Composite tissue allografts in rats: IV. Graft-versus-host disease in recipients of vascularized bone marrow transplants.
This laboratory has used a composite tissue allograft model as a vehicle for studies on a new type of bone marrow transplant, the vascularized bone marrow transplant. The model consists of a rat hind limb transplant that incorporates integumentary musculoskeletal, and lymphopoietic tissues. These transplants, in comparison with conventional marrow transplants, have the advantage of providing a syngeneic microenvironment and immediate engraftment of both mature and progenitor hemopoietic cells at the time of transplantation. The characteristics of graft-versus-host disease were studied in this model. Lewis X Brown Norway F1 (LBN RT-1(1+n)) rats received hind limbs from Lewis (LEW RT-1(1)) donors (n = 19). Animals were observed daily for signs of graft-versus-host disease. Necropsies were performed. A minority of animals developed lethal disease (7 of 19 recipients) and demonstrated cachexia with concomitant histopathologic changes of the disease. Acute and chronic groups emerged with distinct clinical courses, which are similar to other models of this disease. Recipients of vascularized bone marrow transplants (limb transplants) showed clinical and histopathologic changes of the disease. The transplants may be used as a model of graft-versus-host disease in humans. Most interestingly, the transplant has a lower incidence of disease compared with other methods of bone marrow transplantation and represents an alternative to conventional bone marrow transplantation, which deserves further exploration. It may be possible to develop a new technique for bone marrow transplantation based on this surgical approach. It is proposed that the transfer of vascularized blocks of bone/marrow into prospective recipients as opposed to cellular bone marrow transplants may be preferable.


Interstitial MR and CT lymphography with Gd-dTPA-co-alpha, omega-diaminoPEG(1450) and Gd-dTPA-co-1,6-diaminohexane polymers: preliminary experience.
The authors assessed the efficacy of two gadolinium-based polymers used as lymphotrophic contrast media for computed tomography (CT) and magnetic resonance (MR) imaging. Two gadolinium-based polymers, gadolinium diethylenetriaminepentaacetic acid (DTPA)-co-1,6-diaminohexane (NC 22181) and Gd-DTPA-co-alpha, omega-diamino-polyethylene glycol(1450) (NC-66368), were formulated at a concentration of 80 mmol/L gadolinium. Doses of 0.1, 0.25, 1.0, or 2.0 mL per paw were administered subcutaneously into the hindpaws of normal rabbits. Spin-echo T1-weighted MR imaging (1.5 T) of rabbit popliteal and iliac nodes was performed before and immediately, 10 minutes, 2-3 hours, and 24 hours after injection. CT was performed 2-3 hours after injection of the high doses only. MR imaging revealed prompt enhancement of the popliteal nodes with both polymers at doses of 0.25 mL and above. For doses of 1.0 mL or less per paw, nodal percentage enhancement was maximal at 2 hours and then declined at 24 hours. At the highest doses, however, a reservoir of subcutaneous contrast material remained at the injection site and resulted in peak enhancement at 24 hours. At CT, popliteal node enhancement was faintly visible 2-3 hours after the administration of NC 22181. At lower doses, no enhancement was appreciable at CT. At 80 mmol/L formulations, the two gadolinium-based polymers provide excellent popliteal nodal enhancement on MR images. In addition, high doses of one polymer (NC 22181) were sufficiently concentrated in popliteal nodes to be visible on CT scans. Thus, this agent may be useful for both CT and MR lymphography.


Use of shake cultures in a semisolid thioglycolate medium for differentiating staphylococci from micrococci.
The standard diagnostic test for differentiating staphylococci from micrococci is based on the ability of the former to produce acid anaerobically in a glucose-containing growth medium. This test has been modified to provide greater convenience, easier interpretation of results, and better correlation with deoxyribonucleic acid (DNA) base composition. In the modified test, shake cultures in Brewer's fluid thioglycolate medium with 0.3% agar added are observed for growth in the anaerobic zone of the tubes. This test was applied to 125 strains of staphylococci and micrococci, and all except two strains gave results that were consistent with other criteria. Of particular interest were eight strains of Micrococcus saprophyticus and three strains of M. lactis that have a DNA composition of 30 to 37% guanine plus cytosine (GC). All 11 of these cultures produced anaerobic growth and thus would be classified as staphylococci. Strains of M. lactis that have a high GC content in their DNA grew only aerobically. Some cultures of staphylococci produced characteristic band patterns of anaerobic growth and other cultures produced only a few anaerobic colonies from an inoculum of 10(6) to 10(7) cells. These observations suggest some interesting genetic and metabolic capabilities in such cultures.


Differences in hepatocellular iron metabolism underlie sexual dimorphism in hepatocyte ferroptosis.
Males show higher incidence and severity than females in hepatic injury and many liver diseases, but the mechanisms are not well understood. Ferroptosis, an iron-mediated lipid peroxidation-dependent death, plays an important role in the pathogenesis of liver diseases. We determined whether hepatocyte ferroptosis displays gender difference, accounting for sexual dimorphism in liver diseases. Compared to female hepatocytes, male hepatocytes were much more vulnerable to ferroptosis by iron and pharmacological inducers including RSL3 and iFSP1. Male but not female hepatocytes exhibited significant increases in mitochondrial Fe2+ and mitochondrial ROS (mtROS) contents. Female hepatocytes showed a lower expression of iron importer transferrin receptor 1 (TfR1) and mitochondrial iron importer mitoferrin 1 (Mfrn1), but a higher expression of iron storage protein ferritin heavy chain 1 (FTH1). It is well known that TfR1 expression is positively correlated with ferroptosis. Herein, we showed that silencing FTH1 enhanced while knockdown of Mfrn1 decreased ferroptosis in HepG2 cells. Removing female hormones by ovariectomy (OVX) did not dampen but rather enhanced hepatocyte resistance to ferroptosis. Mechanistically, OVX potentiated the decrease in TfR1 and increase in FTH1 expression. OVX also increased FSP1 expression in ERK-dependent manner. Elevation in FSP1 suppressed mitochondrial Fe2+ accumulation and mtROS production, constituting a novel mechanism of FSP1-mediated inhibition of ferroptosis. In conclusion, differences in hepatocellular iron handling between male and female account, at least in part, for sexual dimorphism in induced ferroptosis of the hepatocytes.


Identification and characterization of staphylococcal enterotoxin types G and I from Staphylococcus aureus.
Staphylococcal enterotoxins are exotoxins produced by Staphylococcus aureus that possess emetic and superantigenic properties. Prior to this research there were six characterized enterotoxins, staphylococcal enterotoxin types A to E and H (referred to as SEA to SEE and SEH). Two new staphylococcal enterotoxin genes have been identified and designated seg and sei (staphylococcal enterotoxin types G and I, respectively). seg and sei consist of 777 and 729 nucleotides, respectively, encoding precursor proteins of 258 (SEG) and 242 (SEI) deduced amino acids. SEG and SEI have typical bacterial signal sequences that are cleaved to form toxins with 233 (SEG) and 218 (SEI, predicted) amino acids, corresponding to mature proteins of 27,043 Da (SEG) and 24,928 Da (SEI). Biological activities for SEG and SEI were determined with recombinant S. aureus strains. SEG and SEI elicited emetic responses in rhesus monkeys upon nasogastric administration and stimulated murine T-cell proliferation with the concomitant production of interleukin 2 (IL-2) and gamma interferon (IFN-gamma), as measured by cytokine enzyme-linked immunoassays. SEG and SEI are related to other enterotoxins of S. aureus and to streptococcal pyrogenic exotoxin A (SpeA) and streptococcal superantigen (SSA) of Streptococcus pyogenes. Phylogenetic analysis and comparisons of amino acid and nucleotide sequence identities were performed on related staphylococcal and streptococcal protein toxins to group SEG and SEI among the characterized toxins. SEG is most similar to SpeA, SEB, SEC, and SSA (38 to 42% amino acid identity), while SEI is most similar to SEA, SEE, and SED (26 to 28% amino acid identity). Polyclonal antiserum was generated against purified histidine-tagged SEG and SEI (HisSEG and HisSEI). Immunoblot analysis of the enterotoxins, toxic-shock syndrome toxin 1, and SpeA with antiserum prepared against HisSEG and HisSEI revealed that SEG shares some epitopes with SEC1 while SEI does not.


Scale effects and human impact on the elevational species richness gradients.
Despite two centuries of effort in characterizing environmental gradients of species richness in search of universal patterns, surprisingly few of these patterns have been widely acknowledged. Species richness along altitudinal gradients was previously assumed to increase universally from cool highlands to warm lowlands, mirroring the latitudinal increase in species richness from cool to warm latitudes. However, since the more recent general acceptance of altitudinal gradients as model templates for testing hypotheses behind large-scale patterns of diversity, these gradients have been used in support of all the main diversity hypotheses, although little consensus has been achieved. Here we show that when resampling a data set comprising 400,000 records for 3,046 Pyrenean floristic species at different scales of analysis (achieved by varying grain size and the extent of the gradients sampled), the derived species richness pattern changed progressively from hump-shaped to a monotonic pattern as the scale of extent diminished. Scale effects alone gave rise to as many conflicting patterns of species richness as had previously been reported in the literature, and scale effects lent significantly different statistical support to competing diversity hypotheses. Effects of scale on current studies may be affected by human activities, because montane ecosystems and human activities are intimately connected. This interdependence has led to a global reduction in natural lowland habitats, hampering our ability to detect universal patterns and impeding the search for universal diversity gradients to discover the mechanisms determining the distribution of biological diversity on Earth.


Activation-induced T helper cell death contributes to Th1/Th2 polarization following murine Schistosoma japonicum infection.
In chronic infectious diseases, such as schistosomiasis, pathogen growth and immunopathology are affected by the induction of a proper balanced Th1/Th2 response to the pathogen and by antigen-triggered activation-induced T cell death. Here, by using S. japonicum infection or schistosome antigens-immunized mouse model, or antigens in vitro stimulation, we report that during the early stage of S. japonicum infection, nonegg antigens trigger Th2 cell apoptosis via the granzyme B signal pathway, contributing to Th1 polarization, which is thought to be associated with worm clearance and severe schistosomiasis. Meanwhile, after the adult worms lay their eggs, the egg antigens trigger Th1 cell apoptosis via the caspase pathway, contributing to Th2 polarization, which is associated with mild pathology and enhanced survival of both worms and their hosts. Thus, our study suggests that S. japonicum antigen-induced Th1 and Th2 cell apoptosis involves the Th1/Th2 shift and favorites both hosts and parasites.


