range of general collection efficiencies has been found to vary in a comparison between experiments performed in continuous beams of 120 kVp x ray, and the present investigation of 511 keV annihilation photons. At very high dose rates in continuous beams, there are presently no methods that can be used to correct for general recombination losses and at low dose rates the microLion chamber may be perturbed by ambient electric fields. Increasing the chamber polarizing voltage, which diminishes the general recombination effect, was found to increase the microLion chamber sensitivity to ambient electric fields. Prudence is thus advised when employing the microLion chamber in radiation dosimetry, as ambient electric fields of the strength observed in the present work may be found in many common situations. Due to uncertainties in the theoretical basis for recombination losses in liquids, further studies on the underlying theories for the initial and general recombination effect are needed if liquid ionization chambers are to become a viable option in high precision radiation dosimetry.


What do patients with medically unexplained physical symptoms (MUPS) think? A qualitative study.
Context Medically unexplained physical symptoms (MUPS) are frequently encountered in family medicine, and lead to disability, discomfort, medicalisation, iatrogenesis and economic costs. They cause professionals to feel insecure and frustrated and patients to feel dissatisfied and misunderstood. Doctors seek answers for rather than with the patient. Objectives This study aimed to explore patients' explanations of the medically unexplained physical symptoms that they were experiencing by eliciting their own explanations for their complaints, their associated fears, their expectations of the consultation, changes in their ideas of causality, and the therapeutic approach that they considered would be useful. Methodology A qualitative analysis was under-taken of interviews with 15 patients with MUPS in a family medicine unit, 6 months after diagnosis. Results Experience is crucial in construction of the meaning of symptoms and illness behaviour. Many patients identify psychosocial causes under-lying their suffering. These patients received more medication and fewer requests for diagnostic examinations than they had expected. Normalisation is a common behaviour in the clinical approach. Normalisation without explanation can be effective if an effective therapeutic relationship exists that may dispense with the need for words. Listening is the procedure most valued by patients. Diagnostic tests may denote interest in patients' problems. The clinician's flexibility should allow adaptation to the patient's phases of acceptance of the significance of their physical, emotional and social problems. Conclusion Patients with MUPS have explanations and fears associated with their complaints. The patient comes to the consultation not because of the symptom, but because of what he or she thinks about the symptom. The therapeutic relationship, therapeutic listening, and flexibility should be the basis for approaching patients with MUPS. Patients do not always expect medication, although it is what they most often receive. Diagnostic tests, although used sparingly, can be a way to maintain and build a relationship. Drugs and tests can be a ritual statement of clinical interest in the patient and their symptoms.


A Validated Model for Sudden Cardiac Death Risk Prediction in Pediatric Hypertrophic Cardiomyopathy.
Hypertrophic cardiomyopathy is the leading cause of sudden cardiac death (SCD) in children and young adults. Our objective was to develop and validate a SCD risk prediction model in pediatric hypertrophic cardiomyopathy to guide SCD prevention strategies. In an international multicenter observational cohort study, phenotype-positive patients with isolated hypertrophic cardiomyopathy <18 years of age at diagnosis were eligible. The primary outcome variable was the time from diagnosis to a composite of SCD events at 5-year follow-up: SCD, resuscitated sudden cardiac arrest, and aborted SCD, that is, appropriate shock following primary prevention implantable cardioverter defibrillators. Competing risk models with cause-specific hazard regression were used to identify and quantify clinical and genetic factors associated with SCD. The cause-specific regression model was implemented using boosting, and tuned with 10 repeated 4-fold cross-validations. The final model was fitted using all data with the tuned hyperparameter value that maximizes the c-statistic, and its performance was characterized by using the c-statistic for competing risk models. The final model was validated in an independent external cohort (SHaRe [Sarcomeric Human Cardiomyopathy Registry], n=285). Overall, 572 patients met eligibility criteria with 2855 patient-years of follow-up. The 5-year cumulative proportion of SCD events was 9.1% (14 SCD, 25 resuscitated sudden cardiac arrests, and 14 aborted SCD). Risk predictors included age at diagnosis, documented nonsustained ventricular tachycardia, unexplained syncope, septal diameter z-score, left ventricular posterior wall diameter z score, left atrial diameter z score, peak left ventricular outflow tract gradient, and presence of a pathogenic variant. Unlike in adults, left ventricular outflow tract gradient had an inverse association, and family history of SCD had no association with SCD. Clinical and clinical/genetic models were developed to predict 5-year freedom from SCD. Both models adequately discriminated between patients with and without SCD events with a c-statistic of 0.75 and 0.76, respectively, and demonstrated good agreement between predicted and observed events in the primary and validation cohorts (validation c-statistic 0.71 and 0.72, respectively). Our study provides a validated SCD risk prediction model with >70% prediction accuracy and incorporates risk factors that are unique to pediatric hypertrophic cardiomyopathy. An individualized risk prediction model has the potential to improve the application of clinical practice guidelines and shared decision making for implantable cardioverter defibrillator insertion. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT0403679.


