Male involvement in birth preparedness and complication readiness for emergency obstetric referrals in rural Uganda.
Every pregnant woman faces risk of life-threatening obstetric complications. A birth-preparedness package promotes active preparation and assists in decision-making for healthcare seeking in case of such complications. The aim was to assess factors associated with birth preparedness and complication-readiness as well as the level of male participation in the birth plan among emergency obstetric referrals in rural Uganda. This was a cross-sectional study conducted at Kabale regional hospital maternity ward among 140 women admitted as emergency obstetric referrals in antenatal, labor or the postpartum period. Data was collected on socio-demographics and birth preparedness and what roles spouses were involved in during developing the birth plan. Any woman who attended antenatal care at least 4 times, received health education on pregnancy and childbirth danger signs, saved money for emergencies, made a plan of where to deliver from and made preparations for a birth companion, was deemed as having made a birth plan. Multivariate logistic regression analysis was conducted to analyze factors that were independently associated with having a birth plan. The mean age was 26.8 ± 6.6 years, while mean age of the spouse was 32.8 ± 8.3 years. Over 100 (73.8%) women and 75 (55.2%) of their spouses had no formal education or only primary level of education respectively. On multivariable analysis, Primigravidae compared to multigravidae, OR 1.8 95%CI (1.0-3.0), education level of spouse of secondary or higher versus primary level or none, OR 3.8 95%CI (1.2-11.0), formal occupation versus informal occupation of spouse, OR 1.6 95%CI (1.1-2.5), presence of pregnancy complications OR 1.4 95%CI (1.1-2.0) and the anticipated mode of delivery of caesarean section versus vaginal delivery, OR 1.6 95%CI (1.0-2.4) were associated with having a birth plan. Individual women, families and communities need to be empowered to contribute positively to making pregnancy safer by making a birth plan.


Partition function for a one-dimensional delta-function Bose gas.
The N-particle partition function of a one-dimensional delta-function Bose gas is calculated explicitly using only the periodic boundary condition (the Bethe ansatz equation). The N-particles cluster integrals are shown to be the same as those by the thermal Bethe ansatz method.


Low concentration of extracellular hemoglobin affects shape of RBC in low ion strength sucrose solution.
When red blood cells (RBCs) are placed in isotonic sucrose solution with low chloride content dynamic shape response is observed. Generally, it consists of three phases: i) fast spherulation (phase 1), ii) restoration of shape close to discoid one (phase 2), followed by a second slower spherulation in stomatocyte direction (phase 3). This morphological transformation (morphological response (MR)) is rather a fast process, usually comprises 1-2 min interval with disc retransformation time within 20-30 s. We have found that low concentration of extracellular hemoglobin (Hb) in the range 14-44 nM derived from cell lysate significantly accelerated MR at any stage of process. Increasing NaCl concentration up to 10 mM completely eliminated any influence of Hb. Other inhibitors EDTA and chlorpromazine while retarding some phases of MR did not prevent its activation by Hb. It was established that at conditions of low ionic strength Hb strongly binds to native RBC membrane. The number of binding sites was found to be 1-1.6x10(6) molecules per cell and the equilibrium dissociation constant was less than 2x10(-8) M. After heat denaturation of Hb at 70-72 degrees C an ability of Hb to affect MR was lost. Our data provide evidence that extracellular Hb could be involved in shape regulation of red blood cells at least in low ionic strength solutions.


A Novel Noninvasive Method for Quantitative Detection of Colonic Dysmotility Using Real-Time Ultrasonography.
Colonic motility disorders are a frequent clinical problem caused by various drugs and diseases. However, the etiology of colonic dysmotility is often unclear due to the lack of in vivo methods, including rapid dynamic assessment. The aim of this study was to establish a novel quantitative method to objectively assess colonic motility using ultrasonography. We applied echocardiographic speckle tracking-based strain imaging to analyze murine colonic motility. A trace line was placed on the boundary between the proximal wall of the colon and the inner cavity to analyze colonic wall displacement and strain rate. Locomotion activities of the colonic wall were used to quantify colonic motility via ultrasonography. We found that ultrasonography can quantitatively detect a decrease in colonic motility induced by loperamide, an antidiarrheal drug. These quantitative data were consistent with the imaging findings of colonic peristalsis and colon transit time. Additionally, ultrasonography also revealed changes in colonic motility over short intervals. Furthermore, we have shown that ultrasonography can quantitatively and noninvasively detect colonic dysmotility and hypervascularity of the colonic wall in colitis mice. These findings suggest that ultrasonography is a useful in vivo method for objectively monitoring changes in colonic motility caused by drugs and diseases.


On nodes and modes in resting state fMRI.
This paper examines intrinsic brain networks in light of recent developments in the characterisation of resting state fMRI timeseries--and simulations of neuronal fluctuations based upon the connectome. Its particular focus is on patterns or modes of distributed activity that underlie functional connectivity. We first demonstrate that the eigenmodes of functional connectivity--or covariance among regions or nodes--are the same as the eigenmodes of the underlying effective connectivity, provided we limit ourselves to symmetrical connections. This symmetry constraint is motivated by appealing to proximity graphs based upon multidimensional scaling. Crucially, the principal modes of functional connectivity correspond to the dynamically unstable modes of effective connectivity that decay slowly and show long term memory. Technically, these modes have small negative Lyapunov exponents that approach zero from below. Interestingly, the superposition of modes--whose exponents are sampled from a power law distribution--produces classical 1/f (scale free) spectra. We conjecture that the emergence of dynamical instability--that underlies intrinsic brain networks--is inevitable in any system that is separated from external states by a Markov blanket. This conjecture appeals to a free energy formulation of nonequilibrium steady-state dynamics. The common theme that emerges from these theoretical considerations is that endogenous fluctuations are dominated by a small number of dynamically unstable modes. We use this as the basis of a dynamic causal model (DCM) of resting state fluctuations--as measured in terms of their complex cross spectra. In this model, effective connectivity is parameterised in terms of eigenmodes and their Lyapunov exponents--that can also be interpreted as locations in a multidimensional scaling space. Model inversion provides not only estimates of edges or connectivity but also the topography and dimensionality of the underlying scaling space. Here, we focus on conceptual issues with simulated fMRI data and provide an illustrative application using an empirical multi-region timeseries.


Coelomic fat ectopia in the liver.
We describe a pedunculated, mesothelial-covered liver mass contained in a mesothelial-lined sac. Microscopically, the mass was composed of mature adipose tissue that contained thick-walled arteries and large veins, fibrous tissue, and numerous bundles of smooth muscle. The lesion was thought to represent ectopic coelomic mesenchyme originally destined to form omentum or mesentery. The existence of this entity suggested that previously reported cases of hepatic adipose tissue masses (lipomas) might also have derived from ectopic coelomic mesenchyme. Along with the mesenchymal lesion in the liver, an unclassifiable mesenchymal tumor was present in the cerebellum. Whether the coexistence of the two mesenchymal tissue masses was fortuitous, or related, could not be determined from this solitary case.


Contiguous arrays of satellites 1, 3, and beta form a 1.5-Mb domain on chromosome 22p.
The centromeric heterochromatin of all the human chromosomes is composed of megabases of tandemly repeated satellite DNA. Some of these sequences have been implicated in centromere formation and/or segregation but the arrangement of most of them on a large scale remains largely uncharacterized because of the difficulties in analyzing repetitive DNA. The alpha satellite is the best studied and is present in large tandem arrays at all centromeres, but satellites 1, 3, and beta have also been detected on a number of chromosomes. Here we have used FISH to extended DNA fibers to analyze these satellites on the short arm of the acrocentric chromosome 22. The satellite sequences were found to form a continuous domain spanning about 1.5 Mb and consisting of a major block of satellite 1 flanked by two blocks of beta satellite and three blocks of satellite 3. These six blocks of satellite DNA appear to form contiguous arrays with little intervening DNA.


Characterization and identification of na-cl sources in ground water.
Elevated concentrations of sodium (Na+) and chloride (Cl-) in surface and ground water are common in the United States and other countries, and can serve as indicators of, or may constitute, a water quality problem. We have characterized the most prevalent natural and anthropogenic sources of Na+ and Cl- in ground water, primarily in Illinois, and explored techniques that could be used to identify their source. We considered seven potential sources that included agricultural chemicals, septic effluent, animal waste, municipal landfill leachate, sea water, basin brines, and road deicers. The halides Cl-, bromide (Br), and iodide (I) were useful indicators of the sources of Na+-Cl- contamination. Iodide enrichment (relative to Cl-) was greatest in precipitation, followed by uncontaminated soil water and ground water, and landfill leachate. The mass ratios of the halides among themselves, with total nitrogen (N), and with Na+ provided diagnostic methods for graphically distinguishing among sources of Na+ and Cl- in contaminated water. Cl/Br ratios relative to Cl- revealed a clear, although overlapping, separation of sample groups. Samples of landfill leachate and ground water known to be contaminated by leachate were enriched in I and Br; this provided an excellent fingerprint for identifying leachate contamination. In addition, total N, when plotted against Cl/Br ratios, successfully separated water contaminated by road salt from water contaminated by other sources.


Slowing down fat digestion and absorption by an oxadiazolone inhibitor targeting selectively gastric lipolysis.
Based on a previous study and in silico molecular docking experiments, we have designed and synthesized a new series of ten 5-Alkoxy-N-3-(3-PhenoxyPhenyl)-1,3,4-Oxadiazol-2(3H)-one derivatives (RmPPOX). These molecules were further evaluated as selective and potent inhibitors of mammalian digestive lipases: purified dog gastric lipase (DGL) and guinea pig pancreatic lipase related protein 2 (GPLRP2), as well as porcine (PPL) and human (HPL) pancreatic lipases contained in porcine pancreatic extracts (PPE) and human pancreatic juices (HPJ), respectively. These compounds were found to strongly discriminate classical pancreatic lipases (poorly inhibited) from gastric lipase (fully inhibited). Among them, the 5-(2-(Benzyloxy)ethoxy)-3-(3-PhenoxyPhenyl)-1,3,4-Oxadiazol-2(3H)-one (BemPPOX) was identified as the most potent inhibitor of DGL, even more active than the FDA-approved drug Orlistat. BemPPOX and Orlistat were further compared in vitro in the course of test meal digestion, and in vivo with a mesenteric lymph duct cannulated rat model to evaluate their respective impacts on fat absorption. While Orlistat inhibited both gastric and duodenal lipolysis and drastically reduced fat absorption in rats, BemPPOX showed a specific action on gastric lipolysis that slowed down the overall lipolysis process and led to a subsequent reduction of around 55% of the intestinal absorption of fatty acids compared to controls. All these data promote BemPPOX as a potent candidate to efficiently regulate the gastrointestinal lipolysis, and to investigate its link with satiety mechanisms and therefore develop new strategies to "fight against obesity".