Dramatic changes in mitochondrial substrate use at critically high temperatures: a comparative study using Drosophila.
Ectotherm thermal tolerance is critical to species distribution, but at present the physiological underpinnings of heat tolerance remain poorly understood. Mitochondrial function is perturbed at critically high temperatures in some ectotherms, including insects, suggesting that heat tolerance of these animals is linked to failure of oxidative phosphorylation (OXPHOS) and/or ATP production. To test this hypothesis, we measured mitochondrial oxygen consumption rate in six Drosophila species with different heat tolerance using high-resolution respirometry. Using a substrate-uncoupler-inhibitor titration protocol, we examined specific steps of the electron transport system to study how temperatures below, bracketing and above organismal heat limits affect mitochondrial function and substrate oxidation. At benign temperatures (19 and 30°C), complex I-supported respiration (CI-OXPHOS) was the most significant contributor to maximal OXPHOS. At higher temperatures (34, 38, 42 and 46°C), CI-OXPHOS decreased considerably, ultimately to very low levels at 42 and 46°C. The enzymatic catalytic capacity of complex I was intact across all temperatures and accordingly the decreased CI-OXPHOS is unlikely to be caused directly by hyperthermic denaturation/inactivation of complex I. Despite the reduction in CI-OXPHOS, maximal OXPHOS capacity was maintained in all species, through oxidation of alternative substrates - proline, succinate and, particularly, glycerol-3-phosphate - suggesting important mitochondrial flexibility at temperatures exceeding the organismal heat limit. Interestingly, this failure of CI-OXPHOS and compensatory oxidation of alternative substrates occurred at temperatures that correlated with species heat tolerance, such that heat-tolerant species could defend 'normal' mitochondrial function at higher temperatures than sensitive species. Future studies should investigate why CI-OXPHOS is perturbed and how this potentially affects ATP production rates.


Cryoablation of stellate ganglia and atrial arrhythmia in ambulatory dogs with pacing-induced heart failure.
There is an association between autonomic nerve discharges and atrial arrhythmias (including bradycardia and tachycardia) in ambulatory dogs with pacing-induced heart failure (HF). The purpose of this study was to test the hypothesis that stellate ganglia ablation can reduce the incidence of atrial arrhythmias in a canine model of pacing-induced HF. Cryoablation of the caudal half of the left and right stellate ganglia and T2-T4 thoracic sympathetic ganglia was performed in six dogs (experimental group). Left upper stellate ganglia nerve activity, vagal nerve activity, and electrocardiogram were continuously recorded using an implanted radiotransmitter. After 2 weeks of baseline recording, rapid right ventricular pacing (28 +/- 4 days) was used to induce HF. The control group (N = 6) underwent the same procedures except for cryoablation. The experimental group had no episodes of paroxysmal atrial tachycardia (P <.0001 vs control). Cryoablation significantly (P = .0097) reduced prolonged (>3 seconds) sinus pause episodes from 5 +/- 6 to 0 on day 1, from 250 +/- 424 to 11 +/- 11 on day 7, and from 123 +/- 206 to 30 +/- 33 on day 14 after induction of HF. In the experimental group only, vagal nerve activity may occur alone without concomitant stellate ganglia nerve activity. However, these isolated vagal nerve activity episodes did not result in prolonged sinus pause. Histologic studies confirmed successful cryoablation of the caudal half of the stellate ganglia. Cryoablation of bilateral stellate and T2-T4 thoracic ganglia significantly reduced paroxysmal atrial tachycardia and prolonged sinus pause episodes induced by sympathetic discharges in dogs with pacing-induced HF.


Comparison of transurethral incision of the prostate and silodosin in patients having benign prostatic obstruction in terms of retrograde ejaculation.
To compare the functional outcomes and retrograde ejaculation (RE) after transurethral incision of the prostate (TUIP) or silodosin in bladder outlet obstruction (BOO) secondary to a small prostate. Prospectively collected data from December 2011 through December 2014 of 192 LUTS patients having fertility concerns with prostate volume smaller than 40 ml receiving either TUIP or silodosin treatment were prospectively reviewed. The treatment outcomes were evaluated and compared. TUIP was performed in 96 cases and silodosin 8 mg was prescribed in 96 cases. At 12th months after TUIP or continuous silodosin treatment, the decrease in mean International Prostate Symptom Score (IPSS) and postvoiding residual urine (PVR) and the improvement of mean maximal flow rate (Qmax) were significant (p = 0.000). The improvement in IPPS and Qmax was significantly higher in TUIP group compared to silodosin group (p = 0.005, p = 0.000) with a lower rate of retrograde ejaculation (RE) in TUIP group. (11/96 vs 33/96) (p = 0.000) Conclusions: Both TUIP and silodosin ensures comparable improvement in PVR, IPSS and Qmax with a lower rate of RE on the TUIP group in prostates weighing less than 40 grams suggesting that TUIP is a better choice in younger patiens seeking preservation of ejaculation with fertility concerns.


FDA Approval Summary: Selumetinib for Plexiform Neurofibroma.
On April 10, 2020, the FDA approved selumetinib (KOSELUGO, AstraZeneca) for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. Approval was based on demonstration of a durable overall response rate per Response Evaluation in Neurofibromatosis and Schwannomatosis criteria and supported by observed clinical improvements in plexiform neurofibroma-related symptoms and functional impairments in 50 pediatric patients with inoperable plexiform neurofibromas in a single-arm, multicenter trial. The overall reponse rate per NCI investigator assessment was 66% (95% confidence interval, 51-79) with at least 12 months of follow-up. The median duration of response was not reached, and 82% of responding patients experienced duration of response ≥12 months. Clinical outcome assessment endpoints provided supportive efficacy data. Risks of selumetinib are consistent with MAPK (MEK) inhibitor class effects, including ocular, cardiac, musculoskeletal, gastrointestinal, and dermatologic toxicities. Safety was assessed across a pooled database of 74 pediatric patients with plexiform neurofibromas and supported by adult and pediatric selumetinib clinical trial data in cancer indications. The benefit-risk assessment for selumetinib in patients with inoperable plexiform neurofibromas was considered favorable.


Peripartum Cardiomyopathy.
Peripartum cardiomyopathy is defined by left ventricular dysfunction and development of cardiac failure without a known cause and occurring in the final month of pregnancy and up to 5 months postpartum. Peripartum cardiomyopathy is an important and steadily increasing cause of pregnancy-associated morbidity and mortality. The incidence of peripartum cardiomyopathy in the United States has been estimated recently as 1 in 2,230 births and approximately 1 in 1,000 births worldwide. The etiopathogenesis of peripartum cardiomyopathy remains elusive; however, it is generally thought to be from a two-hit hypothesis in which an underlying cardiomyocyte protein mutation results in apoptosis mediated by vascular and hormonal actions. Clinical recognition is integral to the management of this disease, because there must be careful exclusion of alternative etiologies. Although there are no disease-specific therapies, management of peripartum cardiomyopathy is based on treatment of heart failure and its symptoms, repressing neurohormonal responses, and preventing long-term sequelae. Ventricular function recovery and rates of recurrence of peripartum cardiomyopathy vary by ethnicity and geography. Mortality rates associated with peripartum cardiomyopathy range from 3% to 40%, depending on geographic location. In this review, normal cardiovascular adaptations in pregnancy are summarized and current evidence-based clinical management of the disease is discussed.


Measurement of the Three-Dimensional Muscle Endpoint Forces in the Extended Thumb and Its Application to Determining Muscle Combinations that Enable Lateral Pinch Force Production Throughout the Plane of Flexion-Extension.
Functional outcomes of tendon transfer surgeries, designed to restore lateral pinch grasp to persons following cervical spinal cord injury, have been mixed. That is, pinch force magnitudes have varied by 10-fold and have been reported to be as low as low as tenths of a pound. We believe a novel tendon transfer approach in which the donor muscle actuates a small group of paralyzed thumb muscles, instead of just the flexor pollicis longus (FPL) muscle (the current approach), will enable endpoint forces that are better directed and therefore a consistently stronger pinch force following surgery. We further believe that such surgeries can be better designed to account for grasp force production throughout the entire plane of flexion-extension if muscle endpoint forces in the extended thumb are known. Consequently, we measured muscle endpoint forces in the extended thumb in 6 cadaveric specimens after a force of 10 N was applied to each muscle. Further, we simulated a tendon transfer surgery in which the donor muscle applied equal force to each muscle in 246 small groups of muscles, calculated the direction of the resulting endpoint force throughout the flexion-extension plane, and determined if those groups of muscles produced a better directed force than FPL's. While we found that 3 individual muscles and 52 muscle groups could produce desirably directed endpoint forces in parts of the flexion-extension plane, no muscle or muscle group could produce well-directed endpoint forces throughout the flexion-extension plane. We concluded that a group of muscles could likely be found if the donor muscle provided different levels of force to each of the muscles in a muscle group. This would be possible through intentional geometric manipulation of the donor-to-recipient muscle attachment to allow for unequal splitting of donor muscle force.Clinical Relevance-This work aims to determine whether the same combination of thumb muscles can produce well-directed endpoint forces throughout the flexion-extension plane. If so, then this work informs surgeons which muscle groups could be involved in a tendon transfer to restore lateral pinch grasp ability throughout the plane of flexion-extension in person with cervical spinal cord injury.


Translational invariance in nucleation theories: theoretical formulation.
The consequences of spontaneously broken translational invariance on the nucleation-rate statistical prefactor in theories of first-order phase transitions are analyzed. A hybrid, semiphenomenological approach based on field-theoretic analyses of condensation and modern density-functional theories of nucleation is adopted to provide a unified prescription for the incorporation of translational-invariance corrections to nucleation-rate predictions. A connection between these theories is obtained starting from a quantum-mechanical Hamiltonian and using methods developed in the context of studies on Bose-Einstein condensation. An extremum principle is used to derive an integro-differential equation for the spatially nonuniform mean-field order-parameter profile; the appropriate order parameter becomes the square root of the fluid density. The importance of the attractive intermolecular potential is emphasized, whereas the repulsive two-body potential is approximated by considering hard-sphere collisions. The functional form of the degenerate translational eigenmodes in three dimensions is related to the mean-field order parameter, and their contribution to the nucleation-rate prefactor is evaluated. The solution of the Euler-Lagrange variational equation is discussed in terms of either a proposed variational trial function or the complete numerical solution of the associated boundary-value integro-differential problem. Alternatively, if the attractive potential is not explicitly known, an approach that allows its formal determination from its moments is presented.


