To Evaluate the Effectiveness of TBTS - A Novel Device to do Self-Stretching of Gastroc-Soleus Muscle in Patients with Equinus Deformity.
Various methods have been used for management of equinus deformity. However, stretching gastroc-soleus muscle and achilles tendon is a difficult task. It is labour intensive, which makes the provision of treatment difficult for many patients. To study the effectiveness of Tension Bar Tendon Stretch (TBTS) compared to conventional stretching in patients with equinus deformity in terms of improvement in equinus angle and spasticity. A prospective randomised case control study was done on 16 patients of both the sexes in the age group four years to 56 years. Patients were stratified based on presence or absence of spasticity. Patients were further randomly allotted to the study or control group. Study group received stretching with TBTS in addition to the conventional rehabilitation programme. Patients were assessed in terms of improvement in equinus deformity and spasticity (modified Ashworth scale). These indices were measured at 0 month (pre-treatment), 1 month (post-treatment), and 6 months (follow up). Equinus deformity in patients with spastic equinus changed from 22.4° to 12° in study group while in control group change was from 21° to 17°. The difference was statistically significant with p-value of 0.001. Non-spastic (post accidental) changed from 30° to 15° in study group while in control group change was from 31° to 23° with p-value of 0.001. Modified Ashworth Score (MAS) was assessed only in spastic equinus, while in study group MAS changed from 2.8 to 1.5 and MAS change was 2.6 to 2 in control group; this difference after six months of therapy was statistically significant with a p-value of 0.001. TBTS can be an effective tool in rehabilitation of patients having equinus deformity; it provides an effective and patient controlled stretching and no need for a physical therapist. TBTS is a novel but simple instrument that can be made locally by the patient or the family.


Incidence and prognostic factors of clinically meaningful toxicities of kinase inhibitors in older patients with cancer: The PreToxE study.
Most of the safety data of tyrosine and serine/threonine kinase inhibitors (TKIs) approved for cancer treatment are extrapolated from larger trials in which older patients generally accounted for a small fraction of the participants. The Predicting Severe Toxicity of Targeted Therapies in Elderly Patients With Cancer study (PreToxE)PreToxE study aims to describe the incidence and prognostic factors of clinically meaningful toxicities of TKI in patients with cancer aged over 70 years. The primary endpoint was incidence of severe toxicity, defined as treatment-related death, persistent or significant disability/incapacity, hospitalization or the discontinuation of TKI treatment for more than three weeks. Our results indicate that despite frequent upfront dose reduction, clinically meaningful toxicities occurred in approximately 40% of older patients treated with TKIs. The use of at least three concomitant medications is an independent predictor of clinically meaningful toxicities.


Patient survival in uveal melanoma is not affected by oncogenic mutations in GNAQ and GNA11.
Mutations in GNAQ and GNA11, encoding the oncogenic G-protein alpha subunit q and 11, respectively, occur frequently in the majority of uveal melanomas. Exons 4 and 5 from GNAQ and GNA11 were amplified and sequenced from 92 ciliary body and choroidal melanomas. The mutation status was correlated with disease-free survival (DFS) and other parameters. None of the tumours harboured a GNAQ exon 4 mutation. A GNAQ mutation in exon 5 codon 209 was found in 46 out of 92 (50.0%) of the tumours. Only 1 out of 92 (1.1%) melanomas showed a mutation in GNA11 exon 4 codon 183, whereas 39 out of 92 (42.4%) harboured a mutation in exon 5 of GNA11 codon 209. Six tumours did not show any mutations in exons 4 and 5 of these genes. Univariate analyses showed no correlation between DFS and the mutation status. GNAQ and GNA11 mutations are, in equal matter, not associated with patient outcome.


Classification of Gastroparesis from Glycemic Variability in Type 1 Diabetes: A Proof-of-Concept Study.
Delayed gastric emptying is a substantial challenge for people with diabetes, affecting quality of life and blood glucose regulation. The complication is underdiagnosed, and current diagnostic tests are expensive or time consuming or have modest accuracy. The assessment of glycemic variations has potential use in gastroparesis screening. The aim of this study was to investigate the differences in glycemic variability between type 1 diabetes patients with gastroparesis and without a diagnosis of gastroparesis and the potential for using a classification model to differentiate between groups. Continuous glucose monitoring (CGM) from 425 patients with diabetes was included in the analytic cohort, including 16 patients with a diagnosis of gastroparesis and 409 without a known gastroparesis diagnosis. Sixteen features (9 daytime features and 7 nighttime features) describing glucose dynamics were extracted to assess differences between patients with and without a diagnosis of gastroparesis. A logistic regression model was trained using forward selection and cross-validation. In total, 3 features were included in the model utilizing forward selection of features and cross-validation: mean absolute glucose (MAG), span, and standard deviation during the night. The Receiver operating characteristic (ROC) AUC for the classification model was 0.76. Gastroparesis seems to have an impact on glucose variability, especially during the night. Moreover, CGM could possibly be used as a part of the screening process for delayed gastric emptying, but more studies are needed to determine a realistic accuracy.


A novel intronic variant in ROBO3 associated with horizontal gaze palsy with progressive scoliosis: case report and literature review.
Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare, autosomal recessive inherited disorder caused by mutations in ROBO3 gene. The clinical features of HGPPS include horizontal gaze palsy, progressive scoliosis, other oculomotor abnormalities such as strabismus and nystagmus. Whole-exome sequencing (WES) is used to diagnose rare Mendelian disorders, when routine standard tests have failed to make a formal pathological diagnosis. However, WES may identify variants of uncertain significance (VUS) that may add further ambiguity to the diagnosis. We report the case of a 4-year-old boy with horizontal gaze palsy, progressive scoliosis, microcephaly, and mild developmental delay. WES identified an intronic VUS in ROBO3 gene. We performed minigene splicing functional analysis to confirm the pathogenicity of this VUS. This report illustrates that WES data analysis with supportive functional analysis provides an effective approach to improve the diagnostic yield for unsolved clinical cases. This case also highlights the phenotypic heterogeneity in patients with HGPPS.


Optimum treatment for mediastinal lymph node positive (N2) resectable non-small cell lung cancer: what is the role for surgery?
A third of patients with Non-Small Cell Lung Cancer (NSCLC) present with Stage III disease with mediastinal (N2) nodal involvement representing an extremely heterogeneous population with a generally poor prognosis. Areas covered: This article describes the complexity of Stage III-N2 patients reviewing the outcomes of key clinical trials while highlighting the trial designs and subtleties that have created controversy in management. Both bimodality approaches combining chemotherapy with either surgery or radiation and trimodality approaches combining chemotherapy with both local therapies are reviewed. Finally, prognostic factors and future directions are explored for the management of this population. Expert commentary: Upfront surgery is not recommended for patients with Stage III-N2 NSCLC. Neoadjuvant approaches with both chemotherapy and chemoradiation are acceptable in a multidisciplinary setting if appropriate surgery is performed by a dedicated thoracic surgeon. Non-operative candidates should receive definitive concurrent chemoradiation. Innovative approaches are necessary to improve outcomes in this population.


Natural selection on the dentition of an Arikara population.
The tooth crowns of most mammals do not change in size except by attrition. Therefore, by comparing age groups within a population and finding differences in size or variation, the effects of such agencies as directional or stabilizing selection can be demonstrated. Mesiodistal and buccolingual measurements were taken on the maxillary and mandibular permanent dentition of a protohistoric Arikara Indian population from South Dakota. The tooth sizes of juveniles ages 6 through 15 were compared to those of adults ages 16 through 20. The two age groups were also compared by the cross-sectional areas of the posterior teeth. When a difference between age groups was demonstrated in either size or variation, a selection intensity was estimated using published graphs. Results from the comparisons show that adults, in general, have larger and less variable teeth than juveniles. The data suggest the possibility that both directional and stabilizing selection were operating on the Arikara dentition. Furthermore, the selection intensities suggest that selection was operating not on the individual teeth but on functional complexes such as the posterior teeth. It appears that in populations like the Arikara where crown attrition is severe, selection will be in the direction of large teeth.