Vitreous surgery and retinal detachment.
Vitrectomy has proved to be extremely useful in facilitating reattachment of the retina in a variety of complicated detachments. The author's experience has been exclusively with the vitreous infusion suction cutter. Several other, similar, instruments are now available, and they are described in a recent review article on vitreous surgery [8]. The techniques required for successful surgery are not easily mastered, and it is the author's practice to have a trainee assist on about 50 operations before assuming major responsibility for a difficult microdissection.


The effect of dry needling & muscle energy technique separately and in combination in patients suffering shoulder impingement syndrome and active trigger points of infraspinatus.
The aim of this study was to investigate the effects of a combination of dry needling (DN) and muscle energy technique (MET) on pain intensity (PI), pressure pain threshold (PPT) and shoulder active range of motion (ROM) in patients with shoulder impingement syndrome and active trigger points in the infraspinatus muscle. 39 patients, aged 20-50 participated in this study. All the cases were randomly assigned into three groups: group 1 (n = 13) received DN, group 2 (n = 13) received MET, and group 3 (n = 13) received DN & MET. The patients were treated for three sessions in a one-week period with at least a two-day break between sessions. The results showed a significant improvement in visual analog scale (VAS), PPT and shoulder ROM over time (P < 0.001) in all three groups. There were no significant differences BETWEEN VAS (P = 0.406) PPT (P = 0.293), external rotation(EXT.ROT) (0.476), internal rotation (INT.ROT)(P = 0.476) and extension(EXT) (P = 0.574) ROMs in the three groups; however, DN group was significantly more effective on abduction(ABD) (P = 0.003) and flexion(FLEX) (0.012) ROM compared with other two groups. In line with previous studies, the present study found that the application of DN, MET and combined of these treatment on active trigger points in the infraspinatus muscle of patients with shoulder impingement syndrome helps reduce pain, increase PPT and enhance the shoulder ROM. Both techniques are effective in the treatment of trigger points. Nevertheless, DN is more effective in enhancing the ROM of flexion & abduction.


Advances in nanomaterial vaccine strategies to address infectious diseases impacting global health.
Despite the overwhelming success of vaccines in preventing infectious diseases, there remain numerous globally devastating diseases without fully protective vaccines, particularly human immunodeficiency virus (HIV), malaria and tuberculosis. Nanotechnology approaches are being developed both to design new vaccines against these diseases as well as to facilitate their global implementation. The reasons why a given pathogen may present difficulties for vaccine design are unique and tied to the co-evolutionary history of the pathogen and humans, but there are common challenges that nanotechnology is beginning to help address. In each case, a successful vaccine will need to raise immune responses that differ from the immune responses raised by normal infection. Nanomaterials, with their defined compositions, commonly modular construction, and length scales allowing the engagement of key immune pathways, collectively facilitate the iterative design process necessary to identify such protective immune responses and achieve them reliably. Nanomaterials also provide strategies for engineering the trafficking and delivery of vaccine components to key immune cells and lymphoid tissues, and they can be highly multivalent, improving their engagement with the immune system. This Review will discuss these aspects along with recent nanomaterial advances towards vaccines against infectious disease, with a particular emphasis on HIV/AIDS, malaria and tuberculosis.


A review of the benefits of early treatment initiation with single-pill combinations of telmisartan with amlodipine or hydrochlorothiazide.
This review discusses the rationale for earlier use of single-pill combinations (SPCs) of antihypertensive drugs, with a focus on telmisartan/amlodipine (T/A) and telmisartan/hydrochlorothiazide (T/H) SPCs. Compared with the respective monotherapies, the once-daily T/A and T/H SPCs have been shown to result in significantly higher blood pressure (BP) reductions, BP goal rates, and response rates in patients at all stages of hypertension. As expected, BP reductions are highest with the highest dose (T80/A10 and T80/H25) SPCs. Subgroup analyses of the telmisartan trials have reported the efficacy of both SPCs to be consistent, regardless of the patients' age, race, and coexisting diabetes, obesity, or renal impairment. In patients with mild-to-moderate hypertension, the T/A combination provides superior 24-hour BP-lowering efficacy compared with either treatment administered as monotherapy. Similarly, the T/H SPC treatment provides superior 24-hour BP-lowering efficacy, especially in the last 6 hours relative to other renin-angiotensin system inhibitor-based SPCs. The T/A SPC is associated with a lower incidence of edema than amlodipine monotherapy, and the T/H SPC with a lower incidence of hypokalemia than hydrochlorothiazide monotherapy. Existing evidence supports the use of the T/A SPC for the treatment of hypertensive patients with prediabetes, diabetes, or metabolic syndrome, due to the metabolic neutrality of both component drugs, and the use of the T/H SPC for those patients with edema or in need of volume reduction.


Clinical context and mechanism of functional tricuspid regurgitation in patients with and without pulmonary hypertension.
Functional tricuspid regurgitation (FTR) with structurally normal valve is of poorly defined mechanisms. Prevalence and clinical context of idiopathic FTR (Id-FTR) (without overt TR cause) are unknown. To investigate prevalence, clinical context, and mechanisms specific to FTR types, Id-FTR versus pulmonary hypertension-related (PHTN-FTR, systolic pulmonary pressure ≥50 mm Hg), we analyzed 1161 patients with prospectively quantified TR. Id-FTR (prevalence 12%) was associated with aging and atrial fibrillation. For mechanistic purposes, we measured valvular and right ventricular (RV) remodeling in 141 Id-FTR matched to 140 PHTN-FTR and to 99 controls with trivial TR for age, sex, atrial fibrillation, and ejection fraction. PHTN-FTR and Id-FTR were also matched for TR effective-regurgitant-orifice (ERO). Id-FTR valvular alterations (versus controls) were largest annular area (3.53±0.6 versus 2.74±0.4 cm(2), P<0.0001) and lowest valvular/annular coverage ratio (1.06±0.1 versus 1.45±0.2, P<0.0001) but normal valve tenting height. PHTN-FTR had mild annular enlargement but excessive valve tenting height (0.8±0.3 versus 0.35±0.1 cm, P<0.0001). Valvular changes were linked to specific RV changes, largest basal dilatation, and normal length (RV conical deformation) in Id-FTR versus longest RV with elliptical/spherical deformation in PHTN-FTR. With increasing FTR severity (ERO ≥40 mm(2)), changes specific to each FTR type were accentuated, and RV function (index of myocardial performance) was consistently reduced. Id-FTR is frequent, linked to aging and atrial fibrillation, can be severe, and is of unique mechanism. In Id-FTR, excess annular and RV-basal enlargement exhausts valvular/annular coverage reserve, and RV conical deformation does not cause notable valvular tenting. Conversely, PHTN-FTR is determined by valvular tethering with tenting linked to RV elongation and elliptical/spherical deformation. These specific FTR-mechanisms may be important in considering surgical correction in FTR.


Cell membrane-based biomimetic technology for cancer phototherapy: Mechanisms, recent advances and perspectives.
Despite significant advances in medical technology and antitumour treatments, the diagnosis and treatment of tumours have undergone remarkable transformations. Noninvasive phototherapy methods, such as photodynamic therapy (PDT) and photothermal therapy (PTT), have gained significant interest in antitumour medicine. However, traditional photosensitisers or photothermal agents face challenges like immune system recognition, rapid clearance from the bloodstream, limited tumour accumulation, and phototoxicity concerns. Researchers combine photosensitisers or photothermal agents with natural cell membranes to overcome these obstacles to create a nano biomimetic therapeutic platform. When used to coat nanoparticles, red blood cells, platelets, cancer cells, macrophages, lymphocytes, and bacterial outer membranes could provide prolonged circulation, tumour targeting, immune stimulation, or antigenicity. This article covers the principles of cellular membrane biomimetic nanotechnology and phototherapy, along with recent advancements in applying nano biomimetic technology to PDT, PTT, PCT, and combined diagnosis and treatment. Furthermore, the challenges and issues of using nano biomimetic nanoparticles in phototherapy are discussed. STATEMENT OF SIGNIFICANCE: Currently, there has been significant progress in the field of cell membrane biomimetic technology. Researchers are exploring its potential application in tumor diagnosis and treatment through phototherapy. Scholars have conducted extensive research on combining cell membrane technology and phototherapy in anticancer diagnosis and treatment. This review aims to highlight the mechanisms of phototherapy and the latest advancements in single phototherapy (PTT, PDT) and combination phototherapy (PCT, PRT, and PIT), as well as diagnostic approaches. The review provides an overview of various cell membrane technologies, including RBC membranes, platelet membranes, macrophage cell membranes, tumour cell membranes, bacterial membranes, hybrid membranes, and their potential for anticancer applications under phototherapy. Lastly, the review discusses the challenges and future directions in this field.


Theoretical models for application in school health education research.
Theoretical models that may be useful to research studies in school health education are reviewed. Selected, well-defined theories include social learning theory, problem-behavior theory, theory of reasoned action, communications theory, coping theory, social competence, and social and family theories. Also reviewed are multiple theory models including models of health related-behavior, the PRECEDE Framework, social-psychological approaches and the Activated Health Education Model. Two major reviews of teaching models are also discussed. The paper concludes with a brief outline of the general applications of theory to the field of school health education including applications to basic research, development and design of interventions, program evaluation, and program utilization.


[Ex vivo dermoscopy: synchronic evaluation between dermatologist and dermatopathologist of melanocytic lesions].
Clinicopathologic correlation is essential for diagnostic accuracy. Even though interdependent, dermatology and dermatopathology have become apart. In order to minimize this distance, we have performed ex vivo dermoscopic examinations. We performed comparative in vivo and ex vivo dermoscopy study followed by histopathological mapping. We observed that ex vivo dermoscopy identified the same structures visualized by the in vivo one, but with significant change of colors.