Evaluation of Fecal Incontinence in Pediatric Functional Constipation: Clinical Utility of Anorectal and Colon Manometry.
The aim of the study is to evaluate the utility of motility studies in pediatric functional constipation with/without fecal incontinence. Patients with functional constipation and failure to conventional therapy undergoing colonic manometry (CM) and/or anorectal manometry (ARM) manometry were classified as functional constipation without fecal incontinence (FC) or with fecal incontinence (FCI). Clinical data, motility parameters, and treatment outcomes were compared. A total of 280 were included, and all patients underwent CM (229 FC and 51 FCI) and 219 ARM. We found no difference in CM interpretation and presence of normal high amplitude propagating contractions (HAPCs) between groups; however, patients with FCI had higher frequency and presence of HAPCs and normal gastrocolonic meal response (GC). No CM parameter predicted outcomes. In FC, more patients with an abnormal CM responded to therapy compared to those with a normal study (79% vs 65% respectively, P = 0.04). FCI patients had lower median anal resting pressure compared to FC (49 vs 66 mmHg, respectively, P = 0.03); no other ARM parameter differentiated FC from FCI. We found no association between therapy response and ARM interpretation (P = 0.847) or any ARM parameter. A multivariate analysis found only male gender was associated with FCI (P < 0.001). FCI patients have higher frequency of normal CM parameters compared to FC, but overall interpretation was no different. CM helped predict response to therapy in FC but not in FCI. ARM demonstrated no added benefit in the evaluation of functional constipation with/without soiling. Patients with both normal ARM and CM had a lower response to therapy than those with abnormal studies.


Visual Analytics for Congestive Heart Failure Mortality Prediction.
Several indices exist to classify Congestive Heart Failure (CHF) patients' propensity for early mortality; however, they are primarily based on limited data and are not intuitive to use at the point of care. We investigate a novel, data-driven, risk assessment and visualization approach to investigate mortality prediction of CHF patients using data retrieved from an intensively digitized hospital's data repository. Combining well-known, computationally efficient, dimensionality reduction (DR) methods with 2-d information visualization, the method classifies and visualizes CHF patients into high and low risk groups, contextualized by the factors driving their classification. The DR method performed similar to logistic regression (LR), but visualized the classification and its significant factors at the population level, individual level and the potential impact of interventions for an individual patient. These are encouraging results in favor of the proposed visualization approach, and contributes to the current focus on advancing patient care via large-scale visual analytics.


Strain variation of Lyme disease spirochetes isolated from Ixodes ricinus ticks and rodents collected in two endemic areas in Switzerland.
The relationship among Lyme borreliosis, Borrelia genospecies, rodent reservoirs, and Ixodes ricinus L. ticks was studied in two endemic areas in Switzerland. Ear punch biopsies and sampling of internal organs were used to isolate Borrelia burgdorferi (Johnson, Schmid, Hyde, Steigerwalt and Brenner) from small mammals, Apodemus sylvaticus L., A. flavicollis Melchoir, Clethrionomys glareolus Schreber. Spirochetes were isolated from ear tissue and spleen of the rodents. Isolates were homogeneous and belonged to typing group II identified as B. afzelii (Canica, Nato, du Merle, Mazie, Baranton and Postic). Our data show that a specific association exists between B. afzelii and rodent reservoirs in European foci. Borreliae were also isolated from field-collected I. ricinus ticks from the same study areas. Proteinic and antigenic analysis indicated that more than one genospecies were present in the tick population. This suggests that other vertebrate hosts may serve as reservoirs of other Borrelia genospecies implicated with Lyme disease.


Glycemic Change After Pancreaticoduodenectomy: A Population-Based Study.
The purpose of this population-based study was to determine the change of glucose metabolism in patients undergoing pancreaticoduodenectomy (PD).We conducted a nationwide cohort study using data from Taiwan's National Health Insurance Research Database collected between 2000 and 2010. Our sample included 861 subjects with type 2 diabetes mellitus (DM) and 3914 subjects without DM.Of 861 subjects with type 2 diabetes, 174 patients (20.2%) experienced resolution of their diabetes after PD, including patients with pancreatic ductal adenocarcinoma (PDAC) (20.5%), and non-PDAC (20.1%). Using a multiple logistic regression model, we found that subjects with comorbid chronic pancreatitis (odds ratio, 0.356; 95% CI, 0.167-0.759; P = 0.007) and use of insulin (odds ratio, 0.265; 95% CI, 0.171-0.412; P < 0.001) had significantly lower rates of resolution of diabetes. In the 3914 subjects without diabetes, the only statistically significant comorbidity contributing to pancreatogenic diabetes was chronic pancreatitis (odds ratio, 1.446; 95% CI, 1.146-1.823; P = 0.002).Subjects with comorbid chronic pancreatitis and use of insulin had lower rates of resolution of DM after PD. In subjects without diabetes, chronic pancreatitis contributed significantly to the development of pancreatogenic DM.


When Bio Meets Technology: Biohybrid Neural Interfaces.
The development of electronics capable of interfacing with the nervous system is a rapidly advancing field with applications in basic science and clinical translation. Devices containing arrays of electrodes can be used in the study of cells grown in culture or can be implanted into damaged or dysfunctional tissue to restore normal function. While devices are typically designed and used exclusively for one of these two purposes, there have been increasing efforts in developing implantable electrode arrays capable of housing cultured cells, referred to as biohybrid implants. Once implanted, the cells within these implants integrate into the tissue, serving as a mediator of the electrode-tissue interface. This biological component offers unique advantages to these implant designs, providing better tissue integration and potentially long-term stability. Herein, an overview of current research into biohybrid devices, as well as the historical background that led to their development are provided, based on the host anatomical location for which they are designed (CNS, PNS, or special senses). Finally, a summary of the key challenges of this technology and potential future research directions are presented.


Inside the Black Box of Improving on Nursing Home Quality Measures.
Nursing Home Compare (NHC) reports quality measures (QMs) for nursing homes (NHs) as part of its 5-star rating system. Most of the QMs are based on facility self-reported data, prompting questions about their validity. To better understand how NHs interact with the QMs, we used qualitative methods, including semistructured interviews with NH personnel (n = 110), NH provider association representatives (n = 23), and observations of organizational processes in 12 NHs in three states. We found that most NHs are working to improve the quality of care they provide, not merely their QM scores. However, our interviews and observations revealed limitations with the QMs, suggesting that the QMs-on their own-may not accurately reflect the quality of care NHs provide. Our findings suggest several changes to improve NHC, including adding information related to resident and family experience, providing greater risk adjustment, and providing incentives for NHs that serve socially and medically complex residents.


Multiple resolution skeletons.
This paper presents a new algorithm to compute skeletons of noisy images of objects which can be described as ``amorphous blobs.'' Such a requirement arose from our research to obtain a better understanding of the role of the pseudopod in leukocyte locomotion. It involves the modeling and detection of pseudopods which are by their nature nonrigid bodies appearing on the cell's surface membrane. By computing skeletons at different resolutions, a filtered version can be produced without violating the constraints imposed by the semantic knowledge of pseudopod morphology. The filtered version incorporates all the significant ``events'' that occur at the different resolutions. The resolution at which the shape is examined is related to the degree of smoothing, in that the lower the resolution gets, the higher the degree of smoothing. Skeleton branches that persist over several scales arise from convexities that are locally as well as globally significant. Their stability is related to their perceptual significance. Our approach is to combine an initial region centered description (skeleton) with a boundary analysis executed at different resolutions. Having computed the skeleton at different scales, we then use those computed at the lower resolutions as a measure of how global the underlying convexity is. Clearly the skeletons computed at higher resolutions represent the exact location and orientation of the underlying convexities.


The consequences of including non-additive effects on the genetic evaluation of harvest body weight in Coho salmon (Oncorhynchus kisutch).
In this study, we used different animal models to estimate genetic and environmental variance components on harvest weight in two populations of Oncorhynchus kisutch, forming two classes i.e. odd- and even-year spawners. The models used were: additive, with and without inbreeding as a covariable (A + F and A respectively); additive plus common environmental due to full-sib families and inbreeding (A + C + F); additive plus parental dominance and inbreeding (A + D + F); and a full model (A + C + D + F). Genetic parameters and breeding values obtained by different models were compared to evaluate the consequences of including non-additive effects on genetic evaluation. Including inbreeding as a covariable did not affect the estimation of genetic parameters, but heritability was reduced when dominance or common environmental effects were included. A high heritability for harvest weight was estimated in both populations (even = 0.46 and odd = 0.50) when simple additive models (A + F and A) were used. Heritabilities decreased to 0.21 (even) and 0.37 (odd) when the full model was used (A + C + D + F). In this full model, the magnitude of the dominance variance was 0.19 (even) and 0.06 (odd), while the magnitude of the common environmental effect was lower than 0.01 in both populations. The correlation between breeding values estimated with different models was very high in all cases (i.e. higher than 0.98). However, ranking of the 30 best males and the 100 best females per generation changed when a high dominance variance was estimated, as was the case in one of the two populations (even). Dominance and common environmental variance may be important components of variance in harvest weight in O. kisutch, thus not including them may produce an overestimation of the predicted response; furthermore, genetic evaluation was seen to be partially affected, since the ranking of selected animals changed with the inclusion of non-additive effects in the animal model.


Tolterodine treatment for children with symptoms of urinary urge incontinence suggestive of detrusor overactivity: results from 2 randomized, placebo controlled trials.
We report the results of the first 2 large randomized controlled trials designed to evaluate the efficacy and safety of tolterodine extended release in children 5 to 10 years old with symptoms of urinary urge incontinence suggestive of detrusor overactivity. Two double-blind, placebo controlled trials were conducted sequentially. Children 5 to 10 years old with incontinence suggestive of detrusor overactivity (1 or more diurnal incontinence episodes per 24 hours) were randomized to tolterodine (2 mg daily) or placebo for 12 weeks. The primary end point was the change from baseline to week 12 in the number of incontinence episodes per week. Changes from baseline in the number of voids per 24 hours and volume of urine per void were also evaluated. Exploratory analyses were conducted to determine whether particular subsets of patients showed differential responses to treatment. A total of 224 and 487 children (mean age 8 years) were randomized to placebo and tolterodine, respectively. Differences in the number of incontinence episodes per week, voids per 24 hours, and volume of urine per void between tolterodine and placebo did not reach statistical significance. This finding may be explained by a high placebo response and under dosage of tolterodine among children with greater body weight. Tolterodine was well tolerated. Analysis of the primary efficacy outcome did not reveal a statistically significant effect of treatment. However, secondary analyses demonstrated that tolterodine was well tolerated among 5 to 10-year-old children with diurnal incontinence. Exploratory analyses also showed that children weighing 35 kg or less with detrusor overactivity characterized by incontinence and/or frequent voiding benefited most from tolterodine treatment, suggesting that a weight adjusted dosing regimen may be required for optimal response among older and heavier children.