Rubber and plantain intercropping: Effects of different planting densities on soil characteristics.
Two field experiments were conducted at Ellembelle and Jomoro districts in the Western region of Ghana where rubber cultivation is a predominant farming activity. The objective of the study was to assess the effect of rubber and plantain intercropping systems on selected soil properties. The experiment was arranged in a randomized complete block design (RCBD) with 3 replications. The treatments were the sole crop rubber (R), sole crop plantain (P) and three intercrop systems comprising an additive series of plantain: one row of plantain to one row of rubber (PR), two rows of plantain to one row of rubber (PPR) and three rows of plantain to one row of rubber (PPPR). Generally, agroforestry systems improved the soil hydraulic properties considerably, with the highest cumulative infiltration rates of 5.16 and 8.68 cm/min observed under the PPPR systems at the Ellembelle and Jomoro sites, respectively. Microbial biomass C (Cmic), N (Nmic) and P (Pmic) was significantly improved (P < 0.05) under the agroforestry than the monocrop systems. The Cmic, Nmic and Pmic values were highest under the PPPR system at both Ellembelle (Cmic, = 139.9 mg/kg; Nmic = 36.26 mg/kg and Pmic = 87.6 mg/kg) and Jomoro (Cmic = 78.7 mg/kg; Nmic = 80.3 mg/kg and Pmic = 3.45 mg/kg) sites.


Probability analysis of multiple-tank-car release incidents in railway hazardous materials transportation.
Railroads play a key role in the transportation of hazardous materials in North America. Rail transport differs from highway transport in several aspects, an important one being that rail transport involves trains in which many railcars carrying hazardous materials travel together. By contrast to truck accidents, it is possible that a train accident may involve multiple hazardous materials cars derailing and releasing contents with consequently greater potential impact on human health, property and the environment. In this paper, a probabilistic model is developed to estimate the probability distribution of the number of tank cars releasing contents in a train derailment. Principal operational characteristics considered include train length, derailment speed, accident cause, position of the first car derailed, number and placement of tank cars in a train and tank car safety design. The effect of train speed, tank car safety design and tank car positions in a train were evaluated regarding the number of cars that release their contents in a derailment. This research provides insights regarding the circumstances affecting multiple-tank-car release incidents and potential strategies to reduce their occurrences. The model can be incorporated into a larger risk management framework to enable better local, regional and national safety management of hazardous materials transportation by rail.


Industrial flue gas desulfurization waste may offer an opportunity to facilitate SANI® application for significant sludge minimization in freshwater wastewater treatment.
This paper reports an exploratory study on the use of a sulfite-rich industrial effluent to enable the integration of a sulfite-sulfide-sulfate cycle to the conventional carbon and nitrogen cycles in wastewater treatment to achieve sludge minimization through the non-sludge-producing Sulfate reduction, Autotrophic denitrification and Nitrification Integrated (SANI) process. A laboratory-scale sulfite reduction reactor was set up for treating sulfite-rich synthetic wastewater simulating the wastewater from industrial flue gas desulfurization (FGD) units. The results indicated that the sulfite reduction reactor can be started up within 11 d, which was much faster than that using sulfate. Thiosulfate was found to be the major sulfite reduction intermediate, accounting for about 30% of the total reduced sulfur in the reactor effluent, which may enable additional footprint reduction of the autotrophic denitrification reactor in the SANI process. This study indicated that it was possible to make use of the FGD effluent for applying the FGD-SANI process in treating freshwater-based sewage.


Retinoic Acid Engineered Amniotic Membrane Used as Graft or Homogenate: Positive Effects on Corneal Alkali Burns.
Alkali burns are the most common, severe chemical ocular injuries, their functional prognosis depending on corneal wound healing efficiency. The purpose of our study was to compare the benefits of amniotic membrane (AM) grafts and homogenates for wound healing in the presence or absence of previous all-trans retinoic acid (atRA) treatment. Fifty male CD1 mice with reproducible corneal chemical burn were divided into five groups, as follows: group 1 was treated with saline solution; groups 2 and 3 received untreated AM grafts or grafts treated with atRA, respectively; and groups 4 and 5 received untreated AM homogenates or homogenates treated with atRA, respectively. After 7 days of treatment, ulcer area and depth were measured, and vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MMP-9) were quantified. AM induction by atRA was confirmed via quantification of retinoic acid receptor β (RARβ), a well-established retinoic acid-induced gene. Significant improvements of corneal wound healing in terms of ulcer area and depth were obtained with both strategies. No major differences were found between the efficiency of AM homogenates and grafts. This positive action was increased when AM was pretreated with atRA. Furthermore, AM induced a decrease in VEGF and MMP-9 levels during the wound healing process. The atRA treatment led to an even greater decrease in the expression of both proteins. Amnion homogenate is as effective as AM grafts in promoting corneal wound healing in a mouse model. A higher positive effect was obtained with atRA treatment.


A 25 kDa polypeptide is the ligand for p185neu and is secreted by activated macrophages.
Medium conditioned by mouse peritoneal macrophages, activated by muramyl dipeptide (MDP), was used as a possible source of p185neu-specific ligand. MDP-activated macrophage-conditioned medium (MDP-CM) was shown to induce p185neu down-regulation in NEU-expressing NIH3T3 cells in a dose-dependent and temperature-sensitive manner. To exclude the possibility of an indirect action of proteins/metabolites present in MDP-CM on p185neu turnover, a ligand-trapping approach was used. Secreted NEU protein possessing only the extracellular domain but lacking transmembrane and protein kinase domains was expressed in HeLa cells and then purified from conditioned medium, using affinity chromatography on WGA-Sepharose. Co-incubation of the truncated, soluble NEU protein preparation with MDP-CM abolished MDP-CM-induced p185neu down-regulation and reduced self-phosphorylation. It is concluded that a putative p185neu-specific ligand is produced by macrophages activated by MDP. Using MDP-CM, the presence of a 25 kDa polypeptide distinct from EGF, PDGF, FGF, IGF, TGF-alpha and TGF-beta and TNF-alpha, could be demonstrated by decorating a Western blot with soluble NEU and anti-NEU antibodies. Thus, a 25 kDa (non-reduced) p185neu ligand has been described.


Neuron-restrictive silencer factor-mediated downregulation of μ-opioid receptor contributes to the reduced morphine analgesia in bone cancer pain.
Bone cancer pain has been reported to have unique mechanisms and is resistant to morphine treatment. Recent studies have indicated that neuron-restrictive silencer factor (NRSF) plays a crucial role in modulating the expression of the μ-opioid receptor (MOR) gene. The present study elucidates the regulatory mechanisms of MOR and its ability to affect bone cancer pain. Using a sarcoma-inoculated murine model, pain behaviors that represent continuous or breakthrough pain were evaluated. Expression of NRSF in the dorsal root ganglion (DRG) and spinal dorsal horn was quantified at the transcriptional and translational levels, respectively. Additionally, chromatin immunoprecipitation assays were used to detect NRSF binding to the promoter of MOR. Furthermore, NRSF was genetically knocked out by antisense oligodeoxynucleotide, and the expression of MOR and the effect of morphine were subsequently analyzed. Our results indicated that in a sarcoma murine model, NRSF expression is upregulated in dorsal root ganglion neurons, and the expression of NRSF mRNA is significantly negatively correlated with MOR mRNA expression. Additionally, chromatin immunoprecipitation analysis revealed that NRSF binding to the neuron-restrictive silencer element within the promoter area of the MOR gene is promoted with a hypoacetylation state of histone H3 and H4. Furthermore, genetically knocking down NRSF with antisense oligodeoxynucleotide rescued the expression of MOR and potentiated the systemic morphine analgesia. The present results suggest that in sarcoma-induced bone cancer pain, NRSF-induced downregulation of MOR is involved in the reduction of morphine analgesia. Epigenetically, up-regulation of MOR could substantially improve the effect of system delivery of morphine.