A tester system for detecting each of the six base-pair substitutions in Saccharomyces cerevisiae by selecting for an essential cysteine in iso-1-cytochrome c.
A collection of isogenic yeast strains that is specifically diagnostic for the six possible base-pair substitutions is described. Each strain contains a single, unique base-pair substitution at the Cys-22 codon of the CYC1 gene, which codes for iso-1-cytochrome c. These mutations encode replacements of the functionally critical Cys-22 and render each strain unable to grow on media containing nonfermentable carbon sources (Cyc-). Specific base-pair substitutions, which restore the Cys-22 codon, can be monitored simply by scoring for reversion to the Cyc+ phenotype. These strains revert spontaneously at very low frequencies and exhibit specific patterns of reversion in response to different mutagens. Only true (CYC1+) revertants were recovered after 7 days on selection medium. The following mutagen specificities were observed: ethyl methanesulfonate and N-methyl-N'-nitro-N-nitrosoguanidine, G.C----A.T; 4-nitroquinoline-1-oxide, G.C----T.A and G.C----A.T; diepoxybutane, A.T----T.A, A.T----G.C and G.C----T.A; 5-azacytidine, G.C----C.G. Methyl methanesulfonate induced all six mutations, albeit at relatively low frequencies, with preference for A.T----T.A and A.T----G.C. Ultraviolet light was the most inefficient mutagen used in this study, consistent with its preference for transition mutations at dipyrimidine sequences reported in other systems. This tester system is valuable as a simple and reliable assay for specific mutations without DNA sequence analysis.


Force-length dependence of arterial lamellar, smooth muscle, and myofilament orientations.
Force generation by contractile elements of arterial tissue can be affected by alterations in their alignment with shortening. The orientation and morphometry of smooth muscle (SM) myofilaments, medial lamellae, and elastic laminae were examined as a function of length in intact swine carotid arteries or strips. Intimal-medial tissue strips were fixed during isometric contractions at lengths (L) defined with respect to the optimal length for force generation (Lo). The average orientation of SM cells in two perpendicular planes remained parallel to the long axis of the tissue at all lengths, but the absolute value of angular deviations increased with shortening. Tissue lengthening was associated with decreased folding of the elastic laminae. This decrease in waviness was quantified by a stretch index (SI). Ultrastructural observations indicated that the myofilament absolute angular deviation was greater than that for the cellular alignment. For arteries fixed in situ while constricted, SI was least in the periintimal laminae and increased in the peripheral laminae. The average decrease in force-generating capacity on shortening from Lo to 0.6 Lo attributed to increasing SM and myofilament angular deviations was calculated to be 7%.


Sequential loading of cohesin subunits during the first meiotic prophase of grasshoppers.
The cohesin complexes play a key role in chromosome segregation during both mitosis and meiosis. They establish sister chromatid cohesion between duplicating DNA molecules during S-phase, but they also have an important role during postreplicative double-strand break repair in mitosis, as well as during recombination between homologous chromosomes in meiosis. An additional function in meiosis is related to the sister kinetochore cohesion, so they can be pulled by microtubules to the same pole at anaphase I. Data about the dynamics of cohesin subunits during meiosis are scarce; therefore, it is of great interest to characterize how the formation of the cohesin complexes is achieved in order to understand the roles of the different subunits within them. We have investigated the spatio-temporal distribution of three different cohesin subunits in prophase I grasshopper spermatocytes. We found that structural maintenance of chromosome protein 3 (SMC3) appears as early as preleptotene, and its localization resembles the location of the unsynapsed axial elements, whereas radiation-sensitive mutant 21 (RAD21) (sister chromatid cohesion protein 1, SCC1) and stromal antigen protein 1 (SA1) (sister chromatid cohesion protein 3, SCC3) are not visualized until zygotene, since they are located in the synapsed regions of the bivalents. During pachytene, the distribution of the three cohesin subunits is very similar and all appear along the trajectories of the lateral elements of the autosomal synaptonemal complexes. However, whereas SMC3 also appears over the single and unsynapsed X chromosome, RAD21 and SA1 do not. We conclude that the loading of SMC3 and the non-SMC subunits, RAD21 and SA1, occurs in different steps throughout prophase I grasshopper meiosis. These results strongly suggest the participation of SMC3 in the initial cohesin axis formation as early as preleptotene, thus contributing to sister chromatid cohesion, with a later association of both RAD21 and SA1 subunits at zygotene to reinforce and stabilize the bivalent structure. Therefore, we speculate that more than one cohesin complex participates in the sister chromatid cohesion at prophase I.


Utilization of extracorporeal membrane oxygenation in DCD and DBD lung transplants: a 2-year single-center experience.
Donation after circulatory death (DCD) has the potential to expand the lung donor pool. We aimed to assess whether DCD affected the need for perioperative extracorporeal membrane oxygenation (ECMO) and perioperative outcomes in lung transplantation (LTx) as compared to donation after brain death (DBD). All consecutive LTxs performed between April 2017 and March 2019 at our tertiary center were analyzed. Donor and recipient preoperative characteristics, utilization of ECMO, and perioperative clinical outcomes were compared between DCD and DBD LTx. Multivariate models (frequentist and Bayes) were fitted to evaluate an independent effect of DCD on the intra- and postoperative need for ECMO. Out of 105 enrolled patients, 25 (23.8%) were DCD LTx. Donors' and preoperative recipients' characteristics were comparable between the groups. Intraoperatively, mechanical circulatory support (MCS) was more common in DCD LTx (56.0% vs. 36.2%), but the adjusted difference was minor (RR = 1.16, 95% CI 0.64-2.12; P = 0.613). MCS duration, and first and second lung ischemia time were longer in the DCD group. Postoperatively, DCD recipients more commonly required ECMO (32.0% vs. 7.5%) and the difference remained considerable after adjustment for the pre- and intraoperative covariates: RR = 4.11 (95% CI 0.95-17.7), P = 0.058, Bayes RR = 4.15 (95% CrI 1.28-13.0). Sensitivity analyses (two DCD-DBD matching procedures) supported a higher risk of postoperative ECMO need in DCD patients. Incidence of delayed chest closure, postoperative chest drainage, and renal replacement therapy was higher in the DCD group. Early postoperative outcomes after DCD LTx appeared generally comparable to those after DBD LTx. DCD was associated with a higher need for postoperative ECMO which could influence clinical outcomes. However, as the DCD group had a significantly higher use of EVLP with more common ECMO preoperatively, this might have contributed to worse outcomes in the DCD group.


Theoretical modelling, experimental studies and clinical simulations of urethral cooling catheters for use during prostate thermal therapy.
Urethral cooling catheters are used to prevent thermal damage to the urethra during thermal therapy of the prostate. Quantification of a catheter's heat transfer characteristics is necessary for prediction of the catheter's influence on the temperature and thermal dose distribution in periurethral tissue. Two cooling catheters with different designs were examined: the Dornier Urowave catheter and a prototype device from BSD Medical Corp. A convection coefficient, h. was used to characterize the cooling ability of each catheter. The value of the convection coefficient (h = 330 W m(-2) C(-1) for the Dornier catheter. h = 160 W m(-2) C(-1) for the BSD device) was obtained by comparing temperatures measured in a tissue-equivalent phantom material to temperatures predicted by a finite element method simulation of the phantom experiments. The coefficient was found to be insensitive to the rate of coolant flow inside the catheter between 40 and 120 ml min(-1). The convection coefficient method for modelling urethral catheters was incorporated into simulations of microwave heating of the prostate. Results from these simulations indicate that the Dornier device is significantly more effective than the BSD catheter at cooling the tissue surrounding the urethra.


Reaching youth with out-of-facility HIV and reproductive health services: a systematic review.
Many young people, particularly those who are marginalized and most at risk for HIV and reproductive health-related problems, cannot or will not seek traditional facility-based health services. Policies and programs are being implemented to provide them with these health services in the community. We sought to review the effectiveness of such approaches in increasing HIV and reproductive health service use. A systematic literature review was undertaken to identify policies promoting or programs delivering HIV or reproductive health services in the community. We reviewed studies that evaluated uptake of services or commodities. Data from studies meeting inclusion criteria were qualitatively analyzed. Twenty studies met inclusion criteria, including 10 containing comparative data (e.g., before and after study or control study design). The studies generally demonstrated positive impact, although results varied across settings and approaches. The most successful approaches included mail-based chlamydia screening in the Netherlands, condom distribution via street outreach in Louisiana, home-based HIV counseling and testing in Malawi, and promotion of over-the-counter access to emergency contraception in various countries. Overall, this review suggests that out-of-facility approaches can be important avenues to reach youth. Continued evaluation is necessary to better understand specific approaches that can successfully deliver health services.


Comparison of shoulder and back muscle activation in caregivers according to various handle heights.
[Purpose] This study aims to improve the safety for caregivers and avoid musculoskeletal diseases by examining the shoulder and trunk muscle activity depending on wheelchair handle height as the caregiver provides propulsion to a wheelchair for wheelchair-bound patients. [Subjects] The participants were caregivers who met the criteria for this study (n=30). [Methods] To determine the activity of the shoulder and trunk muscles of caregivers depending on the handle height, the muscle activity was measured as a wheelchair was being pushed under three height conditions. [Results] According to the study results, the deltoid middle fiber, serratus anterior muscle, rhomboid muscle, and erector spinalis of lumbar part showed significantly low muscle activity at a height that produced an elbow joint flexion angle of 30°. Caregivers are highly likely to develop musculoskeletal disease if the handle height is excessively low. In addition, the burden on the shoulder and back muscles can be reduced at heights that lead to flexion of 30°. [Conclusions] As a caregiver pushes a wheelchair, the handle height has a close relationship with the burden on the shoulder and back muscles. If the handle height is excessively low, the caregiver is highly likely to develop musculoskeletal disease.


[Mechanisms of action of synthetic polyelectrolytes and polyampholytes on the immune response].
We investigated the effect of polyacrilic acid (PAA) on the immune response in mice of various strains on sheep red blood cells and also the influence of poly-2-methyl-5-vinyl-pyridine (PMVY), PAA and their statistical copolymers on antibody-forming cells (AFC) production in cultures of T- and B-lymphocytes in vivo. PAA was seen to increase accumulation of AFC in the spleen of mice depending on their genotypes. PMVP and PAA were found to intensify the cooperating interaction of T- and B-lymphocytes, whereas their copolymers exert quite an opposite effect. The injection of copolymers to the recipients of cooperating T- and B-lymphocytes practically results in the complete elimination of the cooperation effect between T- and B-lymphocytes in the immune response to sheep erythrocytes without cytostatic action of cell proliferation.