Variations in Nationwide Readmission Patterns after Umbilical Hernia Repair.
Up to one in three readmissions occur at a different hospital and are thus missed by current quality metrics. There are no national studies examining 30-day readmission, including to different hospitals, after umbilical hernia repair (UHR). We tested the hypothesis that a large proportion were readmitted to a different hospital, that risk factors for readmission to a different hospital are unique, and that readmission costs differed between the index and different hospitals. The 2013 to 2014 Nationwide Readmissions Database was queried for patients admitted for UHR, and cost was calculated. Multivariate logistic regression identified risk factors for 30-day readmission at index and different hospitals. There were 102,650 admissions for UHR and 8.9 per cent readmissions, of which 15.8 per cent readmissions were to a different hospital. The most common reason for readmission was infection (25.8%). Risk factors for 30-day readmission to any hospital include bowel resection, index admission at a for-profit hospital, Medicare, Medicaid, and Charlson Comorbidity Index ≥ 2. Risk factors for 30-day readmission to a different hospital include elective operation, drug abuse, discharge to a skilled nursing facility, and leaving against medical advice. The median cost of initial admission was higher in those who were readmitted ($16,560 [$10,805-$29,014] vs $11,752 [$8151-$17,724], P < 0.01). The median cost of readmission was also higher among those readmitted to a different hospital ($9826 [$5497-$19,139] vs $9227 [$5211-$16,817], P = 0.02). After UHR, one in six readmissions occur at a different hospital, have unique risk factors, and are costlier. Current hospital benchmarks fail to capture this subpopulation and, therefore, likely underestimate UHR readmissions.


Waterborne typhoid fever in Haifa, Israel: clinical, microbiologic, and therapeutic aspects of a major outbreak.
A major outbreak of waterborne typhoid fever involving 77 verified cases occurred in 1985 in a large suburban area of Haifa, Israel. The authors summarize the clinical, microbiologic, and therapeutic aspects of these patients. Fever, usually higher than 39 degrees C, was the hallmark of the disease. Other manifestations of typhoid, although relatively frequent, are presented as part of a mild nonspecific symptom complex, often found only in the prodromal period. An elevated level of serum glutamic-oxaloacetic transaminase (mean, 81 IU/ml) was the most characteristic laboratory abnormality, occurring in 94% of the patients. Blood cultures were positive in 46 of the 50 patients (92%), and were not affected by prior outpatient antibiotic therapy. The first blood culture was diagnostic in 93% of the cases. Although fever tended to disappear more rapidly among patients receiving ampicillin than among those treated with chloramphenicol, results of therapy were similar in both groups. Nevertheless, the relapse rate of 36% among 25 chloramphenicol-treated patients was significantly higher than the 9% noted among 22 patients treated with ampicillin. Except for one case of hemolytic anemia, serious complications were conspicuously absent, and outcomes were uniformly favorable.


Immunohistochemical characterization of immunoglobulin-containing cells and T cells in the colonic mucosa of healthy dogs.
To quantitate numbers of immunoglobulin (Ig)-containing cells (IgA, IgG, and IgM) and T cells (CD3+, CD4+, and CD8+) in the colonic mucosa of healthy dogs, and to determine whether mean cell numbers differ among colonic regions. 10 clinically normal young adult mixed-breed dogs. Endoscopically obtained specimens of ascending, transverse, and descending colonic mucosa were stained specifically for IgA, IgG, and IgM heavy chains and T-cell antigens, CD3+, CD4+, and CD8+, using immunoperoxidase techniques. Morphometric analysis, performed by light microscopy, was used to quantitate numbers in these standardized areas of colonic mucosa. Data analysis allowed determination of mean cell numbers in each colonic region, as well as comparison of mean cell numbers among colonic regions. The CD3+ and CD8+ T cells were the predominant immune cell types in all colonic regions. In the mucosa, CD3+ T cells were significantly (P < 0.05) more numerous than CD8+ T cells, and CD8+ T cells were significantly (P < 0.05) more numerous than CD4+ T cells. The IgA-containing cells were significantly (P < 0.05) more numerous than IgG-containing cells, whereas IgM-containing cells were least numerous (P < 0.05). Differences in mean cell counts among colonic regions were not significant for Ig-containing cells or T cells. Mean numbers of immune cells did not differ significantly among colonic regions in healthy dogs, although differences existed in mean populations of T cells and Ig-containing cells. The CD3+ and CD8+ T cells were the most numerous immune cell types in colonic mucosa. These quantitative data provide a basis for study of alterations in populations of mucosal immune cells and their possible contribution to the pathogenesis of gastrointestinal tract disease.