[Characterization of phenylpyruvic acid and beta-benzyl phenylpyruvic acid by UV, IR, MS, and 1H NMR].
Characterization of phenylpyruvic acid (PPA) and beta-benzyl phenylpyruvic acid (BPPA) by UV, IR, MS and 1H NMR has been carried out. It is found that the absorption at 240 and 365 nm are observed in the UV spectrum of PPA and the absorption at 210 nm is the only one in BPPA. These demonstrate that PPA has the olefinic alcohol structure and BPPA hasn't. The IR absorption at 1,624.38 and 1,697.25 cm-1 of PPA are originated from two carboxy C=O because of its gem-diol structure, and the absorption at 1,706.6 and 1,728.6 cm-1 in BPPA is assignable to keto C=O and carboxy C=O, respectively. The main peaks in the MS spectrum of PPA are 164, 119, 91, 65, 45, 39, and BPPA 254, 236, 209, 181, 91, 77, 65, 39. The peaks at 4.124, 6.381, 7.184-7.748, 9.268 are observed in the 1H NMR spectrum of PPA and the peaks in BPPA are 2.90-3.02, 3.29-3.40, 4.73-4.81, 7.04-7.44, 8.99.


Influence of preculture on the prefreeze and postthaw characteristics of hepatocytes.
Recent studies performed in our laboratory have shown that a brief period of preculture prior to cryopreservation improves the postthaw viability of hepatocytes. The purpose of this investigation is to characterize specific metabolic and biochemical characteristics of the hepatocytes (both frozen and nonfrozen) to help elucidate the role of preculture on the postthaw viability. Fresh and thawed hepatocytes were cultured in a bioartificial liver (BAL) to determine albumin secretion as a function of time in culture. In addition, cell extracts were analyzed using nuclear magnetic resonance (NMR) spectroscopy to quantify changes in cell membrane composition and energetics as a function of time in culture prefreeze and postthaw. The results of these studies showed an increase in albumin concentration in the culture medium with time in culture for the period tested for both fresh and frozen and thawed hepatocytes. NMR spectroscopy of lipid extracts indicates that in vitro culture of hepatocytes results in an increase in cholesterol relative to membrane phospholipid. Moreover, the NMR results also indicate phospholipid interconversion, via specific lipases in cultured hepatocytes, and these changes are consistent with water permeability measurements performed previously. Significant changes in phosphoenergetics were also observed, with the net energy charge for the cells increasing significantly with time in culture. In addition, NMR spectra show increased levels of 6-phosphogluconate, another indicator of the cellular response to the stresses of isolation and ex vivo culture. These results suggest that energetic considerations may be a significant factor in the ability of hepatocytes to survive the stresses of freezing and thawing. Significant shifts in membrane phospholipids may also influence membrane permeability and postthaw survival.


1,25-(OH)2D3 participates and modulates airway remodeling by reducing MGP and TGF-β1 expression in TNF-α-induced airway smooth muscle cells.
Asthma has been proven to be a respiratory disorder that is characterized by the airway remodeling, airway inflammation and reversible airway obstruction. The 1,25-hydroxyvitamin D3 (1,25-(OH)2D3) plays critical roles in delaying remodeling. To investigate the effects of 1,25-(OH)2D3 on the airway remodeling in tumor necrosis factor α (TNF-α)-induced airway smooth muscle cells (ASMCs). The human ASMCs were divided into a blank control group (without treatment), a TNF-α group (treated with 10 ng/mL TNF-α) and a 1,25-(OH)2D3+TNF-α group (pre-treated with 10-7 M 1,25-(OH)2D3, then with 10 ng/mL TNF-α). The MTT assay was used to evaluate cell proliferation. Matrix Gla protein (MGP) and transforming growth factor β1 (TGF-β1) were examined using western blot assay. The TNF-α treatment significantly increased ASMCs proliferation and enhanced MGP and TGF-β1 expression compared to a blank control group (p < 0.05). The 1,25-(OH)2D3 treatment (1,25-(OH)2D3+TNF-α group) significantly inhibited cell viability (0.83 ±0.01), compared to that in the TNF-α group (0.92 ±0.01) (p < 0.05). The 1,25-(OH)2D3 treatment significantly downregulated MGP expression (0.61 ±0.02), compared to that of the TNF-α group (1.51 ±0.35) (p < 0.05). The 1,25-(OH)2D3 treatment significantly reduced TGF-β1 expression (0.69 ±0.17), compared to that of the TNF-α group (1.6 ±0.18) (p < 0.05). The 1,25-(OH)2D3 could participate and modulate airway remodeling by reducing MGP and TGF-β1 expression in TNF-α-induced ASMCs. This study provided therapeutic insight and theoretical basis for clinical research.


Pathogenesis of experimental rhesus cytomegalovirus infection.
Human cytomegalovirus (HCMV) establishes and maintains a lifelong persistence following infection in an immunocompetent host. The determinants of a stable virus-host relationship are poorly defined. A nonhuman primate model for HCMV was used to investigate virological and host parameters of infection in a healthy host. Juvenile rhesus macaques (Macaca mulatta) were inoculated with rhesus cytomegalovirus (RhCMV), either orally or intravenously (i.v. ), and longitudinally necropsied. None of the animals displayed clinical signs of disease, although hematologic abnormalities were observed intermittently in i.v. inoculated animals. RhCMV DNA was detected transiently in the plasma of all animals at 1 to 2 weeks postinfection (wpi) and in multiple tissues beginning at 2 to 4 wpi. Splenic tissue was the only organ positive for RhCMV DNA in all animals. The location of splenic cells expressing RhCMV immediate-early protein 1 (IE1) in i.v. inoculated animals changed following inoculation. At 4 to 5 wpi, most IE1-positive cells were perifollicular, and at 25 wpi, the majority were located within the red pulp. All animals developed anti-RhCMV immunoglobulin M (IgM) antibodies within 1 to 2 wpi and IgG antibodies within 2 to 4 wpi against a limited number of viral proteins. Host reactivity to RhCMV proteins increased in titer (total and neutralizing) and avidity with time. These results demonstrate that while antiviral immune responses were able to protect from disease, they were insufficient to eliminate reservoirs of persistent viral gene expression.


A new reliable reference gene UBA52 for quantitative real-time polymerase chain reaction studies in pyloric cecal tissues of the starfish Asterias rubens.
The starfish Asterias rubens is one of the most abundant echinoderm species in the White, Barents, North, and Baltic Seas. This species is an important component of marine ecosystems and a model object for certain biological studies, in particular those requiring quantitative estimation of gene expression. As a rule, expression at the transcriptional level is estimated by real-time qPCR using the ΔΔCt method, which allows the comparison of the copy number of target gene transcripts in samples with unknown mRNA/cDNA concentration. Application of this method requires normalization of the results relative to genes with stable expression levels (reference genes). The identification of reference genes is still a challenging task since data of this kind are missing for certain taxa, whereas the use of "standard" endogenous control genes without additional tests might lead to erroneous conclusions. We performed a preliminary analysis of the expression of many housekeeping genes in the pyloric ceca of A. rubens by high-throughput sequencing under normal and heat shock conditions. For one of them, the ubiquitin gene UBA52, low variation of expression (not greater than 2-fold) was shown using real-time qPCR. Tissues of pyloric ceca of normal adults and underyearlings and of adults after heat shock were used. The data obtained suggest that the UBA52 gene may be used as reference for normalization of gene expression at the mRNA level in the starfish A. rubens and probably in closely related species.


Dioxin and Related Compound Detection: Perspectives for Optical Monitoring.
Dioxins and related compounds are environmental xenobiotics that are dangerous to human life, due to the accumulation and persistence in the environment and in the food chain. Cancer, reproductive and developmental issues, and damage to the immune system and endocrine system are only a few examples of the impact of such substances in everyday life. For these reasons, it is fundamental to detect and monitor these molecules in biological samples. The consolidated technique for analytical evaluation is gas chromatography combined with high-resolution mass spectrometry. Nowadays, the development of mid-infrared optical components like broadband laser sources, optical frequency combs, high performance Fourier-transform infrared spectroscopy, and plasmonic sensors open the way to new techniques for detection and real time monitoring of these organic pollutants in gaseous or liquid phase, with sufficient sensitivity and selectivity, and in short time periods. In this review, we report the latest techniques for the detection of dioxins, furans and related compounds based on optical and spectroscopic methods, looking at future perspectives.


Diagnostic accuracy of ultrasonography, MRI and MR arthrography in the characterisation of rotator cuff disorders: a systematic review and meta-analysis.
Different diagnostic imaging modalities, such as ultrasonography (US), MRI, MR arthrography (MRA) are commonly used for the characterisation of rotator cuff (RC) disorders. Since the most recent systematic reviews on medical imaging, multiple diagnostic studies have been published, most using more advanced technological characteristics. The first objective was to perform a meta-analysis on the diagnostic accuracy of medical imaging for characterisation of RC disorders. Since US is used at the point of care in environments such as sports medicine, a secondary analysis assessed accuracy by radiologists and non-radiologists. A systematic search in three databases was conducted. Two raters performed data extraction and evaluation of risk of bias independently, and agreement was achieved by consensus. Hierarchical summary receiver-operating characteristic package was used to calculate pooled estimates of included diagnostic studies. Diagnostic accuracy of US, MRI and MRA in the characterisation of full-thickness RC tears was high with overall estimates of sensitivity and specificity over 0.90. As for partial RC tears and tendinopathy, overall estimates of specificity were also high (>0.90), while sensitivity was lower (0.67-0.83). Diagnostic accuracy of US was similar whether a trained radiologist, sonographer or orthopaedist performed it. Our results show the diagnostic accuracy of US, MRI and MRA in the characterisation of full-thickness RC tears. Since full thickness tear constitutes a key consideration for surgical repair, this is an important characteristic when selecting an imaging modality for RC disorder. When considering accuracy, cost, and safety, US is the best option.