Detecting human-to-human transmission of avian influenza A (H5N1).
Highly pathogenic avian influenza A (HPAI) subtype H5N1 has caused family case clusters, mostly in Southeast Asia, that could be due to human-to-human transmission. Should this virus, or another zoonotic influenza virus, gain the ability of sustained human-to-human transmission, an influenza pandemic could result. We used statistical methods to test whether observed clusters of HPAI (H5N1) illnesses in families in northern Sumatra, Indonesia, and eastern Turkey were due to human-to-human transmission. Given that human-to-human transmission occurs, we estimate the infection secondary attack rates (SARs) and the local basic reproductive number, R0. We find statistical evidence of human-to-human transmission (p = 0.009) in Sumatra but not in Turkey (p = 0.114). For Sumatra, the estimated household SAR was 29% (95% confidence interval [CI] 15%-51%). The estimated lower limit on the local R0 was 1.14 (95% CI 0.61-2.14). Effective HPAI (H5N1) surveillance, containment response, and field evaluation are essential to monitor and contain potential pandemic strains.


Metabolic bifunctionality of Rv0812 couples folate and peptidoglycan biosynthesis in Mycobacterium tuberculosis.
Comparative sequence analysis has enabled the annotation of millions of genes from organisms across the evolutionary tree. However, this approach has inherently biased the annotation of phylogenetically ubiquitous, rather than species-specific, functions. The ecologically unusual pathogen Mycobacterium tuberculosis (Mtb) has evolved in humans as its sole reservoir and emerged as the leading bacterial cause of death worldwide. However, the physiological factors that define Mtb's pathogenicity are poorly understood. Here, we report the structure and function of a protein that is required for optimal in vitro fitness and bears homology to two distinct enzymes, Rv0812. Despite diversification of related orthologues into biochemically distinct enzyme families, rv0812 encodes a single active site with aminodeoxychorismate lyase and D-amino acid transaminase activities. The mutual exclusivity of substrate occupancy in this active site mediates coupling between nucleic acid and cell wall biosynthesis, prioritizing PABA over D-Ala/D-Glu biosynthesis. This bifunctionality reveals a novel, enzymatically encoded fail-safe mechanism that may help Mtb and other bacteria couple replication and division.


Calcium entry blockers in the treatment of hypertension. Current status and future prospects.
Calcium entry blockers will be increasingly used for the treatment of hypertension. The currently available calcium entry blockers are similar in antihypertensive efficacy but differ in their effects on the atrioventricular node and the degree of peripheral vasodilatory action. The new generation of dihydropyridine calcium entry blockers exhibits more specific vasodilatory actions with a less negative inotropic effect, which may affect their use in patients with congestive heart failure. The responsiveness to these drugs is little affected by race or age. Because of their mild natriuretic action, the concomitant use of dietary sodium restriction or diuretics may be less necessary. Short-term administration of calcium entry blockers preserves or improves renal function; however, their long-term effect has not been documented. Calcium entry blockers have not exhibited protection against coronary heart disease, but experimental evidence supports the continued search for cardioprotection. Calcium entry blockers are important drugs for the treatment of hypertension; the second generation may provide additional benefits because of its more specific pharmacologic actions.


Sustained endocrine and exocrine function in the pancreas of the Pacific spiny dogfish post-feeding.
Secretions of the exocrine pancreas contain digestive enzymes integral to the digestive process. The Pacific spiny dogfish (Squalus suckleyi) has a discrete pancreas, divided into two lobes termed the dorsal and ventral lobes. These lobes drain into the anterior intestine via a common duct to enable digestion. Previous studies have identified that the exocrine pancreas produces (co)lipases, chymotrypsin, carboxypeptidase, and low levels of chitinases; however, investigations into other digestive enzymes are limited. We detect the presence of lipase, trypsin, and carbohydrase and show that activities are equivalent between both lobes of the pancreas. Additionally, we sought to investigate the influence of a single feeding event (2% body weight ration of herring by gavage) on enzyme activities over an extended time course (0, 20, 48, 72, 168 h) post-feeding. The results indicate that there are no differences in pancreatic tissue digestive enzyme activities between fed or fasted states. Analysis of acinar cell circumference post-feeding demonstrates a significant increase at 20 and 48 h, that returns to fasting levels by 72 h. No significant changes were observed regarding whole-tissue insulin or glucagon mRNA abundance or with glucose transporter (glut) 1 or 3. Yet, a significant and transient decrease in glut4 and sodium glucose-linked transporter mRNA abundance was found at 48 h post-feeding. We propose that the constant enzyme activity across this relatively large organ, in combination with a relatively slow rate of digestion leads to an evenly distributed, sustained release of digestive enzymes regardless of digestive state.


Rat subcutaneous tissue response to calcium silicate containing different arsenic concentrations.
To evaluate the response of rat subcutaneous tissue in implanted polyethylene tubes that were filled with GMTA Angelus and Portland cements containing different arsenic concentrations. Atomic absorption spectrophotometry was utilized to obtain the values of the arsenic concentration in the materials. Thirty-six rats were divided into 3 groups of 12 animals for each experimental period. Each animal received two implants of polyethylene tubes filled with different test cements and the lateral of the tubes was used as a control group. After 15, 30 and 60 days of implantation, the animals were killed and the specimens were prepared for descriptive and morphometric analysis considering: inflammatory cells, collagen fibers, fibroblasts, blood vessels and other components. The results were analyzed utilizing the Kuskal-Wallis test and the Dunn's Multiple test for comparison (p<0.05). The materials showed, according to atomic absorption spectrophotometry, the following doses of arsenic: GMTA Angelus: 5.01 mg/kg, WPC Irajazinho: 0.69 mg/kg, GPC Minetti: 18.46 mg/kg and GPC Votoran: 10.76 mg/kg. In a 60-day periods, all specimens displayed a neoformation of connective tissue with a structure of fibrocellular aspect (capsule). Control groups and MTA Angelus produced the lower amount of inflammatory reaction and GPC Minetti, the highest reaction. There was no direct relationship between the concentration of arsenic present in the composition of the materials and the intensity of the inflammatory reactions. Higher values, as 18.46 mg/kg of arsenic in the cement, produce characteristics of severe inflammation reaction at the 60-day period. The best results were found in MTA angelus.


Combination chemotherapy with methotrexate, bleomycin, and vincristine with or without cisplatin in advanced squamous cell carcinoma of the head and neck.
A total of 185 eligible patients with advanced inoperable squamous cell carcinoma of the head and neck were randomized into two groups; the cisplatin, methotrexate, bleomycin, and vincristine (CABO) group received cisplatin (50 mg/m2; day 4), methotrexate (40 mg/m2; days 1, 15), bleomycin (10 mg; days 1, 8, and 15), and vincristine (2 mg; days 1, 8, and 15) and the ABO group received methotrexate, bleomycin and vincristine in the same doses on days 1, 8, and 15. After three courses, patients in both arms received weekly methotrexate as maintenance therapy; those 34 patients with previously untreated locoregional disease went off the study because of subsequent locoregional treatment in form of radiotherapy +/- surgery. The complete response rate was 16% in patients receiving CABO, compared with 5% among patients given ABO. The corresponding overall response rates were 50% and 28%, respectively (P = 0.003). Among patients with recurrent or metastatic disease, progression was delayed in patients receiving CABO (median, 18 weeks) compared to those receiving ABO (median, 14 weeks) (P = 0.07), but there was no difference in survival time. Myelosuppression consisted mostly of leukopenia, which was seen in 67% of the CABO patients versus 47% in the other arm. Myelosuppression-associated infection and hemorrhage led to death in two patients in the CABO treatment group and six patients in the ABO treatment group. Nausea and vomiting, mostly of grades 1 or 2, occurred in 93% of the patients given CABO and 44% of those receiving ABO. Other toxic effects--neuropathy, alopecia, stomatitis, constipation, fever/chills, diarrhea, cutaneous alterations, and renal impairment--occurred equally in the two treatment groups. This study underlines the role of cisplatin in head and neck cancer, although no impact on survival could be demonstrated. It also supports indirectly the superiority of combination chemotherapy over single-agent treatment for this disease.


Creatine supplementation and health variables: a retrospective study.
Long-term safety of creatine supplementation has been questioned. This retrospective study was performed to examine markers related to health, the incidence of reported side effects and the perceived training benefits in athletes supplementing with creatine monohydrate. Twenty-six athletes (18 M and 8 F, 24.7 +/- 9.2 y; 82.4 +/- 20.0 kg; 176.5 +/- 8.8 cm) from various sports were used as subjects. Blood was collected between 7:00 and 8:30 a.m. after a 12-h fast. Standard clinical examination was performed for CBC and 27 blood chemistries. Testosterone, cortisol, and growth hormone were analyzed using an ELISA. Subjects answered a questionnaire on dietary habits, creatine supplementation, medical history, training history, and perceived effects of supplementation. Body mass was measured using a medical scale, body composition was estimated using skinfolds, and resting heart rate and blood pressure were recorded. Subjects were grouped by supplementation length or no use: Gp1 (control) = no use (N = 7; 3 F, 4 M); Gp2 = 0.8-1.0 yr (N = 9; 2 F, 7 M); and Gp3 = 1(+) (N = 10; 3 F, 7 M). Creatine supplementation ranged from 0.8--4 yr. Mean loading dose for Gp2 and Gp3 was 13.7 +/- 10.0 and the maintenance dose was 9.7 +/- 5.7 g.d(-)1. Group differences were analyzed using one-way ANOVA. Expected gender differences were observed. Of the comparisons made among supplementation groups, only two differences for creatinine and total protein (P < 0.05) were noted. All group means fell within normal clinical ranges. There were no differences in the reported incidence of muscle injury, cramps, or other side effects. These data suggest that long-term creatine supplementation does not result in adverse health effects.


Cytomegalovirus infection of the skin.
A case of fatal generalized cytomegalovirus infection with particular attention to lesions involving the skin is reported. Characteristic cytomegalovirus inclusion bodies were present within nuclei of endothelial cells in the dermis beneath ulcerations. Skin biopsy may be useful in the diagnosis of disseminated infections by cytomegalovirus.