Borehole Diffusive Flux Apparatus for Characterizing Diffusive Mass-transfer in Subsurface Systems.
The concept of the Borehole Diffusive Flux Apparatus (BDFA) is presented herein. The BDFA is an innovative apparatus designed to provide continuous direct access to an undisturbed column of sediment that can be monitored at multiple discrete vertical intervals to provide high-resolution characterization of local-scale mass transfer and attenuation. The conceptual basis and technical design of the device are presented, along with an example of borehole design and installation at a field site. Mathematical simulations are used to illustrate its application for two scenarios. The results of these simulations indicate that test periods of several weeks to a few months should be sufficient to obtain robust results. The device has the potential to improve our ability to characterize critical mass-transfer and attenuation processes and to quantify the associated rates. This information is key to the evaluation of remediation alternatives, for enhancing the accuracy of mathematical models, and to support more effective long-term management of large groundwater contaminant plumes present at many sites.


Hypobaric hypoxia preconditioning attenuates acute lung injury during high-altitude exposure in rats via up-regulating heat-shock protein 70.
HHP (hypobaric hypoxia preconditioning) induces the overexpression of HSP70 (heat-shock protein 70), as well as tolerance to cerebral ischaemia. In the present study, we hypothesized that HHP would protect against HAE (high-altitude exposure)-induced acute lung injury and oedema via promoting the expression of HSP70 in lungs prior to the onset of HAE. At 2 weeks after the start of HHP, animals were exposed to a simulated HAE of 6000 m in a hypobaric chamber for 24 h. Immediately after being returned to ambient pressure, the non-HHP animals had higher scores of alveolar oedema, neutrophil infiltration and haemorrhage, acute pleurisy (e.g. increased exudate volume, increased numbers of polymorphonuclear cells and increased lung myeloperoxidase activity), increased pro-inflammatory cytokines [e.g. TNF-α (tumour necrosis factor-α), IL (interleukin)-1β and IL-6], and increased cellular ischaemia (i.e. glutamate and lactate/pyruvate ratio) and oxidative damage [glycerol, NOx (combined nitrate+nitrite) and 2,3-dihydroxybenzoic acid] markers in the BALF (bronchoalveolar fluid). HHP, in addition to inducing overexpression of HSP70 in the lungs, significantly attenuated HAE-induced pulmonary oedema, inflammation, and ischaemic and oxidative damage in the lungs. The beneficial effects of HHP in preventing the occurrence of HAE-induced pulmonary oedema, inflammation, and ischaemic and oxidative damage was reduced significantly by pretreatment with a neutralizing anti-HSP70 antibody. In conclusion, HHP may attenuate the occurrence of pulmonary oedema, inflammation, and ischaemic and oxidative damage caused by HAE in part via up-regulating HSP70 in the lungs.


Mode of action of Saccharomyces cerevisiae in enteric methane mitigation in pigs.
The objectives of this study were to determine the effect and mode of action of Saccharomyces cerevisiae (YST2) on enteric methane (CH4) mitigation in pigs. A total of 12 Duroc×Landrace×Yorkshire male finisher pigs (60±1 kg), housed individually in open-circuit respiration chambers, were randomly assigned to two dietary groups: a basal diet (control); and a basal diet supplemented with 3 g/YST2 (1.8×1010 live cells/g) per kg diet. At the end of 32-day experiment, pigs were sacrificed and redox potential (Eh), pH, volatile fatty acid concentration, densities of methanogens and acetogens, and expression of methyl coenzyme-M reductase subunit A gene were determined in digesta contents from the cecum, colon and rectum. Results showed that S. cerevisiae YST2 decreased (P<0.05) the average daily enteric CH4 production by 25.3%, lowered the pH value from 6.99 to 6.69 in the rectum, and increased the Eh value in cecum and colon by up to -55 mV (P<0.05). Fermentation patterns were also altered by supplementation of YST2 as reflected by the lower acetate, and higher propionate molar proportion in the cecum and colon (P<0.05), resulting in lower acetate : propionate ratio (P<0.05). Moreover, there was a 61% decrease in Methanobrevibacter species in the upper colon (P<0.05) and a 19% increase in the acetogen community in the cecum (P<0.05) of treated pigs. Results of our study concluded that supplementation of S. cerevisiae YST2 at 3 g/kg substantially decreased enteric CH4 production in pigs.


Correlates of COVID-19 Vaccine Hesitancy among a Community Sample of African Americans Living in the Southern United States.
In the United States, African Americans (AAs) have been disproportionately affected by COVID-19 mortality. However, AAs are more likely to be hesitant in receiving COVID-19 vaccinations when compared to non-Hispanic Whites. We examined factors associated with vaccine hesitancy among a predominant AA community sample. We performed a cross-sectional analysis on data collected from a convenience sample of 257 community-dwelling participants in the Central Savannah River Area from 5 December 2020, through 17 April 2021. Vaccine hesitancy was categorized as resistant, hesitant, and acceptant. We estimated relative odds of vaccine resistance and vaccine hesitancy using polytomous logistic regression models. Nearly one-third of the participants were either hesitant (n = 40, 15.6%) or resistant (n = 42, 16.3%) to receiving a COVID-19 vaccination. Vaccine-resistant participants were more likely to be younger and were more likely to have experienced housing insecurity due to COVID-19 when compared to both acceptant and hesitant participants, respectively. Age accounted for nearly 25% of the variation in vaccine resistance, with 21-fold increased odds (OR: 21.93, 95% CI: 8.97-5.26-91.43) of vaccine resistance in participants aged 18 to 29 compared to 50 and older adults. Housing insecurity accounted for 8% of the variation in vaccine resistance and was associated with 7-fold increased odds of vaccine resistance (AOR: 7.35, 95% CI: 1.99-27.10). In this sample, AAs under the age of 30 and those experiencing housing insecurity because of the COVID-19 pandemic were more likely to be resistant to receiving a free COVID-19 vaccination.


Riverine flow rate drives widespread convergence in the shell morphology of imperiled freshwater mussels.
Frequent and strong morphological convergence suggests that determinism tends to supercede historical contingencies in evolutionary radiations. For many lineages living within the water-column of rivers and streams, hydrodynamic forces drive widespread morphological convergence. Living below the sediment-water interface may release organisms from these hydrodynamic pressures, permitting a broad array of morphologies and thus less convergence. However, here, we show that the semi-infaunal freshwater mussels have environmentally determined convergence in shell morphology. Using 3D morphometric data from 715 individuals among 164 Nearctic species, we find that species occurring in rivers with high flow rates have evolved traits that resist dislodgement from their burrowed position in the streambed: thicker shells for their body size, with the thickest sector of the shell being the most deeply buried. Species occurring in low-flow environments have evolved thinner and more uniformly thickened shells, corresponding to an alternative adaptation to dislodgement: increased burrowing efficiency. Within species, individuals also show increased shell thickness for their body size at higher flow rates, suggesting that ecophenotypy may, in part, be an important mechanism for establishing populations in new environments and thus evolutionary divergence in this highly imperiled invertebrate group.


Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure.
Acetaminophen (APAP) overdose is a major cause of acute liver failure (ALF). Mitochondrial SH3BP5 (also called SAB) and phosphorylation of c-Jun N-terminal kinase (JNK) mediate the hepatotoxic effects of APAP. We investigated the involvement of steroidogenic acute regulatory protein (STARD1), a mitochondrial cholesterol transporter, in this process and sensitization by valproic acid (VPA), which depletes glutathione and stimulates steroidogenesis. Nonfasted C57BL/6J mice (control) and mice with liver-specific deletion of STARD1 (Stard1ΔHep), SAB (SabΔHep), or JNK1 and JNK2 (Jnk1+2ΔHep) were given VPA with or without APAP. Liver tissues were collected and analyzed by histology and immunohistochemistry and for APAP metabolism, endoplasmic reticulum (ER) stress, and mitochondrial function. Adult human hepatocytes were transplanted into Fah-/-/Rag2-/-/Il2rg-/-/NOD (FRGN) mice to create mice with humanized livers. Administration of VPA before administration of APAP increased the severity of liver damage in control mice. The combination of VPA and APAP increased expression of CYP2E1, formation of NAPQI-protein adducts, and depletion of glutathione from liver tissues of control mice, resulting in ER stress and the upregulation of STARD1. Livers from control mice given VPA and APAP accumulated cholesterol in the mitochondria and had sustained mitochondrial depletion of glutathione and mitochondrial dysfunction. Inhibition of ER stress, by administration of tauroursodeoxycholic acid to control mice, prevented upregulation of STARD1 in liver and protected the mice from hepatoxicity following administration of VPA and APAP. Administration of N-acetylcysteine to control mice prevented VPA- and APAP-induced ER stress and liver injury. Stard1ΔHep mice were resistant to induction of ALF by VPA and APAP, despite increased mitochondrial levels of glutathione and phosphorylated JNK; we made similar observations in fasted Stard1ΔHep mice given APAP alone. SabΔHep mice or Jnk1+2ΔHep mice did not develop ALF following administration of VPA and APAP. The ability of VPA to increase the severity of APAP-induced liver damage was observed in FRGN mice with humanized liver. In studies of mice, we found that upregulation of STARD1 following ER stress mediates APAP hepatoxicity via SH3BP5 and phosphorylation of JNK1 and JNK2.


Hamstrings loading contributes to lateral patellofemoral malalignment and elevated cartilage pressures: an in vitro study.
Hamstrings loading has previously been shown to increase tibiofemoral posterior translation and external rotation, which could contribute to patellofemoral malalignment and elevated patellofemoral pressures. The current study characterizes the influence of forces applied by the hamstrings on patellofemoral kinematics and the pressure applied to patellofemoral cartilage. Ten knees were positioned at 40°, 60° and 80° of flexion in vitro, and loaded with 586 N applied through the quadriceps, with and without an additional 200 N applied through the hamstrings. Patellofemoral kinematics were characterized with magnetic sensors fixed to the patella and the femur, while the pressure applied to lateral and medial patellofemoral cartilage was measured with pressure sensors. A repeated measures ANOVA with three levels, combined with paired t-tests at each flexion angle, determined if loading the hamstrings significantly (P<0.05) influenced the output. Loading the hamstrings increased the average patellar flexion, lateral tilt and lateral shift by approximately 1°, 0.5° and 0.2mm, respectively. Each increase was significant for at least two flexion angles. Loading the hamstrings increased the percentage of the total contact force applied to lateral cartilage by approximately 5%, which was significant at each flexion angle, and the maximum lateral pressure by approximately 0.3 MPa, which was significant at 40° and 60°. The increased lateral shift and tilt of the patella caused by loading the hamstrings can contribute to lateral malalignment and shifts pressure toward the lateral facet of the patella, which could contribute to overloading of lateral cartilage.


Photoinduced Bulk Polarization and Its Effects on Photovoltaic Actions in Perovskite Solar Cells.
This article reports an experimental demonstration of photoinduced bulk polarization in hysteresis-free methylammonium (MA) lead-halide perovskite solar cells [ITO/PEDOT:PSS/perovskite/PCBM/PEI/Ag]. An anomalous capacitance-voltage (CV) signal is observed as a broad "shoulder" in the depletion region from -0.5 to +0.5 V under photoexcitation based on CV measurements where a dc bias is gradually scanned to continuously drift mobile ions in order to detect local polarization under a low alternating bias (50 mV, 5 kHz). Essentially, gradually scanning the dc bias and applying a low alternating bias can separately generate continuously drifting ions and a bulk CV signal from local polarization under photoexcitation. Particularly, when the device efficiency is improved from 12.41% to 18.19% upon chlorine incorporation, this anomalous CV signal can be enhanced by a factor of 3. This anomalous CV signal can be assigned as the signature of photoinduced bulk polarization by distinguishing from surface polarization associated with interfacial charge accumulation. Meanwhile, replacing easy-rotational MA+ with difficult-rotational formamidinium (FA+) cations largely minimizes such anomalous CV signal, suggesting that photoinduced bulk polarization relies on the orientational freedom of dipolar organic cations. Furthermore, a Kelvin probe force microscopy study shows that chlorine incorporation can suppress the density of charged defects and thus enhances photoinduced bulk polarization due to the reduced screening effect from charged defects. A bias-dependent photoluminescence study indicates that increasing bulk polarization can suppress carrier recombination by decreasing charge capture probability through the Coulombic screening effect. Clearly, our studies provide an insightful understanding of photoinduced bulk polarization and its effects on photovoltaic actions in perovskite solar cells.


The National Network of Libraries of Medicine's outreach to the public health workforce: 2001-2006.
The paper provides an overview of the National Network of Libraries of Medicine's (NN/ LM's) outreach to the public health workforce from 2001 to 2006. NN/LM conducts outreach through the activities of the Regional Medical Library (RML) staff and RML-sponsored projects led by NN/LM members. Between 2001 and 2006, RML staff provided training on information resources and information management for public health personnel at national, state, and local levels. The RMLs also contributed significantly to the Partners in Information Access for the Public Health Workforce collaboration. Data were extracted from telephone interviews with directors of thirty-seven NN/LM-sponsored outreach projects directed at the public health sector. A review of project reports informed the interviews, which were transcribed and subsequently coded for emergent themes using qualitative analysis software. Analysis of interview data led to the identification of four major themes: training, collaboration, evaluation of outcomes, and challenges. Sixteen subthemes represented specific lessons learned from NN/LM members' outreach to the public health sector. NN/LM conducted extensive information-oriented outreach to the public health workforce during the 2001-to-2006 contract period. Lessons learned from this experience, most notably the value of collaboration and the need for flexibility, continue to influence outreach efforts in the current contract period.


The chloroplast grana proteome defined by intact mass measurements from liquid chromatography mass spectrometry.
Proteomics seeks to address the entire complement of protein gene products of an organism, but experimental analysis of such complex mixtures is biased against low abundance and membrane proteins. Electrospray-ionization mass spectrometry coupled with reverse-phase chromatography was used to separate and catalogue all detectable proteins in samples of photosystem II-enriched thylakoid membrane subdomains (grana) from pea and spinach. Around 90 intact mass tags were detected corresponding to approximately 40 gene products with variable post-translational covalent modifications. Provisional identity of 30 of these gene products was proposed based upon coincidence of measured mass with that calculated from genomic sequence. Analysis of isolated photosystem II complexes allowed detection and resolution of a minor population of D1 (PsbA) that was apparently palmitoylated and not detected in less purified preparations. Based upon observed +80-Da adducts, D1, D2 (PsbD), CP43 (PsbC), two Lhcbs, and PsbH were confirmed to be phosphorylated, and a new phosphoprotein was proposed to be the product of psbT. The appearance of a second +80-Da adduct on PsbH provides direct evidence for a second phosphorylation site on PsbH, complicating interpretation of its role in regulation of thylakoid membrane organization and function, including light-state transitions. Adducts of +32 Da, presumably arising from oxidative modification during illumination, were associated with more highly phosphorylated forms of PsbH implying a relationship between the two phenomena. Intact mass proteomics of organellar subfractions and more highly purified protein complexes provides increasingly detailed insights into functional genomics of photosynthetic membranes.