The physiological effects of smoking on the respiratory system.
Knowledge about the harmful effects of smoking on the lungs is high among the general population. This damage can occur to both active and passive smokers. Although scientific understanding in this area is incomplete we do have some knowledge about how individual toxic substances in cigarette smoke act on the lung tissues. There is great variation in smokers' susceptibility to the harmful effects of tobacco dependence. The reasons for this are complex and the role of genetic factors requires more research.


Association of cytochrome b translational activator proteins with the mitochondrial membrane: implications for cytochrome b expression in yeast.
The products of the nuclear genes CBS1 and CBS2 are both required for translational activation of mitochondrial apocytochrome b in yeast. We report the intramitochondrial localization of both proteins by use of specific antisera. Based on its solubilization properties the CBS1 protein is presumed to be a component of the mitochondrial membrane; the detergent concentrations needed to release CBS1 from mitochondria are almost the same as for cytochrome c1. In contrast, CBS2 behaves like a soluble protein, with some characteristics of a membrane-associated protein. A model is presented for translational activation of cytochrome b, which might also be applicable to translational regulation of other mitochondrial genes.


Chemical-mineralogical characterisation of coarse recycled concrete aggregate.
The construction industry is now putting greater emphasis than ever before on increasing recycling and promoting more sustainable waste management practices. In keeping with this approach, many sectors of the industry have actively sought to encourage the use of recycled concrete aggregate (RCA) as an alternative to primary aggregates in concrete production. The results of a laboratory experimental programme aimed at establishing chemical and mineralogical characteristics of coarse RCA and its likely influence on concrete performance are reported in this paper. Commercially produced coarse RCA and natural aggregates (16-4 mm size fraction) were tested. Results of X-ray fluorescence (XRF) analyses showed that original source of RCA had a negligible effect on the major elements and a comparable chemical composition between recycled and natural aggregates. X-ray diffraction (XRD) analyses results indicated the presence of calcite, portlandite and minor peaks of muscovite/illite in recycled aggregates, although they were directly proportioned to their original composition. The influence of 30%, 50%, and 100% coarse RCA on the chemical composition of equal design strength concrete has been established, and its suitability for use in a concrete application has been assessed. In this work, coarse RCA was used as a direct replacement for natural gravel in concrete production. Test results indicated that up to 30% coarse RCA had no effect on the main three oxides (SiO2, Al2O3 and CaO) of concrete, but thereafter there was a marginal decrease in SiO2 and increase in Al2O3 and CaO contents with increase in RCA content in the mix, reflecting the original constituent's composition.


An updated overview of diabetic nephropathy: Diagnosis, prognosis, treatment goals and latest guidelines.
Diabetic nephropathy (DN) is a major healthcare challenge. It occurs in up to 50% of those living with diabetes, is a major cause of end-stage kidney disease (ESKD) that requires treatment with dialysis or renal transplantation, and is associated with significantly increased cardiovascular morbidity and mortality. DN is a clinical syndrome characterized by persistent albuminuria and a progressive decline in renal function, but it is increasingly recognized that the presentation and clinical course of kidney disease in diabetes is heterogeneous. The term diabetic kidney disease (DKD) is now commonly used to encompass the spectrum of people with diabetes who have either albuminuria or reductions in renal function. In this article, the clinical presentation and approach to diagnosis of DKD will be discussed, as will its prognosis. The general principles of management of DKD will also be reviewed with reference to current international guidelines.


HLA class I binding 9mer peptides from influenza A virus induce CD4 T cell responses.
Identification of human leukocyte antigen class I (HLA-I) restricted cytotoxic T cell (CTL) epitopes from influenza virus is of importance for the development of new effective peptide-based vaccines. In the present work, bioinformatics was used to predict 9mer peptides derived from available influenza A viral proteins with binding affinity for at least one of the 12 HLA-I supertypes. The predicted peptides were then selected in a way that ensured maximal coverage of the available influenza A strains. One hundred and thirty one peptides were synthesized and their binding affinities for the HLA-I supertypes were measured in a biochemical assay. Influenza-specific T cell responses towards the peptides were quantified using IFNgamma ELISPOT assays with peripheral blood mononuclear cells (PBMC) from adult healthy HLA-I typed donors as responder cells. Of the 131 peptides, 21 were found to induce T cell responses in 19 donors. In the ELISPOT assay, five peptides induced responses that could be totally blocked by the pan-specific anti-HLA-I antibody W6/32, whereas 15 peptides induced responses that could be completely blocked in the presence of the pan-specific anti-HLA class II (HLA-II) antibody IVA12. Blocking of HLA-II subtype reactivity revealed that 8 and 6 peptide responses were blocked by anti-HLA-DR and -DP antibodies, respectively. Peptide reactivity of PBMC depleted of CD4(+) or CD8(+) T cells prior to the ELISPOT culture revealed that effectors are either CD4(+) (the majority of reactivities) or CD8(+) T cells, never a mixture of these subsets. Three of the peptides, recognized by CD4(+) T cells showed binding to recombinant DRA1*0101/DRB1*0401 or DRA1*0101/DRB5*0101 molecules in a recently developed biochemical assay. HLA-I binding 9mer influenza virus-derived peptides induce in many cases CD4(+) T cell responses restricted by HLA-II molecules.


Radiographic assessment of bone density around integrated titanium implants after ovariectomy in rats.
This study evaluated the influence of ovariectomy 8 weeks after implant placement on bone integrated to titanium implants. Thirty-eight female rats were submitted to a titanium implant at the tibiae proximal methaphysis. After a healing period of 8 weeks the animals were randomly divided into three groups: control (CTL-10 animals), sham-operated (SHAM-14 animals) and ovariectomy (OVX-14 animals). The CTL group was then sacrificed in order to confirm integration of the implant. The SHAM group was submitted to fictitious surgery and the OVX group was submitted to bilateral ovariectomy. After 12 weeks post-implant placement, the SHAM and OVX groups were sacrificed. In order to confirm the systemic osteopenia in rats, a dual-energy X-ray absorptiometry (DXA) was performed. For the evaluation of bone density, digital radiographs were taken. The grey level of the bone adjacent to implant was measured using image software and the bone density was calculated at six points on both sides of the implant. Densitometry measurements of the femur confirmed systemic bone mass loss in the OVX group. Individualized bone analyses of different regions surrounding the implant showed a significantly lower radiographic bone density (P < 0.05) in the cancellous region of the OVX group (77.48 +/- 23.39 grey levels) when compared with the CTL and SHAM groups (91.61 +/- 32.10 and 102.57 +/- 32.50 grey levels, respectively). The present study showed a decrease of the radiographic bone density in the cancellous region of bone around titanium implants placed 8 weeks before ovariectomy in rats.


Salmonella Typhimurium Infection of Human Monocyte-Derived Macrophages.
The successful infection of macrophages by non-typhoidal serovars of Salmonella enterica is likely essential to the establishment of the systemic disease they sometimes cause in susceptible human populations. However, the interactions between Salmonella and human macrophages are not widely studied, with mouse macrophages being a much more common model system. Fundamental differences between mouse and human macrophages make this less than ideal. Additionally, the inability of human macrophage-like cell lines to replicate some properties of primary macrophages makes the use of primary cells desirable. Here we present protocols to study the infection of human monocyte-derived macrophages with Salmonella Typhimurium. These include a method for differentiating monocyte-derived macrophages in vitro and protocols for infecting them with Salmonella Typhimurium, as well as assays to measure the extent of infection, replication, and death. These protocols are useful for the investigation of both bacterial and host factors that determine the outcome of infection. © 2018 by John Wiley & Sons, Inc.


Do common systems control eye movements and motion extrapolation?
People are able to judge the current position of occluded moving objects. This operation is known as motion extrapolation. It has previously been suggested that motion extrapolation is independent of the oculomotor system. Here we revisited this question by measuring eye position while participants completed two types of motion extrapolation task. In one task, a moving visual target travelled rightwards, disappeared, then reappeared further along its trajectory. Participants discriminated correct reappearance times from incorrect (too early or too late) with a two-alternative forced-choice button press. In the second task, the target travelled rightwards behind a visible, rectangular occluder, and participants pressed a button at the time when they judged it should reappear. In both tasks, performance was significantly different under fixation as compared to free eye movement conditions. When eye movements were permitted, eye movements during occlusion were related to participants' judgements. Finally, even when participants were required to fixate, small changes in eye position around fixation (<2°) were influenced by occluded target motion. These results all indicate that overlapping systems control eye movements and judgements on motion extrapolation tasks. This has implications for understanding the mechanism underlying motion extrapolation.


The PAAD/PYRIN-only protein POP1/ASC2 is a modulator of ASC-mediated nuclear-factor-kappa B and pro-caspase-1 regulation.
Proteins containing PAAD [pyrin, AIM (absent-in-melanoma), ASC [apoptosis-associated speck-like protein containing a CARD (caspase-recruitment domain)] and DD (death domain)-like] (PYRIN, DAPIN) domains are involved in innate immunity, regulating pathways leading to nuclear-factor-kappa B (NF-kappa B) and pro-caspase-1 activation. Many PAAD-family proteins have structures reminiscent of Nod-1, a putative intracellular sensor of lipopolysaccharide. Hereditary mutations in some of the PAAD-family genes are associated with auto-inflammatory diseases. Several of these proteins utilize the bipartite PAAD- and CARD-containing adapter protein ASC/TMS-1 (target of methylation-induced silencing) for linking to downstream signalling pathways. In the present paper, we describe characterization of human PAAD-only protein-1 (POP1)/ASC2, which is highly homologous with the PAAD domain of ASC, and which probably originated by gene duplication on chromosome 16. We demonstrate that POP1/ASC2 associates with ASC via PAAD-PAAD interactions and modulates NF-kappa B and pro-caspase-1 regulation by this adapter protein. In gene transfer experiments, POP1/ASC2 suppressed cytokine-mediated NF-kappa B activation similar to other PAAD-family proteins previously tested. Immunohistochemical studies showed expression of POP1/ASC2 predominantly in macrophages and granulocytes. We propose that POP1/ASC2 functions as a modulator of multidomain PAAD-containing proteins involved in NF-kappa B and pro-caspase-1 activation and innate immunity.