CAR-modified T-cell therapy for cancer: an updated review.
The use of chimeric antigen receptor (CAR)-modified T cells is a promising approach for cancer immunotherapy. These genetically modified receptors contain an antigen-binding moiety, a hinge region, a transmembrane domain, and an intracellular costimulatory domain resulting in T-cell activation subsequent to antigen binding. Optimal tumor removal through CAR-modified T cells requires suitable target antigen selection, co-stimulatory signaling domain, and the ability of CAR T cells to traffic, persist, and retain antitumor function after adoptive transfer. There are several elements which can improve antitumor function of CAR T cells, including signaling, conditioning chemotherapy and irradiation, tumor burden of the disease, T-cell phenotype, and supplementary cytokine usage. This review outlines four generations of CAR. The pre-clinical and clinical studies showed that this technique has a great potential for treatment of solid and hematological malignancies. The main purpose of the current review is to focus on the pre-clinical and clinical developments of CAR-based immunotherapy.


Active control of microcapsules in artificial blood vessel by producing local acoustic radiation force.
Micrometer-sized microcapsules collapse upon exposure to ultrasound. Use of this phenomenon for a drug delivery system (DDS), not only for local delivery of medication but also for gene therapy, should be possible. However, enhancing the efficiency of medication is limited because capsules in suspension diffuse in the human body after injection, since the motion of capsules in blood flow cannot be controlled. To control the behavior of microcapsules, acoustic radiation force was introduced. We detected local changes in microcapsule density by producing acoustic radiation force in an artificial blood vessel. Furthermore, we theoretically estimated the conditions required for active path selection of capsules at a bifurcation point in the artificial blood vessel. We observed the difference in capsule density at both in the bifurcation point and in alternative paths downstream of the bifurcation point for different the acoustic radiation forces. Also we confirmed the microcapsules are trapped against flow with the condition when the acoustic radiation force is more than fluid resistance of the capsules. The possibility of controlling capsule flow towards a specific point in a blood vessel was demonstrated.


ES2, a gene deleted in DiGeorge syndrome, encodes a nuclear protein and is expressed during early mouse development, where it shares an expression domain with a Goosecoid-like gene.
ES2 is a gene deleted in DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS) which has homologs in species as distant as Caenorhabditis elegans and Drosophila . The function of ES2 is unknown, and the predicted protein sequence does not contain motifs which suggest a particular role in the developmental defects present in DGS and VCFS. Here we show that the mouse homolog, Es2 , is transcribed in two forms resulting from the use of alternative polyadenylation signals. Structural analysis programs predict that the Es2 -encoded peptide has a coiled-coil domain, and transfection experiments with an Es2 -green fluorescent protein (GFP) fusion construct show that the peptide is recruited into the nucleus. Es2 is highly expressed during mouse embryogenesis from E7 onwards. In situ hybridization with an RNA probe revealed that the gene is widely expressed; however, relatively higher expression was detected in the nervous system, with a particularly high area of expression in a sub-region of the pons. The Es2 expression domain in the pons is shared with a Goosecoid-like gene ( Gscl) which is located upstream of Es2 , and raises the possibility that the two genes share regulatory elements and/or interact in this region of the developing brain. This finding suggests that different genes in the deleted region may be functionally related and might explain the occurrence of the characteristic phenotype in patients with non-overlapping genetic lesions.


Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity.
The short arm of chromosome 16 is rich in segmental duplications, predisposing this region of the genome to a number of recurrent rearrangements. Genomic imbalances of an approximately 600-kb region in 16p11.2 (29.5-30.1 Mb) have been associated with autism, intellectual disability, congenital anomalies, and schizophrenia. However, a separate, distal 200-kb region in 16p11.2 (28.7-28.9 Mb) that includes the SH2B1 gene has been recently associated with isolated obesity. The purpose of this study was to better define the phenotype of this recurrent SH2B1-containing microdeletion in a cohort of phenotypically abnormal patients not selected for obesity. Array comparative hybridization was performed on a total of 23,084 patients in a clinical setting for a variety of indications, most commonly developmental delay. Deletions of the SH2B1-containing region were identified in 31 patients. The deletion is enriched in the patient population when compared with controls (P = 0.003), with both inherited and de novo events. Detailed clinical information was available for six patients, who all had developmental delays of varying severity. Body mass index was ≥95th percentile in four of six patients, supporting the previously described association with obesity. The reciprocal duplication, found in 17 patients, does not seem to be significantly enriched in our patient population compared with controls. Deletions of the 16p11.2 SH2B1-containing region are pathogenic and are associated with developmental delay in addition to obesity.


Multimodal integration and stimulus categorization in putative mushroom body output neurons of the honeybee.
Flowers attract pollinating insects like honeybees by sophisticated compositions of olfactory and visual cues. Using honeybees as a model to study olfactory-visual integration at the neuronal level, we focused on mushroom body (MB) output neurons (MBON). From a neuronal circuit perspective, MBONs represent a prominent level of sensory-modality convergence in the insect brain. We established an experimental design allowing electrophysiological characterization of olfactory, visual, as well as olfactory-visual induced activation of individual MBONs. Despite the obvious convergence of olfactory and visual pathways in the MB, we found numerous unimodal MBONs. However, a substantial proportion of MBONs (32%) responded to both modalities and thus integrated olfactory-visual information across MB input layers. In these neurons, representation of the olfactory-visual compound was significantly increased compared with that of single components, suggesting an additive, but nonlinear integration. Population analyses of olfactory-visual MBONs revealed three categories: (i) olfactory, (ii) visual and (iii) olfactory-visual compound stimuli. Interestingly, no significant differentiation was apparent regarding different stimulus qualities within these categories. We conclude that encoding of stimulus quality within a modality is largely completed at the level of MB input, and information at the MB output is integrated across modalities to efficiently categorize sensory information for downstream behavioural decision processing.


Estimation of confidence limits for descriptive indexes derived from autoregressive analysis of time series: Methods and application to heart rate variability.
The growing interest in personalized medicine requires making inferences from descriptive indexes estimated from individual recordings of physiological signals, with statistical analyses focused on individual differences between/within subjects, rather than comparing supposedly homogeneous cohorts. To this end, methods to compute confidence limits of individual estimates of descriptive indexes are needed. This study introduces numerical methods to compute such confidence limits and perform statistical comparisons between indexes derived from autoregressive (AR) modeling of individual time series. Analytical approaches are generally not viable, because the indexes are usually nonlinear functions of the AR parameters. We exploit Monte Carlo (MC) and Bootstrap (BS) methods to reproduce the sampling distribution of the AR parameters and indexes computed from them. Here, these methods are implemented for spectral and information-theoretic indexes of heart-rate variability (HRV) estimated from AR models of heart-period time series. First, the MS and BC methods are tested in a wide range of synthetic HRV time series, showing good agreement with a gold-standard approach (i.e. multiple realizations of the "true" process driving the simulation). Then, real HRV time series measured from volunteers performing cognitive tasks are considered, documenting (i) the strong variability of confidence limits' width across recordings, (ii) the diversity of individual responses to the same task, and (iii) frequent disagreement between the cohort-average response and that of many individuals. We conclude that MC and BS methods are robust in estimating confidence limits of these AR-based indexes and thus recommended for short-term HRV analysis. Moreover, the strong inter-individual differences in the response to tasks shown by AR-based indexes evidence the need of individual-by-individual assessments of HRV features. Given their generality, MC and BS methods are promising for applications in biomedical signal processing and beyond, providing a powerful new tool for assessing the confidence limits of indexes estimated from individual recordings.


Pentobarbital inhibits the billiary excretion of organic acids: a study with succinysulfathiazole in the rat.
The present study was undertaken to determine whether the use of pentobarbital as an anesthetic reduces the biliary excretion of acidic drugs in rats. The drug chosen for the experiment was succinylsulfathiazole, a compound excreted unmetabolized in the bile. Animals anesthetized with urethane excreted 22.1% of the dose in the bile as compared to only 8.4% for the same time period in pentobarbital anesthetized animals. The choice of anesthetic did not affec the bile flow but did influence the bile/liver concentration gradient of succinylsulfathiazole, with the pentobarbital treated rats demonstrating a significantly lower value. Despite the higher biliary excretion of succinylsulfathiazole in the urethane treated rats, the total amount in the bile plus urine was 60% of the dose in the urethane anesthetized animals as compared with 62% in the pentobarbital treated rats. These results suggest that pentobarbital reduced the hepatic transport of succiylsulfathiazole into the bile. The question whether urethane is a preferred anesthetic for biliary excretion studies warrants further investigation.


The Arabidopsis MOS4-Associated Complex Promotes MicroRNA Biogenesis and Precursor Messenger RNA Splicing.
In Arabidopsis thaliana, the MOS4-ASSOCIATED COMPLEX (MAC) is required for defense and development. The evolutionarily conserved, putative RNA helicase MAC7 is a component of the Arabidopsis MAC, and the human MAC7 homolog, Aquarius, is implicated in pre-mRNA splicing. Here, we show that mac7-1, a partial loss-of-function mutant in MAC7, and two other MAC subunit mutants, mac3a mac3b and prl1 prl2 (pleiotropic regulatory locus), exhibit reduced microRNA (miRNA) levels, indicating that MAC promotes miRNA biogenesis. The mac7-1 mutant shows reduced primary miRNA (pri-miRNA) levels without affecting miRNA gene (MIR) promoter activity or the half-life of pri-miRNA transcripts. As a nuclear protein, MAC7 is not concentrated in dicing bodies, but it affects the localization of HYPONASTIC LEAVES1 (HYL1), a key protein in pri-miRNA processing, to dicing bodies. Immunoprecipitation of HYL1 retrieved 11 known MAC subunits, including MAC7, indicating association between HYL1 and MAC. We propose that MAC7 links MIR transcription to pri-miRNA processing. RNA-seq analysis showed that downregulated genes in MAC subunit mutants are mostly involved in plant defense and stimulus responses, confirming a role of MAC in biotic and abiotic stress responses. We also discovered global intron retention defects in mutants in three subunits of MAC, thus linking MAC function to splicing in Arabidopsis.


CD40 and IFN-gamma dependent T cell activation by human bronchial epithelial cells.
We examined whether freshly isolated human bronchial cells (HBEC) and bronchial epithelial cell line/BEAS-2B cells expressed surface molecules required for APC function. These cells expressed CD40 and ICAM-1, but not B7-1, B7-2 or HLA-DR molecules. Treatment of these cells with IFN-gamma resulted in enhanced expression of CD40 and ICAM-1 as well as induction of HLA-DR expression. Th2 cytokines such as IL-4 and IL-5, proinflammatory cytokine of GM-CSF and nonspecific activator endotoxin had no effect on these phenotypic expressions. Functional examinations showed that allogeneic lymphocytes purified from peripheral blood strongly proliferated in response to BEAS-2B cells cultured with IFN-gamma, but only weakly compared with those without IFN-gamma. When allogeneic lymphocytes were purified to CD4+ cells, the proliferative response against BEAS-2B cells was abolished. Blockade of CD40-CD40L interaction by anti-CD40 antibody also inhibited the proliferation of lymphocytes to BEAS-2B cells, although this treatment showed a minimum effect on the response to allogeneic MNC. Thus, bronchial epithelial cells have the ability to present allogeneic antigens to T cells in both CD40- and IFN-gamma-dependent manners under the presence of third party cells that transduce co-stimulatory signals.