Practitioners' perspectives on effective practices for Hispanic teenage pregnancy prevention.
In the United States, the pregnancy rate and birthrate of Hispanic teenagers are higher than those of other races and ethnicities. Although recommendations for culturally appropriate pregnancy prevention programs are commonplace, little is known about how practitioners address such recommendations. In individual interviews, 58 teenage pregnancy prevention practitioners who work primarily with Mexican American female teenagers from two regions in California were asked about their understanding of recommendations for best practices and discussed the strategies they have used and challenges they have faced in implementing the recommendations. Qualitative methods were used to categorize responses and identify themes. Practitioners indicated that knowledge and awareness of Hispanic culture are essential, as is commitment to teenagers and their needs. They regard activities that encourage educational and career achievement as critical program components, and view both male partners' and family members' involvement in programs as important but challenging. Furthermore, practitioners feel that the implicit program goals of continued education and female self-sufficiency are often at odds with traditional Hispanic cultural values. Practitioners have valuable insight into the reality of implementing culturally sensitive programs. Programs need to balance the often competing values and goals of prevention programs with those of Hispanic youth culture and experiences.


Cold Agglutinin Autoantibodies in a Patient without a Visible Coronary Sinus Ostium: Strategies for Myocardial Protection without Using Retrograde Cardioplegia.
The presence of cold agglutinins (CA) during cardiac surgery with cardiopulmonary bypass usually creates the need for an altered surgical plan. In this case, the CA were discovered after the initiation of bypass, limiting the time, and cardioplegia solutions that could be used in the new approach. The inability to cannulate the coronary sinus with a retrograde cardioplegia catheter excluded the standard approach to myocardial preservation with CA of using continuous warm blood. For this case, we used intermittent cold crystalloid delivered via the antegrade needle for the first half of the procedure and through the saphenous vein graft anastomosis during the aortic valve portion of the cross-clamp period.


Impact of US and Canadian precursor regulation on methamphetamine purity in the United States.
Reducing drug purity is a major, but largely unstudied, goal of drug suppression. This study examines whether US methamphetamine purity was impacted by the suppression policy of US and Canadian precursor chemical regulation. Autoregressive integrated moving average (ARIMA)-intervention time-series analysis. Continental United States and Hawaii (1985-May 2005). Interventions US federal regulations targeting precursors, ephedrine and pseudoephedrine, in forms used by large-scale producers were implemented in November 1989, August 1995 and October 1997. US regulations targeting precursors in forms used by small-scale producers (e.g. over-the-counter medications) were implemented in October 1996 and October 2001. Canada implemented federal precursor regulations in January 2003 and July 2003 and an essential chemical (e.g. acetone) regulation in January 2004. Monthly median methamphetamine purity series. US regulations targeting large-scale producers were associated with purity declines of 16-67 points; those targeting small-scale producers had little or no impact. Canada's precursor regulations were associated with purity increases of 13-15 points, while its essential chemical regulation was associated with a 13-point decrease. Hawaii's purity was consistently high, and appeared to vary little with the 1990s/2000s regulations. US precursor regulations targeting large-scale producers were associated with substantial decreases in continental US methamphetamine purity, while regulations targeting over-the-counter medications had little or no impact. Canada's essential chemical regulation was also associated with a decrease in continental US purity. However, Canada's precursor regulations were associated with purity increases: these regulations may have impacted primarily producers of lower-quality methamphetamine, leaving higher-purity methamphetamine on the market by default. Hawaii's well-known preference for 'ice' (high-purity methamphetamine) may have helped to constrain purity there to a high, attenuated range, possibly limiting its sensitivity to precursor regulation.


Improving the genetic potential of okra (Abelmoschus esculentus L.) germplasm to tolerate salinity stress.
Okra (Abelmoschus esculentus L.) is the most consumed vegetable worldwide with the potential for diverse ecological adaptation. However, increasing salinization and changing climatic conditions are posing serious threats to the growth, yield, and quality of okra. Therefore, to mitigate increasing soil salinization and ensure sustainable okra production under rapidly changing climatic conditions, evaluation of new okra germplasm to develop salt tolerant cultivars is direly needed. The present study was designed to evaluate the genetic resources of okra genotypes for salt tolerance at growth and reproductive phases. Based on mophological and physio-biochemical responses of plants under stress condition, genotypes were divided into salt tolerant and succeptible groups. The experiment was comprised of 100 okra genotypes and each genotype was grown under control conditions and 6.5 dS m-1 NaCl concentration in a pot having 10 kg capacity. The experiment was conducted in a completely randomized design and each treatment was replicated three times. The results showed vast genetic variability among the evaluated okra germplasm traits like days to emergence, pod length, pod diameter, plant height, stem girth, and other yield-related parameters. Correlation analysis showed a highly significant positive association among the number of leaves at first flower and plant height at first flower.Likewise, pod weight also revealed a highly significant positive relationship for pod weight plant-1, pod length, and K+: Na+. Principal Component Analysis (PCA) revealed that out of 16 principal components (PCs), five components showed more than one eigenvalue and the first six PCs contributed 67.2% of the variation. Bi-plot analysis illustrated that genotypes 95, 111, 133, 99, and 128, under salt stress conditions, exhibited both high yield per plant and salt-tolerant behavior in other yield-related traits. On the basis of all studied traits, a salt susceptible group and a salt-tolerant group were formed. The salt tolerant group comprised of 97, 68, 95, 114, 64, 99, 111, 133, 128, and 109 genotypes, whereas, the salt susceptible group contained 137, 139, 130, 94, and 125 genotypes. Salt-tolerant okra genotypes were suggested to be used in further breeding programs aimed to develop salt tolerance in okra. These insights will empower precision breeding, underscore the importance of genetic diversity, and bear the potential to address the challenges of salt-affected soils while promoting broader agricultural resilience, economic prosperity, and food security.


Pharmacokinetics of [(14)C]Genistein in the rat: gender-related differences, potential mechanisms of biological action, and implications for human health.
Mass balance, plasma pharmacokinetics, tissue distribution, and metabolism of [(14)C]genistein were investigated in male and female rats (n = 5) following an oral dose of [(14)C]genistein (4 mg kg(-1)) to determine potential sites and mechanisms of biological action. Mean total excretion of radioactivity in urine and feces for both sexes was 66 and 33% of the dose respectively at 166 h after administration. Mean and maximal concentrations of radioactivity in plasma were significantly (p < 0.02) higher in male than female rats, with half-lives of 12.4 and 8.5 h, respectively. The concentration of radioactivity was significantly (p < 0.002) higher in liver from females than males and in reproductive (vagina, uterus, ovary, and prostate) compared with other peripheral organs. Analysis of plasma extracts by radio-HPLC-MS indicated that the predominant metabolites were genistein glucuronides, 4-hydroxyphenyl-2-propionic acid, and trace amounts of parent compound (<5%). Radioactive residues in uterus and prostate were predominantly parent compound and 4-hydroxyphenyl-2-propionic acid, respectively. Significantly (p < 0. 05) increased retention of [(14)C]genistein or metabolites was associated with reproductive organs, such as vagina, uterus, ovary, and prostate, likely to contain relatively high concentrations of estrogen receptors or binding proteins compared with other peripheral tissues. Factors liable to influence bioavailability of biologically active genistein or metabolites, such as dietary intake, warrant further investigation to determine the risks or benefits for different consumer groups of phytoestrogen-containing foods.