High tidal volume ventilation is not deleterious in infant rats exposed to severe hemorrhage.
Both high tidal volume (V(T)) ventilation and hemorrhage induce acute lung injury in adult rodents. It is not known whether injurious ventilation augments lung injury in infant rats exposed to severe hemorrhage. Two-week-old rats were allocated for ventilation with VT 7 mL/kg and positive end-expiratory pressure (PEEP) 5 cm H₂O (low V(T)) or V(T) 21 mL/kg and PEEP 1 (high V(T)) for 4 hours. Additional rats were subjected to volume-controlled hemorrhage and delayed saline resuscitation, followed by low V(T) or high V(T) ventilation for 4 hours. Nonventilated control groups were also included. Airway resistance and the coefficient of tissue elastance were derived from respiratory input impedance measurements using the low-frequency forced oscillation technique. Pressure-volume curves were obtained at baseline and at the end of the study. Interleukin-6, macrophage inflammatory protein-2, and tumor necrosis factor alpha were determined in bronchoalveolar lavage fluid (BALF) and serum. In both healthy and hemorrhage-exposed animals, high V(T) resulted in reduced elastance (better lung compliance) and increased transcutaneous oxygen saturation. Interleukin-6 in BALF was greater in ventilated animals when compared with nonventilated controls, but not different among ventilated groups. No significant differences were found for all other inflammatory mediators, total protein concentration in BALF, and histology. High V(T) ventilation with low PEEP improves respiratory system mechanics without causing additional damage to healthy and hemorrhage-exposed infant rats after 4 hours of ventilation. This study highlights the tolerance to high V(T) ventilation in infant rats and underscores the need for age-specific animal models.


High-resolution seismic constraints on flow dynamics in the oceanic asthenosphere.
Convective flow in the mantle and the motions of tectonic plates produce deformation of Earth's interior, and the rock fabric produced by this deformation can be discerned using the anisotropy of the seismic wave speed. This deformation is commonly inferred close to lithospheric boundaries beneath the ocean in the uppermost mantle, including near seafloor-spreading centres as new plates are formed via corner flow, and within a weak asthenosphere that lubricates large-scale plate-driven flow and accommodates smaller scale convection. Seismic models of oceanic upper mantle differ as to the relative importance of these deformation processes: seafloor spreading fabric is very strong just beneath the crust-mantle boundary (the Mohorovičić discontinuity, or Moho) at relatively local scales, but at the global and ocean-basin scales, oceanic lithosphere typically appears weakly anisotropic when compared to the asthenosphere. Here we use Rayleigh waves, recorded across an ocean-bottom seismograph array in the central Pacific Ocean (the NoMelt Experiment), to provide unique localized constraints on seismic anisotropy within the oceanic lithosphere-asthenosphere system in the middle of a plate. We find that azimuthal anisotropy is strongest within the high-seismic-velocity lid, with the fast direction coincident with seafloor spreading. A minimum in the magnitude of azimuthal anisotropy occurs within the middle of the seismic low-velocity zone, and then increases with depth below the weakest portion of the asthenosphere. At no depth does the fast direction correlate with the apparent plate motion. Our results suggest that the highest strain deformation in the shallow oceanic mantle occurs during corner flow at the ridge axis, and via pressure-driven or buoyancy-driven flow within the asthenosphere. Shear associated with motion of the plate over the underlying asthenosphere, if present, is weak compared to these other processes.


Gata6 is an important regulator of mouse pancreas development.
Gata4, Gata5, and Gata6 represent a subfamily of zinc-finger transcriptional regulators that are important in the development and differentiation of numerous tissues, including many endodermally-derived organs. We demonstrate that Gata4 and Gata6 have overlapping expression patterns in the early pancreatic epithelium. Later, Gata4 becomes restricted to exocrine tissue and Gata6 becomes restricted to a subset of endocrine cells. In addition, we show Gata6, but not Gata4, physically interacts with Nkx2.2, an essential islet transcription factor. To begin determining the roles that Gata4 and Gata6 play during pancreatic development, we expressed Gata4-Engrailed and Gata6-Engrailed dominant repressor fusion proteins in the pancreatic epithelium and in the islet. At e17.5, transgenic Gata6-Engrailed embryos exhibit two distinct phenotypes: a complete absence of pancreas or a reduction in pancreatic tissue. In the embryos that do form pancreas, there is a significant reduction of all pancreatic cell types, with the few differentiated endocrine cells clustered within, or in close proximity to, enlarged ductal structures. Conversely, the majority of transgenic Gata4-Engrailed embryos do not have a pancreatic phenotype. This study suggests that Gata6 is an important regulator of pancreas specification.