College students' perceptions of their experiences: what do minority students think?
Despite substantial evidence that a diverse nursing workforce is needed, slow growth continues in the number of ethnically diverse RNs. This study examined whether students' race/ethnicity was associated with perceptions about institutional, dispositional, and situational factors and whether perceptions differed by college. African American, Latino, Asian, Filipino, Southeast Asian, and non-Latino White nursing students (N = 1,377) reported their perceptions. Seven regression models were estimated to assess the association of race/ethnicity with these factors. Being a minority was associated with negative perceptions of institutional diversity. African Americans had fewer peer and faculty interactions. Filipinos reported less work interference with attending classes. Students' ethnicity is important to institutional and situational outcomes. Adding school-level variables to the regression models helped explain some additional variance in student perceptions. A comprehensive, long-term commitment to the retention of students from diverse backgrounds is needed.


Liquid plug propagation in computer-controlled microfluidic airway-on-a-chip with semi-circular microchannels.
This paper introduces a two-inlet, one-outlet lung-on-a-chip device with semi-circular cross-section microchannels and computer-controlled fluidic switching that enables a broader systematic investigation of liquid plug dynamics in a manner relevant to the distal airways. A leak-proof bonding protocol for micro-milled devices facilitates channel bonding and culture of confluent primary small airway epithelial cells. Production of liquid plugs with computer-controlled inlet channel valving and just one outlet allows more stable long-term plug generation and propagation compared to previous designs. The system also captures both plug speed and length as well as pressure drop concurrently. In one demonstration, the system reproducibly generates surfactant-containing liquid plugs, a challenging process due to lower surface tension that makes the plug formation less stable. The addition of surfactant decreases the pressure required to initiate plug propagation, a potentially significant effect in diseases where surfactant in the airways is absent or dysfunctional. Next, the device recapitulates the effect of increasing fluid viscosity, a challenging analysis due to higher resistance of viscous fluids that makes plug formation and propagation more difficult particularly in airway-relevant length scales. Experimental results show that increased fluid viscosity decreases plug propagation speed for a given air flow rate. These findings are supplemented by computational modeling of viscous plug propagation that demonstrate increased plug propagation time, increased maximum wall shear stress, and greater pressure differentials in more viscous conditions of plug propagation. These results match physiology as mucus viscosity is increased in various obstructive lung diseases where it is known that respiratory mechanics can be compromised due to mucus plugging of the distal airways. Finally, experiments evaluate the effect of channel geometry on primary human small airway epithelial cell injury in this lung-on-a-chip. There is more injury in the middle of the channel relative to the edges highlighting the role of channel shape, a physiologically relevant parameter as airway cross-sectional geometry can also be non-circular. In sum, this paper describes a system that pushes the device limits with regards to the types of liquid plugs that can be stably generated for studies of distal airway fluid mechanical injury.


Plakophilin 2A is the dominant isoform in human heart tissue: consequences for the genetic screening of arrhythmogenic right ventricular cardiomyopathy.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease in which mutations affecting Plakophilin-2 (PKP2) are the most frequently detected. However, pathogenicity of variants is not always fully determined. PKP2 encodes two isoforms, the longest (PKP2b) includes the alternatively spliced exon 6, which is routinely screened for molecular diagnosis, despite the absence of data on cardiac expression of PKP2 isoforms. To examine the pathogenicity of PKP2 exon 6 mutations by focusing on a missense variant located in this exon. The PKP2 heterozygous p.Arg490Trp variant was identified in two unrelated ARVC probands (absent from 470 controls). In silico analysis suggested that PKP2 exon 6 is an Alu-derived sequence with very low expression level. PKP2a mRNA, which does not include the sequence encoded by exon 6, was the dominant isoform transcribed; at western blot analysis PKP2A was the only clearly detectable isoform in all human heart samples analysed (from six different controls and the proband). Moreover, in the proband's sample, p.Arg490Trp was not associated with aberrant exon 6 splicing or mutant mRNA downregulation. Finally, a heterozygous missense variant (p.Glu2343Lys) in Desmoplakin was identified in this proband and is likely to be the disease-causing mutation. PKP2A was shown to be the major isoform expressed in human heart tissue and PKP2B protein was undetectable. The results strongly suggest that p.Arg490Trp and other variants located in PKP2 exon 6 may not be disease causing. Variant splicing also has important consequences for the interpretation of mutation analysis and genetic counselling in ARVC and other hereditary cardiac diseases.


Use of specific contrast-enhanced CT regions of interest to differentiate renal oncocytomas from small clear cell and chromophobe renal cell carcinomas.
PURPOSE We aimed to examine the usefulness of utilizing a specific contrast-enhanced computed tomog raphy (CT) region of interest (ROI) to differentiate renal oncocytoma (RO) from small clear cell renal cell carcinoma (ccRCC) and chromophobe renal cell carcinoma (chRCC). METHODS A retrospective analysis of pre-contrast phase (PCP), corticomedullary phase (CMP), and nephro graphic phase (NP) contrast-enhanced CT images of the histopathologically confirmed initial cohort (27 ROs, 74 ccRCCs, and 36 chRCCs) was conducted. Small, medium, large, and whole ROIs (S-ROI, M-ROI, L-ROI, and W-ROI, respectively) were utilized for CT attenuation value of tumor (AVT), lesion-to-cortex attenuation (L/C), and heterogeneous degree of tumor (HDT) calcula tions. Differences in these parameters were then compared between RO and ccRCC/chRCC, with receiver operating characteristic (ROC) curves being utilized to gauge the diagnostic utility of the statistically significant parameters. Logistic regression analyses were employed to identify key factors capable of differentiating RO and ccRCC/chRCC, with predictive models further being established. A validation cohort (6 ROs, 30 ccRCCs, and 12 chRCCs) was then employed to vali date the performance of the predictive models. RESULTS Of the parameters evaluated using different ROIs, L/C-CMP (S-ROI) (0.88 ± 0.15 vs. 1.13 ± 0.25, P < .001) and HDT-CMP (W-ROI) (23.02 (12.00-51.21) vs. 37.81 (16.09-89.45), P < .001) were best suited to differentiating RO and ccRCC, yielding respective area under the curve (AUC) values of 0.803 and 0.834. AVT-NP (S-ROI) (122.85 ± 18.87 vs. 86.50 ± 18.65, P < .001) and AVT-NP (M-ROI) (119 (86-167) vs. 81.5 (53-142), P < .001) were better able to differentiate RO and chRCC, yielding respective AUC values of 0.918 and 0.906. Logistic regression analyses revealed that L/C-CMP (S-ROI) and HDT-PCP, as well as AVT-NP (S-ROI) and HDT-CMP, were the primary factors capable of differentiating RO from ccRCC and chRCC, respectively. The predictive model developed to dif ferentiate between RO and ccRCC exhibited a sensitivity of 66.67% and 55.14% in the initial and validation cohorts, respectively, with corresponding specificity of 94.59% and 93.55%, accuracy of 87.13% and 86.84%, and AUC of 0.908 and 0.876. The predictive model developed to differ entiate between RO and chRCC exhibited a sensitivity of 85.19% and 100.00% in the initial and validation cohorts, respectively, with corresponding specificity of 94.59% and 92.86%, accuracy of 87.30% and 95.24%, and AUC of 0.944 and 0.959. CONCLUSION These data demonstrate that a combination of quantitative parameters measured with particu lar ROIs can enable the efficient and reliable differentiation of RO from ccRCC and chRCC for use in routine patient differential diagnosis.


High-dose thiotepa, busulfan, cyclophosphamide and ASCT without whole-brain radiotherapy for poor prognosis primary CNS lymphoma.
Treatment of primary central nervous system lymphoma (PCNSL) with combined high-dose methotrexate (HD-MTX)-based chemotherapy and whole-brain radiotherapy (WBRT) is associated with severe neurotoxicity, but high relapse rates are associated with the use of either modality alone. In an attempt to improve upon these dismal results, we treated seven PCNSL patients with HD-MTX-based induction therapy followed by thiotepa, busulfan, cyclophosphamide (TBC), and autologous stem cell transplant (ASCT), without WBRT. Six of these patients had at least one of the following poor prognostic features: Karnofsky performance status (KPS) <or=50%, age >60 years, or relapsed disease. All but one patient tolerated the treatment well and experienced improvements in neurological function and overall performance status post-transplant. No treatment-induced neurotoxicity (dementia, ataxia, and incontinence) was observed although the follow-up is short. One early treatment-related death occurred in a patient with multiple comorbid medical conditions. The other six patients achieved a complete response (CR) after TBC and ASCT. Five patients are currently alive and relapse-free at 5, 8, 24, 36, and 42 months from diagnosis. One additional patient relapsed and died 33 months after diagnosis. Two of the seven patients received TBC/ASCT as the only treatment after disease progression following their initial chemotherapy and both remain relapse-free at the time of this report, 22 and 31 months post-TBC/ASCT. In conclusion, prolonged CR can be attained after chemotherapy-only treatment of poor prognosis PCNSL. Furthermore, this small series suggests that high-dose chemotherapy for PCNSL should include drugs that penetrate the CNS such as busulfan and thiotepa rather than standard lymphoma regimens such as BEAM.


[Study of the response of caudate nucleus neurons to direct electric stimulation of the medial geniculate body in the cat].
Extracellular activity of 124 caudate nucleus neurons during stimulation of parvo- and magnocellular parts of the medial geniculate body by rectangular electrical stimuli were investigated in chronic experiments on cats. Reactions were observed in 54 neurons (43%). Main types of responses were: phasic activation in the form of a single spike or spike discharge, initial activation followed by inhibition and pure inhibition. Excitatory responses prevailed (81% of the reacting neurons). The latent periods in different units fluctuated from 2.7 to 64 ms. In the same unit the latent periods were also very variable, which permits considering them as orthodromic. The mode of the histogram of the latent periods of the excitatory responses was in the range of 9-12 ms. The latent periods of the inhibitory responses varied from 12 to 130 ms and were in most neurons in a range of 40-60 ms. The increase in stimulus intensity led to an increase in response regularity, an increase in the number of spikes, reduced latent periods. In the same neuron the character and the structure of responses to stimulation of the relay nucleus and to sound clicks were usually identical. The latent period of responses to clicks was larger. Peculiarities of functional connection of the medial geniculate body with the caudate nucleus as a forebrain polymodal unspecific structure are discussed.