Methylation of the calcium channel-related gene, CACNA2D3, is frequent and a poor prognostic factor in gastric cancer.
The calcium channel voltage-dependent alpha2delta subunit consists of 4 genes, CACNA2D1 to CACNA2D4, of which CACNA2D2 and CACNA2D3 are located on 3p21.3 and 3p21.1, respectively. Here, we examined the relation between alpha2delta subunit gene alterations and gastric carcinogenesis. The expression and methylation status of the alpha2delta subunit genes were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and methylation-specific PCR in gastric cancers (GCs). The effects of CACNA2D3 expression were examined by cell proliferation and adhesion assays, and they predicted target gene alterations. Aberrant methylation of CACNA2D1 and CACNA2D3 mostly corresponded to their expression status in GC cell lines. CACNA2D1/3 methylation was detected in 10 (12.5%) and 24 (30%) of the 80 GC cases, respectively, but no CACNA2D2 methylation was seen in 32 cases. CACNA2D3 methylation was more frequently found in diffuse type than in intestinal type (16/38 [42.1%] vs 8/42 [19.0%]; P = .025) GCs. Among the 53 patients with advanced GCs, patients with cancers showing CACNA2D3 methylation had a significantly shorter survival time than patients without this methylation (P = .003). Exogenous CACNA2D3 expression strongly inhibited cell growth and adhesion and up-regulated p21 and p27 expression in HEK-293T and NUGC4 cells. Inverse effects were seen by CACNA2D3 small interfering RNA treatment in the CACNA2D3-positive cell lines, indicating that CACNA2D3 may have tumor suppressive functions. Loss of CACNA2D3 expression through aberrant promoter hypermethylation may contribute to gastric carcinogenesis, and CACNA2D3 methylation is a useful prognostic marker for patients with advanced GC.


[A guide to prevent decubitus ulcers in bedridden patients].
The authors present a report they produced dealing with how to prevent decubitus ulcers in bedridden patients. This report, designed in a practical use format, can be easily understood by all those nursing care professionals who have to care for bedridden patients; it is a highly useful tool for the nursing field.


Fitness of isogenic colony morphology variants of Pseudomonas aeruginosa in murine airway infection.
Chronic lung infections with Pseudomonas aeruginosa are associated with the diversification of the persisting clone into niche specialists and morphotypes, a phenomenon called 'dissociative behaviour'. To explore the potential of P. aeruginosa to change its morphotype by single step loss-of-function mutagenesis, a signature-tagged mini-Tn5 plasposon library of the cystic fibrosis airway isolate TBCF10839 was screened for colony morphology variants under nine different conditions in vitro. Transposon insertion into 1% of the genome changed colony morphology into eight discernable morphotypes. Half of the 55 targets encode features of primary or secondary metabolism whereby quinolone production was frequently affected. In the other half the transposon had inserted into genes of the functional categories transport, regulation or motility/chemotaxis. To mimic dissociative behaviour of isogenic strains in lungs, pools of 25 colony morphology variants were tested for competitive fitness in an acute murine airway infection model. Six of the 55 mutants either grew better or worse in vivo than in vitro, respectively. Metabolic proficiency of the colony morphology variant was a key determinant for survival in murine airways. The most common morphotype of self-destructive autolysis did unexpectedly not impair fitness. Transposon insertions into homologous genes of strain PAO1 did not reproduce the TBCF10839 mutant morphotypes for 16 of 19 examined loci pointing to an important role of the genetic background on colony morphology. Depending on the chosen P. aeruginosa strain, functional genome scans will explore other areas of the evolutionary landscape. Based on our discordant findings of mutant phenotypes in P. aeruginosa strains PAO1, PA14 and TBCF10839, we conclude that the current focus on few reference strains may miss modes of niche adaptation and dissociative behaviour that are relevant for the microevolution of complex traits in the wild.


High throughput quantitative phenotyping of plant resistance using chlorophyll fluorescence image analysis.
In order to select for quantitative plant resistance to pathogens, high throughput approaches that can precisely quantify disease severity are needed. Automation and use of calibrated image analysis should provide more accurate, objective and faster analyses than visual assessments. In contrast to conventional visible imaging, chlorophyll fluorescence imaging is not sensitive to environmental light variations and provides single-channel images prone to a segmentation analysis by simple thresholding approaches. Among the various parameters used in chlorophyll fluorescence imaging, the maximum quantum yield of photosystem II photochemistry (Fv/Fm) is well adapted to phenotyping disease severity. Fv/Fm is an indicator of plant stress that displays a robust contrast between infected and healthy tissues. In the present paper, we aimed at the segmentation of Fv/Fm images to quantify disease severity. Based on the Fv/Fm values of each pixel of the image, a thresholding approach was developed to delimit diseased areas. A first step consisted in setting up thresholds to reproduce visual observations by trained raters of symptoms caused by Xanthomonas fuscans subsp. fuscans (Xff) CFBP4834-R on Phaseolus vulgaris cv. Flavert. In order to develop a thresholding approach valuable on any cultivars or species, a second step was based on modeling pixel-wise Fv/Fm-distributions as mixtures of Gaussian distributions. Such a modeling may discriminate various stages of the symptom development but over-weights artifacts that can occur on mock-inoculated samples. Therefore, we developed a thresholding approach based on the probability of misclassification of a healthy pixel. Then, a clustering step is performed on the diseased areas to discriminate between various stages of alteration of plant tissues. Notably, the use of chlorophyll fluorescence imaging could detect pre-symptomatic area. The interest of this image analysis procedure for assessing the levels of quantitative resistance is illustrated with the quantitation of disease severity on five commercial varieties of bean inoculated with Xff CFBP4834-R. In this paper, we describe an image analysis procedure for quantifying the leaf area impacted by the pathogen. In a perspective of high throughput phenotyping, the procedure was automated with the software R downloadable at http://www.r-project.org/. The R script is available at http://lisa.univ-angers.fr/PHENOTIC/telechargements.html.


"I Didn't Expect to Be So Caught Up in It": a Qualitative Study of Experiences of Medical Students' Volunteering for Ukrainian Refugees.
Russia's invasion of Ukraine in February 2022 triggered a huge wave of migration, with thousands of refugees arriving at Prague's Central Station. With no medical service available, medical students started to volunteer and were running an infirmary available around the clock. The research aimed to explore medical students' professional experiences, emotionally challenging situations, and coping strategies in this demanding setting. The authors used a qualitative analysis of semi-structured in-depth interviews with 19 participants recruited through purposive sampling. Interviews took place between April and May 2022. Data were recorded, transcribed, and processed by using thematic qualitative analysis. The research identified five emotionally challenging situations: caring for traumatized refugees, refusal of treatment, disruption of everyday life, independent decision-making, and complexity of voluntary work. Students adopted both adaptive and maladaptive coping strategies for dealing with stress and trauma. Almost half the students reported signs of secondary traumatization and moral distress; however, no one asked for psychological help. Medical school curricula should cover trauma-informed approaches, healthy coping strategies, and destigmatization of psychological problems.


On the delayed self-heterodyne interferometric technique for determining the linewidth of fiber lasers.
The delayed self-heterodyne interferometric technique, first proposed in the context of semiconductor lasers, has been commonly used for over 20 years in the determination of the optical linewidth of lasers. We examine this technique in the light of recent work on fiber lasers, and point out further constraints in the applicability of these measurements. An approximate but simple and intuitive expression is provided for assessing the self-heterodyne technique when applied to fiber lasers.