Prevalence and Distribution of Diffuse Idiopathic Skeletal Hyperostosis on Whole-spine Computed Tomography in Patients With Cervical Ossification of the Posterior Longitudinal Ligament: A Multicenter Study.
This was a retrospective multicenter study. To clarify the progression of diffuse idiopathic skeletal hyperostosis (DISH) using whole-spine computed tomography in patients with cervical ossification of the posterior longitudinal ligament (OPLL). DISH and cervical OPLL frequently coexist, and can cause ankylosing spinal fractures due to biomechanical changes and fragility of the affected vertebrae. The epidemiology and pathophysiology of DISH occurring with cervical OPLL are unclear. We used whole-spine computed tomography to determine the prevalence of DISH in 234 patients with a diagnosis of cervical OPLL based on plain cervical radiographs. We established a novel system for grading the progression of DISH based on a cluster analysis of the DISH distribution along the spine. We calculated the correlation coefficient between this grading system and patient age. The prevalence of DISH in patients with cervical OPLL was 48.7%. Patients with DISH were significantly older than those who did not have DISH (67.3 vs. 63.4 y; P=0.005). Cluster analysis classified the DISH distribution into 6 regions, based on the levels affected: C2-C5, C3-T1, C6-T5, T3-10, T8-L2, and T12-S1. DISH was observed most frequently at T3-T10. We defined a system for grading DISH progression based on the number of regions involved, from grade 0 to 6. DISH was distributed at T3-T10 in >60% of the grade 1 patients, whereas most patients with DISH at the cervical or lumbar spine were grade 4 or 5. There was a weak but significant correlation between the DISH grade and patient age. DISH was present in nearly half of the patients with cervical OPLL. DISH was more common in older patients. DISH developed at the thoracic level and progressed into the cervical and/or lumbar spine with age. Level III.


Management of colon-invading renal cell carcinoma: Operative technique and systematic review.
Invasion into adjacent organs by non-metastatic renal cell carcinoma (RCC) occurs in 1% of patients suitable for resection. Colonic invasion is rare and presents technical challenges. No prospective data exists to guide management of these patients. We present the first reported case of a colon-invading RCC managed with simultaneous open right radical nephrectomy and extended right hemicolectomy. PubMed, Scopus and EMBASE databases were searched for relevant case reports reporting management of colon-invading renal cell carcinoma. Case reports, case series and cohort studies were eligible. A chart review was performed on a patient who presented with right-sided colon-invading RCC. Four previously reported cases were identified. The current case was managed with simultaneous open radical nephrectomy and extended right hemicolectomy. The patient remains well six months postoperatively with no evidence of disease recurrence. Histopathological evaluation of the resected specimen confirmed a T4 clear cell RCC with sarcomatoid differentiation. Colon-invading RCC is rare. This is the first reported case of right-sided, colon-invading RCC treated with radical resection. The current case confirms radical resection is a feasible management strategy for similar presentations. En bloc resection of involved organs remains the only potentially curative option for locally advanced disease.


Emergency surgery after unsuccessful coronary angioplasty: a review of 15 years' experience.
Emergency coronary artery bypass grafting (CABG) is occasionally necessary for failed percutaneous transluminal coronary angioplasty (PTCA). The aim of this study was to assess the outcome of patients receiving emergency CABG after unsuccessful PTCA over a 15-year study period. From January 1982 through December 1996, 74 patients underwent emergency CABG after unsuccessful PTCA (crash group). This group was compared with a matched group of 74 patients having primary elective CABG (control group). All 74 crash group patients were to have PTCA of one coronary system. After PTCA failure, 58 patients (78.3%) developed electrocardiographic changes of evolving acute myocardial infarction (AMI). The overall rate of AMI was 8.1% for the crash group and 2.7% for the control group. Two patients in the crash group died, with no deaths in the control group. There was no significant difference between mean in-hospital length of stay. With prompt, aggressive, and complete myocardial revascularization, patients who required emergency CABG after PTCA failure had an outcome not significantly different from that of patients having elective CABG.