Bedside index (BISAP) v/s Ranson scores in predicting mortality and severity in patients with acute pancreatitis.
To determine the diagnostic accuracy of the bedside index for severity in acute pancreatitis in comparison with Ranson scores in predicting mortalities and severities in patients with acute pancreatitis. The cross-sectional study was conducted at the Department of Emergency Medicine, Aga Khan University Hospital, Karachi, from July 1, 2017, to January 1, 2018, and comprised patients who presented with acute pancreatitis. The bedside index for severity in acute pancreatitis score was applied in the emergency department and the patients were followed up in ward/intensive care unit where Ranson scores were calculated within the following 48 hours. Both the scores were calculated and compared for the prediction of severity and mortality for each patient. Data was analysed using SPSS 20. Of the 136 patients, 88(64.7%) were males and 48(35.3%) were females. The overall mean age was 42.04±16.42 years (16-75 years), On the basis of two scores, mild and moderate acute pancreatitis was diagnosed in 123(90.4%) and 119(87.5%) patients respectively, while severe condition was diagnosed in 13(9.6%) and 17(12.5%) patients respectively. The bedside index had specificity 94.62% compared to 91.54% for Ranson score; sensitivity 100% vs 100%; negative predictive value 100% vs 100%; positive predictive value 46.15% vs 35.29%; and diagnostic accuracy 94.85% vs 91.91%. The bedside index for severity in acute pancreatitis and Ranson score were both found to be reliable tools in predicting mortalities and severities in patients with acute pancreatitis.


Belle Maudsley Lecture. Digits, dummies and malocclusions.
When considering the aetiology of malocclusion in general, factors are often cited as having a genetic basis or an environmental basis. An individual malocclusion is likely to be a result of the variable effects of multiple environmental influences, upon an equally variable genetic predisposition. One of the most tangible 'environmental' factors is that of sucking habits involving digits or dummies. This review considers the nature of these habits, their effects on the developing dentition and methods used to combat the problem.


The fatty acid composition of chylomicrons influences the rate of their lipolysis in vivo.
Previous work in our laboratory has shown that chylomicron triacylglycerol is lipolysed in vitro by lipoprotein lipase more rapidly when the particles are enriched with n-6 polyunsaturated as compared to saturated, monounsaturated or n-3 polyunsaturated fatty acids. It is possible, however, that this does not reflect the situation in vivo, where the active enzyme is bound to the vascular endothelium. The aim of the present study is to investigate the effect of the fatty acid composition of chylomicrons on their lipolysis in the rat in vivo. [3H]Oleate-labelled chylomicrons derived from palm, olive, corn or fish oil (enriched in saturated, monounsaturated, n-6 polyunsaturated and n-3 polyunsaturated fatty acids respectively) containing > 90% of the label in triacylglycerol were injected intravenously into functionally hepatectomised rats and blood samples were taken at time intervals up to 40 min. The radioactivity in serum triacylglycerol decreased significantly more rapidly when corn oil as compared to palm, olive or fish oil chylomicrons were used. Conversely, the radioactivity in serum free fatty acid derived from corn oil chylomicrons showed a faster increase than that derived from the other three types of particles. These results indicate that chylomicrons enriched with n-6 polyunsaturated fatty acids are converted to chylomicron remnants in vivo more rapidly than those enriched with saturated, monounsaturated or n-3 polyunsaturated fatty acids. This provides a partial explanation for the differential rate of removal from the blood of cholesterol carried in chylomicrons of different fatty acid composition demonstrated in previous work from this laboratory.


Effect of outlying standard points on curve fitting in radioimmunoassay.
Outlying points often appear in standard curves for radioimmunoassay. We have examined the effect of outlying standard points on the ability of various automated data-processing routines, and of manual operators, to position a radioimmunoassay standard curve correctly. Manual operators were found to be highly subjective in their handling of a standard curve containing outlying points. Automated methods without outlier rejection capability produced standard curves that were significantly erroneous. In contrast, a data-processing method with automated outlier rejection capability successfully identified outliers, but occasionally rejected valid points--and consequently misplaced the standard curve. Visual identification of outliers is unsatisfactory. Automated identification can be more satisfactory, but some patterns of outliers make it less so. We conclude that any automated data-processing method should contain an outlier rejection facility, but its results should be treated with caution.


Structural Connections of Functionally Defined Human Insular Subdivisions.
The organization of the human insular cortex has traditionally been considered as an anterior-posterior dichotomy, where anterior and posterior subdivisions have unique structural and functional connections. However, recent functional neuroimaging research proposes a tripartite organization where insular subdivisions have both unique and overlapping functional profiles. Studies examining unique profiles show that the dorsal anterior insula (dAI) has connections with frontal areas supporting higher-level cognitive processes, the ventral anterior insula (vAI) has connections with limbic areas supporting affective processes, and the posterior insula (PI) has connections with sensorimotor areas supporting interoceptive processes. Studies examining overlapping profiles demonstrate that all 3 subdivisions can also have similar functional profiles. The structural organization supporting a functional tripartite insula organization presenting with overlapping and unique connections is currently unknown. We used a large HARDI diffusion magnetic resonance imaging (MRI) dataset (n = 199) to demonstrate novel visualizations of insula white matter tracts supporting a tripartite structure-function insula organization. Overlapping connections of all 3 insula subdivisions consisted of association pathways (inferior fronto-occipital fasciculus, uncinate fasciculus, arcuate fasciculus) while unique connections included the corona radiata, subcortical-cortical tracts, and horizontal and u-shaped tracts. These results generally support a tripartite structure-function organization of the insular cortex, with subdivisions that exhibit both overlapping and unique connectivity profiles.


Using Nonlinear Kinematic Parameters as a Means of Predicting Motion Sickness in Real-Time in Virtual Environments.
This article presents two studies (one simulation and one pilot) that assess a custom computer algorithm designed to predict motion sickness in real-time. Virtual reality has a wide range of applications; however, many users experience visually induced motion sickness. Previous research has demonstrated that changes in kinematic (behavioral) parameters are predictive of motion sickness. However, there has not been research demonstrating that these measures can be utilized in real-time applications. Two studies were performed to assess an algorithm designed to predict motion sickness in real-time. Study 1 was a simulation study that used data from Smart et al. (2014). Study 2 employed the algorithm on 28 new participants' motion while exposed to virtual motion. Study 1 revealed that the algorithm was able to classify motion sick participants with 100% accuracy. Study 2 revealed that the algorithm could predict if a participant would become motion sick with 57% accuracy. The results of the present study suggest that the motion sickness prediction algorithm can predict if an individual will experience motion sickness but needs further refinement to improve performance. The algorithm could be used for a wide array of VR devices to predict likelihood of motion sickness with enough time to intervene.


The in vitro performance of laser fluorescence and caries-detector dye for detecting residual carious dentin during tooth preparation.
The aim of this in vitro study was to compare the performance of a laser fluorescence device (DIAGNOdent) and a caries-detector dye for detecting residual dentinal caries. Forty extracted human molar teeth with deep dentinal carious lesions on their approximal surfaces were used for the study. The caries were removed by a new chemomechanical system, Carisolv. Three independent observers checked all cavities for residual caries using caries-detector dye and DIAGNOdent. The presence or absence of residual caries was verified using polarized light microscopy as the gold standard. Three observers recorded two different measurements at the same site after 2 weeks to determine intra- and interexaminer reproducibility of the DIAGNOdent. Average kappa values of 0.61 for interexaminer reproducibility and 0.94 for intraexaminer reproducibility were determined. The specificity of caries-detector dye was found to be 100% and the specificity of the DIAGNOdent was 86%. Although DIAGNOdent showed greater sensitivity than caries-detector dye (P < .05), low sensitivity values for each diagnostic system may lead to teeth with residual caries being undetected. Therefore, it might be advisable to reconsider the criteria for detecting residual caries during tooth preparation.


Angiotensin Converting Enzyme 2 Does Not Facilitate Porcine Epidemic Diarrhea Virus Entry into Porcine Intestinal Epithelial Cells and Inhibits It-induced Inflammatory Injury by Promoting STAT1 Phosphorylation.
ACE2 has been confirmed to be a functional receptor for SARS-CoV and SARS-CoV-2, but research on animal coronaviruses, especially PEDV, are still unknown. The present study investigated whether ACE2 plays a role in receptor recognition and subsequent infection during PEDV invasion of host cells. IPEC-J2 cells stably expressing porcine ACE2 did not increase the production of PEDV-N but inhibited its expression. Porcine ACE2 knockout cells was generated by CRISPR/Cas9 genome editing in IPEC-J2 cells. The expression of PEDV-N did not decrease but slightly increased. The Co-IP results showed that there was no significant association between ACE2 and PEDV-S. There were no obvious interaction between PEDV-S, PEDV-E, PEDV-M and porcine ACE2 promoters, but PEDV-N could inhibit the activity of ACE2 promoters. PEDV-N degraded STAT1 and prevented its phosphorylation, thereby inhibiting the expression of interferon-stimulated genes. Repeated infection of PEDV further confirmed the above results. PEDV activated ACE-Ang II-AT1R axis, while ACE2-Ang (1-7)-MasR axis activity was decreased and inflammatory response was intensified. However, excess ACE2 can reverse this reaction. These results reveal that ACE2 does not facilitate PEDV entry into cells, but relieves PEDV-induced inflammation by promoting STAT1 phosphorylation.


[Differential diagnosis of tumors of the gastrointestinal tract and retroperitoneal space from abdominal aortic aneurysms].
Aneurysm of the abdominal aorta is often erroneously identified as a gastrointestinal or retroperitoneal tumor of cyst. Out of 54 cases of this disease, 22 patients had undergone long-term examinations at various hospitals, oncological establishments included, while exploratory laparatomy had been carried out in 9 patients. The symptoms of aneurysm are described and compared with those of said tumors. Diagnostic procedures for identification of aneurysm and differentiation from gastrointestinal and retroperitoneal tumors and cysts are discussed.


Diabetic pulmonary microangiopathy - fact or fiction?
Elevated levels of serum glucose have deleterious effects on the walls of blood vessels, leading to microangiopathy. Such a destructive process involves also pulmonary circulation, where it is referred to as diabetic pulmonary microangiopathy. This hypothesis has been confirmed in histopathologic examinations of pulmonary parenchyma, as well as in pulmonary function tests. However, so far there have been no clinical implications of these findings. Another phenomenon requiring further discussion involves diabetics with clinically silent respiratory dysfunction. That may result from significant vascular and ventilation reserves that compensate for partial loss of pulmonary parenchyma in the course of diabetes. In this review, we present an overview of the available publications on pulmonary microangiopathy and its influence on the functioning of the respiratory system.