Surface-enhanced Raman spectroscopy analysis reveals biochemical difference in urine of patients with perianal fistula.
Perianal fistulising Crohn's disease (PFCD) is different from the characteristics and outcomes of traditional non-inflammatory bowel disease (IBD) anal fistulas. The presence of perianal disease was a poor prognostic indicator for Crohn's disease (CD) patients and PFCD patients were more likely to bear an increased risk of recurrence. However, the effective and accurate diagnosis methods to early distinguish PFCD from simple perianal fistula were still scarce. The purpose of this study is to develop a non-invasive detecting approach to predict CD in patients with perianal fistulas. Data on patients with anal fistulizing disease were collected from July 2020 to September 2020 in two IBD centers. Urine samples from PFCD and simple perianal fistula patients were investigated by surface-enhanced Raman spectroscopy (SERS). Principal component analysis (PCA)-support vector machine (SVM) was utilized to establish classification models to distinguish PFCD from simple perianal fistula. After a case-matched 1:1 selection by age and gender, 110 patients were included in the study. By analyzing the average SERS spectra of PFCD and simple perianal fistula patients, it revealed that there were significant differences in intensities at 11 Raman peaks. The established PCA-SVM model distinguished PFCD from simple perianal fistula with a sensitivity of 71.43%, specificity 80.00% and accuracy 75.71% in the leave-one-patient-out cross-validation. The accuracy of the model in validation cohort was 77.5%. Investigation of urine samples by SERS helps clinicians to predict Crohn's disease from perianal fistulas, which make patients achieve benefit from a more individualized treatment strategy.


Does intermittent pneumatic compression reduce the risk of post stroke deep vein thrombosis? The CLOTS 3 trial: statistical analysis plan.
Venous thromboembolism (VTE) is a common and important complication of stroke. The CLOTS 3 trial aims to determine whether, compared with best medical care, best medical care plus intermittent pneumatic compression (IPC) in immobile stroke patients reduces the risk of proximal deep vein thrombosis (DVT). The CLOTS 3 trial is a multicenter, parallel group trial with centralized randomization (minimization) to ensure allocation concealment. The protocol has been published (Trials 2012, 13:26) and is available in full at: http://www.clotstrial.com. Between December 2008 and September 2012, 105 centers in the UK recruited 2,876 immobile stroke patients within the first 3 days of their hospital admission. Patients were allocated to best medical care or best medical care plus IPC. Ultrasonographers performed a compression Doppler ultrasound scan to detect DVT in each treatment group at 7 to 10 days and 25 to 30 days. The primary outcome cluster includes symptomatic or asymptomatic DVT in the popliteal or femoral veins detected on either scan. Patients will be followed up by postal or telephone questionnaire at 6 months from randomization to detect later symptomatic DVT and pulmonary embolism (PE), and to measure functional outcome (Oxford Handicap Scale) and quality of life (EQ-5D-3L). The ultrasonographers performing the scans are blinded to treatment allocation, whereas the patients and caregivers are not. The trial has more than 90% power to detect a 4% absolute difference (12% versus 8%) in risk of the primary outcome and includes a health economic analysis.Follow-up will be completed in April 2013 and the results reported in May 2013. In this update, we describe the statistical analysis plan. ISRCTN: ISRCTN93529999.


Impaired erythropoietin production in mice treated with cyclosporin A.
Because recent data indicate that erythropoietin (Epo) production is defective in allogeneic bone marrow transplant (BMT) patients, we investigated the role of the immunosuppressant, nephrotoxic, agent cyclosporin A (CsA) on renal Epo production using an animal model. Mice were injected with 1.0 to 40.0 mg/kg/d CsA for 15 days. Thereafter, circulating Epo levels were evaluated in both intact animals and in mice made anemic with phenylhydrazine (PHZ). Serum Epo levels measured in CsA-treated animals were then compared with the predicted levels, which had been calculated in a reference population of normal, either intact or anemic, mice. In CsA-treated, intact animals both hematocrit and serum Epo levels were not significantly different from controls. However, serum Epo levels in CsA-treated, anemic mice were significantly lower than those expected in a control population of untreated, anemic mice with similar degrees of anemia. No significant increase in serum creatinine was recorded even at the highest doses of CsA used, nor were we able to document signs of renal toxicity by histologic examination of the kidneys. Therefore, therapeutical doses of CsA appear to affect the production of Epo under conditions in which the demand of the hormone is increased, as in response to anemia. We suggest that a subclinical kidney toxicity produced by CsA might have a role in the pathogenesis of the impaired Epo production observed in BMT patients, and may contribute to a delayed erythroid engraftment in at least some BMT patients.


Cloning and characterization of the human and rat islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) genes.
Islet-specific glucose-6-phosphatase (G6Pase) catalytic subunit-related protein (IGRP) is a homolog of the catalytic subunit of G6Pase, the enzyme that catalyzes the terminal step of the gluconeogenic pathway. Its catalytic activity, however, has not been defined. Since IGRP gene expression is restricted to islets, this suggests a possible role in the regulation of islet metabolism and, hence, insulin secretion induced by metabolites. We report here a comparative analysis of the human, mouse, and rat IGRP genes. These studies aimed to identify conserved sequences that may be critical for IGRP function and that specify its restricted tissue distribution. The single copy human IGRP gene has five exons of similar length and coding sequence to the mouse IGRP gene and is located on human chromosome 2q28-32 adjacent to the myosin heavy chain 1B gene. In contrast, the rat IGRP gene does not appear to encode a protein as a result of a series of deletions and insertions in the coding sequence. Moreover, rat IGRP mRNA, unlike mouse and human IGRP mRNA, is not expressed in islets or islet-derived cell lines, an observation that was traced by fusion gene analysis to a mutation of the TATA box motif in the mouse/human IGRP promoters to TGTA in the rat sequence. The results provide a framework for the further analysis of the molecular basis for the tissue-restricted expression of the IGRP gene and the identification of key amino acid sequences that determine its biological activity.


[Laparoscopic intervention in patients affected by Chernobyl AES disaster].
Comparative analysis of laparoscopic interventions was conducted as well as their results and the frequency of complications occurrence in patients, who were the Chernobyl power atomic station disaster survivors and those who were not exposed to radiation.


Status of lung transplant recipients surviving beyond five years.
Prolonged survival after lung transplantation is now commonplace as a result of advances in surgical techniques and postoperative management protocols. Although 1- and 5-year functional and survival data after lung transplantation are well known, sparse information is available regarding functional status of recipients surviving beyond 5 years. The medical records and pulmonary function study results of lung transplant recipients who had survived at least 5 years as of September 1995 were retrospectively reviewed. Of the 76 transplantations performed between November 1983 and September 1990, 30 (39.5%) were double lung transplantations, and 46 (60.5%) were single lung transplantations. Thirty-one recipients were alive 5 years after transplantation (12 double lung transplantations, 19 single lung transplantations). The 5-, 6-, and 7-year survival rates were 44%, 34%, and 29%, respectively. There was no association or difference in cytomegalovirus status, sex, and blood group between those who died within 5 years and those who survived beyond 5 years. The median percent predicted FEVs for single and double lung transplant recipients were as follows: 5 yrs-75%, 75%; 6 years-73%, 75%; 7 years-68%, 73%. The proportion of recipients with bronchiolitis obliterans syndrome according to published criteria was as follows: stage 0, 32%; stage I, 19%; stage II, 16%; and stage III, 19%. The functional status (i.e., active, working, disabled) 5 years after transplantation was as follows: active/working, 74%; active but not working, 13%; some limitation/independent, 10%; and disabled, 3%. Bronchiolitis obliterans syndrome is a frequent occurrence in long-term survivors. Nevertheless, in spite of this condition, most recipients have acceptable lung function, are active, and are generally working.


Head circumference charts updated.
Head circumference measurements from birth to 7 years, obtained from longitudinal data on children born between 1970 and 1977, are set against those from studies made in the United Kingdom earlier this century. A positive secular trend is shown. The children's heads were significantly larger than those born in the same locality 25 years earlier. Growth charts should be updated, as necessary, with each succeeding generation.


Cognitive-motor interference during postural control indicates at-risk cerebellar profiles in females with the FMR1 premutation.
Recent investigations report a higher risk of motor symptoms in females with the FMR1 premutation (PM-carriers) than has hitherto been appreciated. Here we examined basic sensorimotor and postural control under different sensory and attentional dual-task demands. Physiological performance and postural sway measures from the Physiological Profile Assessment (Lord et al., 2003 [39]) were conducted in 28 female PM-carriers (mean age: 41.32±8.03) and 31 female controls with normal FMR1 alleles (mean age: 41.61±8.3). Multiple regression analyses were conducted to examine the moderating role of CGG-repeat length on the relation between age and postural sway under dual-task interference. In female PM-carriers, our results showed significantly poorer proprioceptive awareness, slower reaction time, and greater postural displacement when performing a concurrent verbal fluency task. Significantly, these findings showed age- and genetically-modulated changes in dual-task postural displacement in the medio-lateral direction in female PM-carriers. These findings highlight the sensitivity of postural control paradigms in identifying early cerebellar postural changes that may act as surrogate markers of future decline in female PM-carriers.


Isolation of poliovirus 2C mutants defective in viral RNA synthesis.
Two poliovirus mutants were isolated that contain an oligonucleotide linker insertion in the 2C-coding region of the viral genome. One, 2C-31, has a strongly temperature-sensitive phenotype and the other, 2C-32, forms small plaques on HeLa cell monolayers at all temperatures. Both mutants have a severe temperature-sensitive defect in viral RNA synthesis but little effect on the types of viral protein that are made. Temperature shift experiments showed that the 2C function is continuously required for viral RNA synthesis to proceed. The 2C mutants could be complemented in trans by mutants with mutations in other viral proteins. Protein 2C is also the locus of the guanidine resistance and dependence mutants, a drug whose action also affects viral RNA synthesis. Thus, protein 2C is one that is needed continually for viral RNA synthesis and, at least with these temperature-sensitive alleles, can be provided in trans.