Toward an unbiased evolutionary platform for unraveling Xenopus developmental gene networks.
The availability of both the Xenopus tropicalis genome and the soon to be released Xenopus laevis genome provides a solid foundation for Xenopus developmental biologists. The Xenopus community has presently amassed expression data for ∼2,300 genes in the form of published images collected in the Xenbase, the principal Xenopus research database. A few of these genes have been examined in both X. tropicalis and X. laevis and the cross-species comparison has been proven invaluable for studying gene function. A recently published work has yielded developmental expression profiles for the majority of Xenopus genes across fourteen developmental stages spanning the blastula, gastrula, neurula, and the tail-bud. While this data was originally queried for global evolutionary and developmental principles, here we demonstrate its general use for gene-level analyses. In particular, we present the accessibility of this dataset through Xenbase and describe biases in the characterized genes in terms of sequence and expression conservation across the two species. We further indicate the advantage of examining coexpression for gene function discovery relating to developmental processes conserved across species. We suggest that the integration of additional large-scale datasets--comprising diverse functional data--into Xenbase promises to provide a strong foundation for researchers in elucidating biological processes including the gene regulatory programs encoding development.


Immune mechanisms in contact allergic dermatitis.
The problem of contact allergic dermatitis in humans and contact hypersensitivity in animals begins with the observation that certain reactive compounds, when placed on skin, lead to a reproducible and characteristic inflammatory reaction. The immunologic processes that conspire to produce this damaging tissue reaction are derived from the normal immunologic balance between the protection of self and the destruction of nonself. Experimental work in the last decade has focused on the role of antigen-presenting cells, and specifically Langerhans cells, in the initiation of contact hypersensitivity, as well as on the competing roles of subsets of T lymphocytes in its regulation. For humans, an important goal has been the development of techniques by which tolerization and desensitization may be achieved, and for those who work with laboratory animals, contact hypersensitivity has provided methods to examine immune regulation in general. In the coming decade, we anticipate that new techniques from molecular biology, molecular genetics, tissue culture, and, above all, shrewd clinical observation will provide a new array of ideas and possibilities.


Time-resolved FTIR spectroscopy of the photointermediates involved in fast transient H+ release by proteorhodopsin.
Proteorhodopsin (pR) is a homologue of bacteriorhodopsin (bR) that has been recently discovered in oceanic bacterioplankton. Like bR, pR functions as a light-driven proton pump. As previously characterized by laser flash induced absorption spectroscopy (Krebs, R. A.; Alexiev, U.; Partha, R.; DeVita, A. M.; Braiman, M. S. BMC Physiol. 2002, 2, 5), the pR photocycle shows evidence of light-induced H(+) release on the 10-50 micros time scale, and of substantial accumulation of the M intermediate, only at pH values above 9 and after reconstitution into phospholipid followed by extensive washing to remove detergent. We have therefore measured the time-resolved FTIR difference spectra of pR intermediates reconstituted into DMPC vesicles at pH 9.5. A mixture of K- and L-like intermediates, characterized by a 1516 cm(-1) positive band and a 1742 cm(-1) negative band respectively, appears within 20 micros after photolysis. This mixture decays to an M-like state, with a clear band at 1756 cm(-1) due to protonation of Asp-97. The 50-70 micros rise of M at pH 9.5 is similar to (but a little slower than) the rise times for M formation and H(+) release that were reported earlier based on flash photolysis measurements of pR reconstituted into phospholipids with shorter acyl chains. We conclude that, at pH 9.5, H(+) release occurs while Asp-97 is still protonated; i.e., this aspartic acid cannot be the H(+) release group observed by flash photolysis under similar conditions.


Anthropometric and calorimetric evidence for the protein sparing effects of a new protein supplemented low calorie preparation.
A commercial protein sparing modified fast (PSMF) preparation has been evaluated for the protein sparing effects in 15 morbidly obese patients. During a 500 kcal preparation, given during a 6-week period, mean body weight and BMI decreased significantly. Total body fat decreased from 55.8 to 41.4 kg and lean body mass and arm muscle circumference (AMC) remained unchanged. Using indirect calorimetry and under the same degree of energy expenditure, carbohydrate metabolic consumption was significantly diminished (166 to 61 g/24 hr; p less than 0.001) but fat consumption was increased (116 to 155 g/24 hr; p less than 0.05) while the metabolic turn-over of protein was unchanged. This new presented PSMF preparation seems to present the typical properties of a protein sparing modified fast.