Health care transition from pediatric care to adult care: opportunities and challenges under the Affordable Care Act.
Enrollment of young adults is foundational to the success of the Affordable Care Act (ACA). This article analyzes the implications for young adults transitioning from pediatric to adult care with the implementation of the ACA. We review the key characteristics of this population relevant to health care utilization and access as well as the impact of private insurance market reforms, health insurance marketplaces, Medicaid expansion, and workforce development provisions on this population. We then analyze how reform is impacting and will continue to impact specific populations of young adults, including individuals with disabilities, college students, immigrants, young adults who age out of the foster care system and individuals involved with the criminal justice system. Finally, we look at the socio-economic and political factors influencing outreach efforts, and make recommendations to maximize the benefits of the law for young adults to empower them to have access to care and financial security.


Flow cytometry of breast cancer.
Flow cytometry (FCM) has become a generally accepted analytical method of worldwide application. Considerably achievements in flow cytometry hardware, staining techniques, especially immunoflow cytometry, together with progress in software programmes have significantly contributed to persistent expansion of the method. Some of the inbuilt rapidity of FCM has been lost because of additional preparatory steps and incubations. Mammary carcinoma is one of those malignant tumours which have been most extensively investigated by FCM. Evidence has been repeatedly produced to the existence of correlations among the most important FCM data, prognostic factors, and follow-up findings. Further improvement of the method and search for the best possible clinical application actually are the main challenges to FCM of breast cancer, today.


Complexes of HLA-G protein on the cell surface are important for leukocyte Ig-like receptor-1 function.
The nonclassical class I MHC molecule HLA-G is selectively expressed on extravillous cytotrophoblast cells at the maternal-fetal interface during pregnancy. HLA-G can inhibit the killing mediated by NK cells via interaction with the inhibitory NK cell receptor, leukocyte Ig-like receptor-1 (LIR-1). Comparison of the sequence of the HLA-G molecule to other class I MHC proteins revealed two unique cysteine residues located in positions 42 and 147. Mutating these cysteine residues resulted in a dramatic decrease in LIR-1 Ig binding. Accordingly, the mutated HLA-G transfectants were less effective in the inhibition of NK killing and RBL/LIR-1 induced serotonin release. Immunoprecipitation experiments demonstrated the involvement of the cysteine residues in the formation of HLA-G protein oligomers on the cell surface. The cysteine residue located at position 42 is shown to be critical for the expression of such complexes. These oligomers, unique among the class I MHC proteins, probably bind to LIR-1 with increased avidity, resulting in an enhanced inhibitory function of LIR-1 and an impaired killing function of NK cells.


G2 cell cycle arrest and cyclophilin A in lentiviral gene transfer.
Lentiviral vectors derived from the human immunodeficiency virus-1 (HIV-1) have a higher propensity to transduce nondividing cells compared to vectors based on oncoretroviruses. We report here that genistein, a previously known protein tyrosine kinase (PTK) inhibitor and G2 cell cycle arrest inducer, significantly enhanced lentiviral transduction in a dose-dependent manner. Increased transduction, as measured by vector expression, was seen in a variety of human cell lines, murine primary lymphocytes, and primary human CD34(+) peripheral blood progenitor cells as well. Increased vector expression was also associated with an increase in vector DNA copy number, as assessed by quantitative PCR. Genistein-mediated G2 cell cycle arrest, rather than PTK inhibition, appears to be the major factor responsible for increased gene transfer. Genistein also increases cyclophilin A (CypA) protein, a cellular protein important for efficient HIV-1 infection. While we show that CypA(-/-) Jurkat cells transduce poorly with lentiviral vectors, genistein does increase gene transfer in CypA-deficient cells. CypA and G2 cell cycle arrest appear to be two independent factors important for efficient lentiviral gene transfer. The role of genistein and other G2-arresting agents may be useful for improving the efficiency of lentiviral gene therapy.


Anti-rancidity effect of essential oils, application in the lipid stability of cooked turkey meat patties and potential implications for health.
Twenty-three commercial essential oils were tested for their anti-rancidity effect and potential implications to prolong the induction time of corn oil and extend the shelf life of cooked turkey patties. Moreover, the potential health benefit was investigated through DPPH, ABTS, β-carotene bleaching, FRAP, and α-amylase inhibitory assays. Essential oils' composition was investigated by GC-MS. Cumin, thyme, clove, and cinnamon oils improved oxidative stability and increased the induction time of the corn oil 1.5-3 fold. Clove and cinnamon oils were particularly effective in delaying lipid oxidation of cooked turkey patties (time of induction 11.04 and 9.43 h) compared with the plain burger (5.04 h). Both oils are also characterized by a potent radical scavenging activity in ABTS test (IC(50) values of 1.43 and 2.05 μg/ml for cinnamon and clove, respectively). In the α-amylase inhibitory assay, cumin and grape fruits were the most potent with IC(50) values of 21.88 and 23.95 μg/ml, respectively.


Global Grassland Diazotrophic Communities Are Structured by Combined Abiotic, Biotic, and Spatial Distance Factors but Resilient to Fertilization.
Grassland ecosystems cover around 37% of the ice-free land surface on Earth and have critical socioeconomic importance globally. As in many terrestrial ecosystems, biological dinitrogen (N2) fixation represents an essential natural source of nitrogen (N). The ability to fix atmospheric N2 is limited to diazotrophs, a diverse guild of bacteria and archaea. To elucidate the abiotic (climatic, edaphic), biotic (vegetation), and spatial factors that govern diazotrophic community composition in global grassland soils, amplicon sequencing of the dinitrogenase reductase gene-nifH-was performed on samples from a replicated standardized nutrient [N, phosphorus (P)] addition experiment in 23 grassland sites spanning four continents. Sites harbored distinct and diverse diazotrophic communities, with most of reads assigned to diazotrophic taxa within the Alphaproteobacteria (e.g., Rhizobiales), Cyanobacteria (e.g., Nostocales), and Deltaproteobacteria (e.g., Desulforomonadales) groups. Likely because of the wide range of climatic and edaphic conditions and spatial distance among sampling sites, only a few of the taxa were present at all sites. The best model describing the variation among soil diazotrophic communities at the OTU level combined climate seasonality (temperature in the wettest quarter and precipitation in the warmest quarter) with edaphic (C:N ratio, soil texture) and vegetation factors (various perennial plant covers). Additionally, spatial variables (geographic distance) correlated with diazotrophic community variation, suggesting an interplay of environmental variables and spatial distance. The diazotrophic communities appeared to be resilient to elevated nutrient levels, as 2-4 years of chronic N and P additions had little effect on the community composition. However, it remains to be seen, whether changes in the community composition occur after exposure to long-term, chronic fertilization regimes.


[Life experience of patients suffering from Crohn's disease].
The purpose of this study was to describe and explore the experience process of life of patients with Crohn's disease. Using a grounded theory methodology, 24 interviews were performed with 7 men and 5 women, 17-47 years of age, suffering from Crohn's disease. 'Tuning of two conflicting lives' was identified as the core category, and 5 subcategories were identified and they were integrated into the core category. The identified outcomes were 'Living a withdrawn life', 'coping flexibly', 'drifting with tangled emotions' and 'maintaining long-term remission'. When caring for these patients, it is important to identify needs, allow patients to express what they want at that moment and support them in maintaining a daily life that can be perceived as normal.


[Procedure adverse events: nursing care in central venous catheter fracture].
In a intensive care unit (ICU) there are many factors that can lead to the occurrence of adverse events. A high percentage of these events are associated with the administration of drugs. Diagnostic tests, such as computed tomography, is common in critically ill patients and technique can be performed with injection of contrast agent to enhance the visualization of soft tissue. The contrast is a medication and the nurse is responsible for its proper administration. The management of the critically ill patient is complex. ICU team and radiology shares responsibility for the care and safety of the patient safety during the transfer and performing tests with contrast. The World Health Organisation patient safety strategies, recommends analysing errors and learning from them. Therefore, it was decided to investigate the causes of the category E severity adverse events that occurred in a patient who was admitted to the ICU for septic shock of abdominal origin. An abdominal computed tomography was performed with contrast which was injected through a central venous catheter. The contrast did not appear in the image. What happened? Causal analysis helped to understand what triggered the event. A care plan and an algorithm were drafted to prevent it from happening again, with the following objectives: improving knowledge, skills and promoting positive attitudes towards patient safety, working at primary, secondary and tertiary care levels.


[Spatiotemporal variation of soil pH in Guangdong Province of China in past 30 years].
Based on the 1980s' soil inventory data and the 2002-2007 soil pH data of Guangdong Province, the spatiotemporal variation of soil pH in the Province in past 30 years was studied. In the study period, the spatial distribution pattern of soil pH in the Province had less change (mainly acidic), except that in Pearl River Delta and parts of Qingyuan and Shaoguan (weak alkaline). The overall variation of soil pH was represented as acidification, with the average pH value changed from 5.70 to 5.44. Among the soil types in the Province, alluvial soil had an increased pH, lateritic red soil, paddy soil, and red soil had a large decrement of pH value, and lime soil was most obvious in the decrease of pH value and its area percentage. The soil acidification was mainly induced by soil characteristics, some natural factors such as acid rain, and human factors such as unreasonable fertilization and urbanization. In addition, industrialization and mining increased the soil pH in some areas.


Do cyclosporin profiles provide useful information in the management of renal transplant recipients?
This study investigated the relationships between cyclosporin A (CsA) blood levels and episodes of renal allograft rejection and nephrotoxicity following renal transplantation, with the aim of establishing whether CsA profiles provided more useful information than single CsA blood levels in respect of these relationships. One hundred and sixty-two profiles were performed over 16 months in 40 patients and analysed retrospectively. Blood samples were taken at 0, 2, 4, 6 and 8 h after the morning CsA dose. Rejection episodes were diagnosed by renal biopsy and CsA nephrotoxicity by a fall in serum creatinine 1 week after a cut in CsA dose. The mean area under the curve (AUC) was lower for profiles performed at the time of rejection (3821 h.ng/ml) than that of a matched group of non-rejecting profiles (5479 h.ng/ml; P < 0.02). An AUC above 6400 h.ng/ml significantly discriminated rejection from non-rejection, whereas pre-dose and peak CsA concentrations did not have such discriminating cut-off values. A comparison of CsA-toxic and non-toxic profiles showed that there were no significant differences between mean CsA concentrations nor between the mean AUCs of these groups. We conclude that basing CsA dosing on CsA profiles could help to avoid some early episodes of rejection without increasing the risk of nephrotoxicity.