Implementing Trauma-Informed Partner Violence Assessment in Family Planning Clinics.
Intimate partner violence (IPV) and reproductive coercion (RC) are associated with poor reproductive health. Little is known about how family planning clinics implement brief IPV/RC assessment interventions in practice. We describe the uptake and impact of a brief, trauma-informed, universal IPV/RC assessment and education intervention. Intervention implementation was evaluated via a mixed methods study among women ages 18 and up receiving care at one of two family planning clinics in greater Baltimore, MD. This mixed methods study entailed a quasi-experimental, single group pretest-posttest study with family planning clinic patients (baseline and exit survey n = 132; 3-month retention n = 68; retention rate = 52%), coupled with qualitative interviews with providers and patients (total n = 35). Two thirds (65%) of women reported receiving at least one element of the intervention on their exit survey immediately following the clinic-visit. Patients reported that clinic-based IPV assessment is helpful, irrespective of IPV history. Relative to those who reported neither, participants who received either intervention element reported greater perceived caring from providers, confidence in provider response to abusive relationships, and knowledge of IPV-related resources at follow-up. Providers and patients alike described the educational card as a valuable tool. Participants described trade-offs of paper versus in-person, electronic medical record-facilitated screening, and patient reluctance to disclose current situations of abuse. In real-world family planning clinic settings, a brief assessment and support intervention was successful in communicating provider caring and increasing knowledge of violence-related resources, endpoints previously deemed valuable by IPV survivors. Results emphasize the merit of universal education in IPV/RC clinical interventions over seeking IPV disclosure.


Master kinase PDK1 in tumorigenesis.
3-phosphoinositide-dependent protein kinase 1 (PDK1) is considered as master kinase regulating AGC kinase family members such as AKT, SGK, PLK, S6K and RSK. Although autophosphorylation regulates PDK1 activity, accumulating evidence suggests that PDK1 is manipulated by many other mechanisms, including S6K-mediated phosphorylation, and the E3 ligase SPOP-mediated ubiquitination and degradation. Dysregulation of these upstream regulators or downstream signals involves in cancer development, as PDK1 regulating cell growth, metastasis, invasion, apoptosis and survival time. Meanwhile, overexpression of PDK1 is also exposed in a plethora of cancers, whereas inhibition of PDK1 reduces cell size and inhibits tumor growth and progression. More importantly, PDK1 also modulates the tumor microenvironments and markedly influences tumor immunotherapies. In summary, we comprehensively summarize the downstream signals, upstream regulators, mouse models, inhibitors, tumor microenvironment and clinical treatments for PDK1, and highlight PDK1 as a potential cancer therapeutic target.


Visual Parameter Selection for Spatial Blind Source Separation.
Analysis of spatial multivariate data, i.e., measurements at irregularly-spaced locations, is a challenging topic in visualization and statistics alike. Such data are inteGral to many domains, e.g., indicators of valuable minerals are measured for mine prospecting. Popular analysis methods, like PCA, often by design do not account for the spatial nature of the data. Thus they, together with their spatial variants, must be employed very carefully. Clearly, it is preferable to use methods that were specifically designed for such data, like spatial blind source separation (SBSS). However, SBSS requires two tuning parameters, which are themselves complex spatial objects. Setting these parameters involves navigating two large and interdependent parameter spaces, while also taking into account prior knowledge of the physical reality represented by the data. To support analysts in this process, we developed a visual analytics prototype. We evaluated it with experts in visualization, SBSS, and geochemistry. Our evaluations show that our interactive prototype allows to define complex and realistic parameter settings efficiently, which was so far impractical. Settings identified by a non-expert led to remarkable and surprising insights for a domain expert. Therefore, this paper presents important first steps to enable the use of a promising analysis method for spatial multivariate data.


Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY-Xe): a proof-of-concept, open-label, randomised controlled trial.
Moderate cooling after birth asphyxia is associated with substantial reductions in death and disability, but additional therapies might provide further benefit. We assessed whether the addition of xenon gas, a promising novel therapy, after the initiation of hypothermia for birth asphyxia would result in further improvement. Total Body hypothermia plus Xenon (TOBY-Xe) was a proof-of-concept, randomised, open-label, parallel-group trial done at four intensive-care neonatal units in the UK. Eligible infants were 36-43 weeks of gestational age, had signs of moderate to severe encephalopathy and moderately or severely abnormal background activity for at least 30 min or seizures as shown by amplitude-integrated EEG (aEEG), and had one of the following: Apgar score of 5 or less 10 min after birth, continued need for resuscitation 10 min after birth, or acidosis within 1 h of birth. Participants were allocated in a 1:1 ratio by use of a secure web-based computer-generated randomisation sequence within 12 h of birth to cooling to a rectal temperature of 33·5°C for 72 h (standard treatment) or to cooling in combination with 30% inhaled xenon for 24 h started immediately after randomisation. The primary outcomes were reduction in lactate to N-acetyl aspartate ratio in the thalamus and in preserved fractional anisotropy in the posterior limb of the internal capsule, measured with magnetic resonance spectroscopy and MRI, respectively, within 15 days of birth. The investigator assessing these outcomes was masked to allocation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00934700, and with ISRCTN, as ISRCTN08886155. The study was done from Jan 31, 2012, to Sept 30, 2014. We enrolled 92 infants, 46 of whom were randomly assigned to cooling only and 46 to xenon plus cooling. 37 infants in the cooling only group and 41 in the cooling plus xenon group underwent magnetic resonance assessments and were included in the analysis of the primary outcomes. We noted no significant differences in lactate to N-acetyl aspartate ratio in the thalamus (geometric mean ratio 1·09, 95% CI 0·90 to 1·32) or fractional anisotropy (mean difference -0·01, 95% CI -0·03 to 0·02) in the posterior limb of the internal capsule between the two groups. Nine infants died in the cooling group and 11 in the xenon group. Two adverse events were reported in the xenon group: subcutaneous fat necrosis and transient desaturation during the MRI. No serious adverse events were recorded. Administration of xenon within the delayed timeframe used in this trial is feasible and apparently safe, but is unlikely to enhance the neuroprotective effect of cooling after birth asphyxia. UK Medical Research Council.


Quantitative and qualitative effects of isoflurane on movement occurring after noxious stimulation.
Anesthetic potency is assessed by determination of the anesthetic concentration that prevents gross, purposeful movement in response to noxious stimulation. It is unclear whether anesthetics cause a progressive decrease in the number and force of limb movements evoked by noxious stimulation, or a step decrease (consistent with an all-or-none effect at the site of action). The authors hypothesized that isoflurane and halothane would progressively depress the movement response. Isoflurane minimum alveolar concentration (MAC) was determined in rats (N = 14) using a clamp applied to a hind paw. Lateral head movements and flexions of the forelimbs and hindlimbs were measured with force transducers. Isoflurane was adjusted to 0.6, 0.9, 1.1, and 1.4 MAC, the noxious stimulus applied, and the force and number of limb and head movements determined. Force and movement determinations were made in seven additional halothane-anesthetized rats. Isoflurane MAC was 1.3 +/- 0.1%. In general, if movement occurred after application of the noxious clamp, the head and all limbs were involved. At 0.6 MAC, the median number of extremity and head movements was 3.5 (10th-90th percentile, 2.0-11.4) with force generated per movement (force/movement) = 6.4 (2.0-13.2) N-s. Movement number decreased to 2.1 (0.25-4.2) at 0.9 MAC (P < 0.05), but force/movement was unchanged at 4.5 (0.4-15.1) N-s (Newton-second). At 1.1 MAC, movement number and force/movement decreased to 0.2 (0.0-1.5) and 0.1 (0.0-3.2) N-s, respectively (P < 0.005). No significant movement occurred at 1.4 MAC. The halothane-anesthetized rats had similar findings, although at 0.6 MAC they generated more movements (10.5 [5.2-19.8]) than the rats receiving isoflurane (P < 0.05). The results indicate that increasing anesthetic concentration from 0.6 to 0.9 MAC had little effect on the motor system controlling the force of limb movements, and the neural system generating repeated limb movements was depressed, consistent with a differential anesthetic effect at separate sites.


Mechanism of electrocardiographic T-wave flattening in diabetes mellitus: experimental and simulation study.
In the present study we investigated the contribution of ventricular repolarization time (RT) dispersion (the maximal difference in RT) and RT gradients (the differences in RT in apicobasal, anteroposterior and interventricular directions) to T-wave flattening in a setting of experimental diabetes mellitus. In 9 healthy and 11 diabetic (alloxan model) open-chest rabbits, we measured RT in ventricular epicardial electrograms. To specify the contributions of apicobasal, interventricular and anteroposterior RT gradients and RT dispersion to the body surface potentials we determined T-wave voltage differences between modified upper- and lower-chest precordial leads (T-wave amplitude dispersions, TWAD). Expression of RT gradients and RT dispersion in the correspondent TWAD parameters was studied by computer simulations. Diabetic rabbits demonstrated flattened T-waves in precordial leads associated with increased anteroposterior and decreased apicobasal RT gradients (P<0.05) due to RT prolongation at the apex. For diabetics, simulations predicted the preserved T-vector length and altered sagittal and longitudinal TWAD proven by experimental measurements. T-wave flattening in the diabetic rabbits was not due to changes in RT dispersion, but reflected the redistributed ventricular repolarization pattern with prolonged apical repolarization resulting in increased anteroposterior and decreased apicobasal RT gradients.


Functional modules integrating essential cellular functions are predictive of the response of leukaemia cells to DNA damage.
Childhood B-precursor lymphoblastic leukaemia (ALL) is the most common paediatric malignancy. Despite the fact that 80% of ALL patients respond to anti-cancer drugs, the patho-physiology of this disease is still not fully understood. mRNA expression-profiling studies that have been performed have not yet provided novel insights into the mechanisms behind cellular response to DNA damage. More powerful data analysis techniques may be required for identifying novel functional pathways involved in the cellular responses to DNA damage. In order to explore the possibility that unforeseen biological processes may be involved in the response to DNA damage, we have developed and applied a novel procedure for the identification of functional modules in ALL cells. We have discovered that the overall activity of functional modules integrating protein degradation and mRNA processing is predictive of response to DNA damage. Supplementary material including R code, additional results, experimental datasets, as well as a detailed description of the methodology are available at http://www.bip.bham.ac.uk/vivo/fumo.html. Supplementary data are available at Bioinformatics online.