Swallowing performance after radiotherapy for squamous cell carcinoma oesophagus.
To consider assessment of swallowing performance status as an alternative to survival in reporting results of treatment in patients with carcinoma oesophagus. Twenty five patients of squamous cell carcinoma of oesophagus treated with radiotherapy were evaluated clinically, radiologically and endoscopically, to assess their response to treatment. Two months after radiotherapy, 10 of 25 patients had swallowing score-1. During radiotherapy, oesophagitis involving normal oesophagus and diseased segment was seen in 64% of cases. Fifty six percent of patients developed stricture (24% malignant, 32% benign). At the end of two years, only five patients were alive, two with swallowing score of 2, two with swallowing score of 3 and one with swallowing score of 4. As the overall survival in carcinoma oesophagus is poor, the short term criteria for assessing the response of treatment should be swallowing performance status. Radiotherapy treatment can provide substantial palliation for patients debilitated by dysphagia.


The Ras-mitogen-activated protein kinase pathway is critical for the activation of matrix metalloproteinase secretion and the invasiveness in v-crk-transformed 3Y1.
To search for the intracellular signaling pathway critical for the secretion of matrix metalloproteinases (MMP), we studied the effects of dominant negative Ras (S17N Ras) and dominant negative MEK1 (MEK1AA) expression in v-crk-transformed 3Y1. Expression of either S17N Ras or MEK1AA dramatically suppressed the augmented secretion of MMP-2 and MMP-9 in v-crk-transfected 3Y1. Similarly, a Ras farnesyltransferase inhibitor, manumycin A, and a MEK1 inhibitor, U0126, suppressed MMP secretion in a dose-dependent manner, whereas a PI3 kinase inhibitor, wortmannin, could not. In addition, the suppression of MMP secretion by S17N Ras showed good correlation with the inhibition of in vitro invasiveness of the cells. In contrast, expression of dominant negative C3G did not suppress MMP secretion, although it substantially blocked the c-Jun N-terminal kinase activation. Taken together, the Ras-MEK1 pathway, but not the C3G-JNK pathway, seems to play a key role in the activation of MMP secretion and, hence, the invasiveness of v-crk-transformed cells.


Skin and homograft cartilage reconstruction.
Conservative vertical hemilaryngectomy poses the problem of relating the need to remove the tumor completely to the aim of reconstructing an adequate airway lined with epithelium. An attempt has has been made in experimental animals to overcome this problem using pedicled skin and homograft cartilage. The findings suggest that this is a feasible technique, although somewhat hampered by problems unique to the animals concerned. The use of skin pedicles provides adequate cover without shrinkage, and although it is doubtful whether cartilage can survive intact in the long-term, it would seem that it may be adequate for the purposes intended.


Assessing Preferences for Rare Disease Treatment: Qualitative Development of the Paroxysmal Nocturnal Hemoglobinuria Patient Preference Questionnaire (PNH-PPQ©).
To develop a patient preference questionnaire (PPQ) assessing eculizumab and ravulizumab treatment for paroxysmal nocturnal hemoglobinuria (PNH). The development of the PNH-PPQ© was consistent with Food and Drug Administration guidelines for patient-reported outcome measure development, and included 1) a targeted literature review; 2) PNH expert clinician input on treatment preferences; 3) review of existing qualitative data on the PNH treatment and disease experience; 4) concept elicitation interviews with 8 PNH patients who received eculizumab and/or ravulizumab; 5) translatability review; and 6) cognitive debriefing with 5 patients. Interview participants were recruited through a United Kingdom PNH patient advocacy group and a Canadian clinical site involved in clinical trial ALXN1210-PNH-302. Six themes were identified as most relevant to the PNH treatment experience from the concept elicitation interviews: disease symptoms (n=8/8); treatment frequency (n=7/8); quality of life impact of treatment/disease (n=7/8); treatment burden (n=7/8); treatment efficacy (n=5/8); and treatment side effects (n=5/8). An initial list of 88 preference questions was reduced to 11 highly relevant and non-redundant questions reflecting the 6 themes. Cognitive interview participants unanimously agreed that the PNH-PPQ instructions were clear; response options were understandable, easy to use, and provided enough choices; and the questions captured the factors that inform treatment preferences. When new drugs have similar efficacy to existing medications, documenting patient preferences is important for confirming patient benefit from the new medication. Understanding what matters most to patients is essential for delivering patient-centered care and may play a particularly significant role in treatment decision making. The availability of such a tool may be especially important as new orphan drugs are developed and patients with rare diseases have more than one treatment option to consider. The PNH-PPQ provides a patient-centered approach for evaluating preferences for the treatment of PNH. The PNH-PPQ has subsequently assessed patient preference in the clinical trial sub-study ALXN1210-PNH-302s.


Disease outcome in inflammatory bowel disease: mortality, morbidity and therapeutic management of a 796-person inception cohort in the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD).
The course of inflammatory bowel diseases (IBD) has mainly been studied using different methods in single patient cohorts. The aim of the present study was to assess clinical aspects of disease outcome in a population-based cohort of IBD patients over a 4-year period in multiple centres across Europe. A total of 796 patients with IBD diagnosed in 10 centres between October 1991 and October 1993, registered at the EC IBD study centre (98% of the original cohort), participated in the study. Investigators filled out a standard follow-up form containing questions on the method of follow-up, vital status of the patient, change in diagnosis, extraintestinal manifestations, medical and surgical treatment, and physician's global assessment of disease activity. Complete relief of the complaints was reported in 255 (48%) patients with ulcerative colitis (UC), 9 (50%) with indeterminate colitis (IC), but only in 87 (35%) of patients with Crohn disease (CD). Improvement was reported in 195 (37%) patients with UC, 113 (45%) with CD and 6 (33%) with IC. During the 4-year follow-up period, 23 patients died (14 UC, 8 CD. and 1 IC). The mean age at death was 69.3 years (s, 14.9 years). The deaths of three patients were recorded as directly due to IBD. With the present approach to therapeutic management the short-term outcome of patients with IBD seems to be favourable in 10 medical centres in the north and south of Europe. However, more detailed studies including both objective and subjective measures are necessary.


Medical apartheid. An American perspective.
The suppressive policies and practices of apartheid in South Africa have directly contributed to preventable morbidity and mortality in black Africans. Due to socioeconomic segregation ("functional apartheid"), America's citizens of color also suffer excess death and disability. Health status measurements in the United States confirm the failure of the current fragmented health care system to recognize or respond to the unmet need or the barriers that exist. Predictably, the changes needed to improve the health status of black South Africans are similar to those that are necessary to remedy the situation in the United States. Community-Oriented Primary Care is a health service provision model that holds promise as a comprehensive community-based strategy that can begin to address some of the shortcomings of the current medical care systems of both nations.


Emetic potential of daily oral etoposide.
Chemotherapeutic agents are classified by their degree of emetogenicity. Highly and moderately emetogenic agents require antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. Intravenous etoposide is listed as having low emetic potential. However, oral etoposide is categorized as having moderate emetogenicity. Daily oral etoposide is used in refractory germ cell cancer patients. We prospectively evaluated the emetic potential of oral etoposide in this patient population. Between August 2003 and February 2006, 16 patients with refractory germ cell cancer received single-agent, daily oral etoposide 50 mg/M(2) for 21 consecutive days every 4 weeks. All patients had progressed after cisplatin combination chemotherapy and had received high-dose chemotherapy with carboplatin plus etoposide (intravenously) with peripheral blood stem cell transplant. No patient received prophylactic antiemetics. Patients completed a six-question Multinational Association of Supportive Care in Cancer (MASCC) antiemetic tool during each day of etoposide during the first 21-day course. Nausea intensity and duration were recorded. Number of emetic episodes and any antiemetic medications were recorded. All 16 patients completed the six-question MASCC form. Eleven of 16 had no nausea or vomiting and two other patients had only minimal nausea, despite absence of any prophylactic antiemetics. Only two patients required antiemetic support. Two patients experienced emesis for a single episode. One patient had nausea on days 9-20 with a MASCC rating of 3-6, and one patient had continued mild nausea (MASCC rating 1-3) for all 21 days. Daily oral etoposide has a low probability of producing chemotherapy-induced nausea and/or vomiting and, in our opinion, does not require prophylactic antiemetics.