Relationship of age and menopausal status to estrogen receptor content in primary carcinoma of the breast.
The cytosolic estrogen receptor (CER) content of 1037 primary breast carcinomas was evaluated by sucrose density gradient analysis. Tumor specimens from premenopausal patients had significantly lower levels of CER (14.6 +/- 1.5 (mean +/- SEM) 8S binding fmole/mg protein) compared with carcinomas from postmenopausal patients (57.5 +/- 3.9 fmole/mg protein; p less than 0.001). The proportion of specimens with CER levels above threshold values of 3, 7, or 10 fmoles/mg protein were significantly higher for postmenopausal patients (72%, 63%, 59%, respectively) than for premenopausal patients (56%, 42%, 36%, p less than 0.001). When compared within half-decades, no statistically significant differences between premenopausal and postmenopausal patients were observed for mean, median, or rank sums of CER levels (p greater than 0.3). When patients were compared by half-decades, both mean and ranked sums of CER levels were significantly different (p less than 0.001). The proportion of specimens that demonstrated CER levels above a threshold value of 10 fmole/mg protein increased sequentially from a low of 13/51 (26%) for patients less than 35 years to a high of 60/81 (74%) for patients greater than 75 years.


Decomposition of buried bodies and methods that may aid in their location.
This is the second report on an ongoing study conducted to collect data on the decompositional rates of human cadavers and the first on buried cadavers. Six unembalmed human cadavers were buried separately in unlined trenches of various depths and allowed to naturally decompose for a time period ranging from a month to a year. During the period of burial, data were collected daily on the air, soil, and cadaver temperature at each burial site. At the end of each specified burial period the cadavers were exhumed and examined for the degree of decomposition which had taken place as well as changes in the soil pH, surface vegetation, and carrion insect activity. Analysis of the data shows that the decomposition rate of buried cadavers is highly dependent on the depth of burial and environmental temperatures. The depth at which the cadaver was buried also directly affected the degree of soil and vegetational changes as well as access by carrion insects. Application of this information can contribute to a more accurate estimation of time since death of a buried corpse and may aid in the location of such corpses.


HTR2A is associated with SSRI response in major depressive disorder in a Japanese cohort.
Several recent investigations reported that the serotonin 2A receptor gene (HTR2A) was associated with selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder. There have also been two reported association analyses of HTR2A with SSRI response in Japanese MDD patients, but the results were rather inconsistent and both studies had the problem of small sample sizes. Therefore, we conducted a replication association study using a sample larger than those in the two original Japanese studies (265 MDD patients), and found that four SNPs, two functional SNPs (-A1438G: rs6311 and T102C: rs6313) and two SNPs (rs7997012 and rs1928040) in HTR2A, were associated with the therapeutic response to SSRIs. HTR2A was associated with the therapeutic response SSRIs in Japanese MDD patients in a haplotype-wise analysis (P(all markers) = 0.0136), and a significant association between rs1928040 in HTR2A and SSRI response was detected in MDD (P(allele-wise analysis) = 0.0252). However, this significance disappeared after Bonferroni correction (P(allele-wise analysis) = 0.101). In conclusion, we suggest that HTR2A may play an important role in the pathophysiology of the therapeutic response to SSRIs in Japanese MDD patients. However, it will be important to replicate and confirm these findings in other independent studies using large samples.


Predictors of high and low mental well-being and common mental disorders: findings from a Danish population-based study.
Mental well-being is fundamental for a good life. Previous literature has examined the predictors of mental disorders and continuous measures of positive mental health. Very few studies have specifically focused on the predictors of different levels of mental well-being, but those that have suggest a different picture. This study aimed to compare socioeconomic and relational/recreational behaviour predictors of different levels of mental well-being as well as common mental disorders (CMDs). Data from 3508 adults aged 16+ years old from the Danish Mental Health and Well-Being Survey 2016 were linked to Danish national register-based data. Mental well-being was assessed using the Warwick-Edinburgh Mental Well-being Scale, and information on CMDs was assessed using the Patient Health Questionnaire (PHQ-4). Regression analyses were conducted to estimate the predictors of low and high mental well-being compared to moderate mental well-being and also of CMDs. Lower socioeconomic position (education, income and employment status) was associated with increased odds of low mental well-being and the presence of CMDs, but did not significantly predict high mental well-being. Relational/recreational behaviours (informal and formal social participation, social support and recreational activity) were associated with reduced odds of low mental well-being and CMDs, and also with increased odds of high mental well-being. Socioeconomic predictors of high mental well-being do not mirror those of low mental well-being and CMDs, whereas relational/recreational predictors of high mental well-being do mirror those of low mental well-being and CMDs. These findings have important implications for public mental health strategies.


The fine structure and the protein composition of gamma phage of Bacillus anthracis.
The fine structure of gamma phage of Bacillus anthracis was studied by electron microscopy with a negative-staining technique. The phage has a hexagonal head and a long tail without a sheath. By electrophoresis on polyacrylamide gels, the proteins of the phage particles are separate into 10 polypeptides with molecular weights ranging from 140 000 to 12 000.


Control of dengue fever with active surveillance and the use of insecticidal aerosol cans.
An interventional study was conducted in southern Vietnam to evaluate the feasibility and effectiveness of a new approach to control dengue fever. The approach consisted of active surveillance of dengue patients and the use of insecticidal aerosol cans. Febrile patients were tested serologically at local health centers and insecticidal aerosol cans were given to the family and employed in the neighborhood of dengue patients instead of ultra low volume (ULV) fogging with insecticide. The number of dengue IgM antibody positive cases among febrile patients, the number of reported dengue hemorrhagic fever patients and the total cost were compared in the 2 approaches (prompt focal ULV fogging and the use of insecticidal aerosol cans) in 1997. The aerosol cans were employed 5 times (in June, July, August, September and October) in the study area. ULV fogging in the control area was performed 5 times (in March, May, July, August and September). Twenty-two serologically positive cases were found in the study area which was about half that found in the control area (43 cases). A total of 16 dengue hemorrhagic fever patients was reported in the study area and 43 in the control area. Compared with the reported numbers of the previous year, the reduction rate in the number of dengue hemorrhagic fever cases was 71.4% in the study area and 51.7% in the control area. There were statistically significant differences in the morbidity of dengue fever and the reduction rate of dengue hemorrhagic fever. The cost of the insecticidal aerosol cans was US$393 which was lower than the cost of US$553 for ULV fogging. The findings suggest that insecticidal aerosol cans were effective and feasible for dengue fever control.


Nonepileptic seizure provoked by cardiac dysrhythmia with STEMI.
Acute seizures represent 1% of all visits to emergency departments in the United States. While many acute seizures are correctly attributable to underlying epilepsy, approximately one-third of acute seizures are provoked by underlying and potentially life-threatening acute conditions. Many clinical syndromes associated with seizure-like activity are well-established and readily identified in the acute setting. Cardiac dysrhythmias are known causes of acute seizure-like activity and, if transient and not captured by electrocardiogram tracings during acute episodes, may be incorrectly diagnosed as epileptic seizures. We report a case of acute ST-segment elevation myocardial infarction presenting with acute symptomatic seizure due to occult transient cardiac dysrhythmia.


Evidence-based psychosocial treatments for self-injurious thoughts and behaviors in youth.
The purpose of this study was to review the current evidence base of psychosocial treatments for suicidal and nonsuicidal self-injurious thoughts and behaviors (SITBs) in youth. We reviewed major scientific databases (HealthSTAR, MEDLine, PsycINFO, PubMed) for relevant studies published prior to June 2013. The search identified 29 studies examining interventions for suicidal or nonsuicidal SITBs in children or adolescents. No interventions currently meet the Journal of Clinical Child and Adolescent Psychology standards for Level 1: well-established treatments. Six treatment categories were classified as Level 2: probably efficacious or Level 3: possibly efficacious for reducing SITBs in youth. These treatments came from a variety of theoretical orientations, including cognitive-behavioral, family, interpersonal, and psychodynamic theories. Common elements across efficacious treatments included family skills training (e.g., family communication and problem solving), parent education and training (e.g., monitoring and contingency management), and individual skills training (e.g., emotion regulation and problem solving). Several treatments have shown potential promise for reducing SITBs in children and adolescents. However, the probably/possibly efficacious treatments identified each have evidence from only a single randomized controlled trial. Future research should focus on replicating studies of promising treatments, identifying active treatment ingredients, examining mediators and moderators of treatment effects, and developing brief interventions for high-risk periods (e.g., following hospital discharge).


Tumescent liposuction versus internal ultrasonic-assisted tumescent liposuction. A side-to-side comparison.
Tumescent liposuction (TL) performed according to accepted guidelines has proven to be a safe and effective outpatient procedure. The recent introduction of internal ultrasonic assistance may be a beneficial adjunct to the proven technique of tumescent liposuction at no additional risk to the patient. To determine whether there are differences in the intra- and postoperative course and the final cosmetic result between TL and internal ultrasonic-assisted tumescent liposuction (I-UATL) with a device using a double-lumen, saline-cooled cannula. Twenty-eight patients were enrolled in a randomized, prospective, side-to-side comparative study of TL with and without internal ultrasonic assistance. Intraoperative data including patient and physician observations are reported. A blinded evaluation was performed by the nonoperating surgeon of postoperative bruising, swelling, nodularity, skin retraction, decrease in cellulite, and symmetry at regular intervals after the procedure. Patients assessed variables concurrently. In most cases, the surgeon sensed a greater ease of cannula motion on the I-UATL side, associated with less physician exertion and fatigue. Patients tended to note a more pleasant intraoperative experience on the I-UATL side. We found no significant difference in the degree of postoperative bruising, nodularity, skin retraction, or decreased cellulite as evaluated by the observing physician, although swelling at 1 week was greater on the I-UATL side. The degree of bruising, swelling, soreness, numbness, skin retraction, or decrease in cellulite as reported by the patient did not differ significantly. There were no major complications attributable to either technique. This study suggests that the addition of internal ultrasonic assistance to the tumescent liposuction procedure may be advantageous regarding less physician effort and increased patient comfort during the procedure. We have not shown a significant difference in the postoperative course or the final cosmetic result when comparing TL with I-UATL.