A framework for estimating and testing qualitative interactions with applications to predictive biomarkers.
An effective treatment may only benefit a subset of patients enrolled in a clinical trial. We translate the search for patient characteristics that predict treatment benefit to a search for qualitative interactions, which occur when the estimated response-curve under treatment crosses the estimated response-curve under control. We propose a regression-based framework that tests for qualitative interactions without assuming linearity or requiring pre-specified risk strata; this flexibility is useful in settings where there is limited a priori scientific knowledge about the relationship between features and the response. Simulations suggest that our method controls Type I error while offering an improvement in power over a procedure based on linear regression or a procedure that pre-specifies evenly spaced risk strata. We apply our method to a publicly available dataset to search for a subset of HER2+ breast cancer patients who benefit from adjuvant chemotherapy. We implement our method in Python and share the code/data used to produce our results on GitHub (https://github.com/jhroth/data-example).


The quality of life of Sri Lankan patients with cutaneous leishmaniasis.
The effect of cutaneous leishmaniasis on the quality of life (QoL) in Sri Lankan patients' had not been evaluated before. This study was done to identify the factors resulting poor QoL in cutaneous leishmaniasis. The standard one-week Dermatology Life Quality Index (DLQI) questionnaire was used on 146 patients. The children <15 years of age, illiterates, who could not understand the questionnaire were excluded. Twenty one percent had no effect; overall 86% had DLQI ≤10 indicating low/moderate effect. The least affected area was sexual function with some 92% stating they were not affected at all, while the areas of feelings, shopping, social, partner and treatment, (in descending order), being endorsed as the most affected areas. Facial lesions, lesions ≥25mm diameter, 21-40 age group were identified as being associated with poor QoL. Overall cutaneous leishmaniasis in Sri Lanka was a mild disease having low/moderate impact on 86% of patient's, in which 'feelings' being the most affected and 'sexual function' being the least affected domain.


Short-Term Synaptic Plasticity: Microscopic Modelling and (Some) Computational Implications.
Synaptic transmission is transiently adjusted on a spike-by-spike basis, with the adjustments persisting from hundreds of milliseconds up to seconds. Such a short-term plasticity has been suggested to significantly augment the computational capabilities of neuronal networks by enhancing their dynamical repertoire. In this chapter, after reviewing the basic physiology of chemical synaptic transmission, we present a general framework-inspired by the quantal model-to build simple, yet quantitatively accurate models of repetitive synaptic transmission. We also discuss different methods to obtain estimates of the model's parameters from experimental recordings. Next, we show that, indeed, new dynamical regimes appear in the presence of short-term synaptic plasticity. In particular, model neuronal networks exhibit the co-existence of a stable fixed point and a stable limit cycle in the presence of short-term synaptic facilitation. It has been suggested that this dynamical regime is especially relevant in working memory processes. We provide, then, a short summary of the synaptic theory of working memory and discuss some of its specific predictions in the context of experiments. We conclude the chapter with a short outlook.


Low birth weight and intelligence in adolescence and early adulthood: a meta-analysis.
Research has demonstrated an association between low birth weight (LBW; <2500 g) and adverse intelligence quotient (IQ) outcomes in childhood and early adolescence. We systematically evaluated whether this association persists into late adolescence and early adulthood and also assessed the influence of age of IQ assessment on effect size. During Stage 1 (meta-analysis of data on adolescents/adults), we searched for relevant articles in PsychINFO, PubMed, Ovid, CINAHL, ProQuest and ERIC until February 2011 (no lower limit). Studies which assessed full-scale IQ among LBW individuals (<2500 g), aged 13 years and older, with a normal birth weight (NBW; ≥2500 g) comparison group were eligible. A random-effects meta-analysis provided a pooled estimate of the difference in IQ scores between LBW and NBW individuals. Publication bias was assessed using Rosenthal's classic fail-safe N and Duval and Tweedie's Trim and Fill. During Stage 2, we added data from the Kerr-Wilson et al. meta-analysis (which included data from children; in Meta-analysis of the association between preterm delivery and intelligence. Journal Public Health 2011;33:1-8) to our sample from Stage 1 and conducted a meta-regression to evaluate the effect of age of IQ assessment. Using a total of 15 studies in Stage 1, it was demonstrated that NBW individuals scored an average of 7.63 IQ points higher than LBW individuals, CI = 5.95-9.31. After adjusting for publication bias, NBW samples demonstrated an IQ of 4.98 points higher than LBW samples, CI = 3.20-6.77. Furthermore, age at IQ assessment was a significant moderator of the association between birth weight and IQ, in that the effect size decreased from childhood into young adulthood. Cognitive impairments associated with LBW persist into adolescence and early adulthood; however, the influence of LBW on IQ decreases from childhood to young adulthood. These conclusions must be interpreted with caution due to unmeasured variables and possible influence from publication bias.


Prognostic Significance of Large Airway Dimensions on Computed Tomography in the General Population. The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study.
Large airway dimensions on computed tomography (CT) have been associated with lung function, symptoms, and exacerbations in chronic obstructive pulmonary disease (COPD), as well as with symptoms in smokers with preserved spirometry. Their prognostic significance in persons without lung disease remains undefined. To examine associations between large airway dimensions on CT and respiratory outcomes in a population-based cohort of adults without prevalent lung disease. The Multi-Ethnic Study of Atherosclerosis recruited participants ages 45-84 years without cardiovascular disease in 2000-2002; we excluded participants with prevalent chronic lower respiratory disease (CLRD). Spirometry was measured in 2004-2006 and 2010-2012. CLRD hospitalizations and deaths were classified by validated criteria through 2014. The average wall thickness for a hypothetical airway of 10-mm lumen perimeter on CT (Pi10) was calculated using measures of airway wall thickness and lumen diameter. Models were adjusted for age, sex, principal components of ancestry, body mass index, smoking, pack-years, scanner, percent emphysema, genetic risk score, and initial forced expiratory volume in 1 second (FEV1) percent predicted. Greater Pi10 was associated with 9% faster FEV1 decline (95% confidence interval [CI], 2 to 15%; P = 0.012) and increased incident COPD (odds ratio, 2.22; 95% CI, 1.43-3.45; P = 0.0004) per standard deviation among 1,830 participants. Over 78,147 person-years, higher Pi10 was associated with a 57% higher risk of first CLRD hospitalization or mortality (P = 0.0496) per standard deviation. Of Pi10's component measures, both greater airway wall thickness and narrower lumen predicted incident COPD and CLRD clinical events. In adults without CLRD, large airway dimensions on CT were prospectively associated with accelerated lung function decline and increased risks of COPD and CLRD hospitalization and mortality.


Prostaglandin E2 Receptor Antagonist with Antimicrobial Activity against Methicillin-Resistant Staphylococcus aureus.
Polymicrobial intra-abdominal infections (IAI) involving Candida albicans and Staphylococcus aureus are associated with severe morbidity and mortality (∼80%). Our laboratory discovered that the immunomodulatory eicosanoid prostaglandin E2 (PGE2) plays a key role in the lethal inflammatory response during polymicrobial IAI using a mouse model of infection. In studies designed to uncover key PGE2 biosynthesis/signaling components involved in the response, selective eicosanoid enzyme inhibitors and receptor antagonists were selected and prescreened for antimicrobial activity against C. albicans or S. aureus Unexpectedly, we found that the EP4 receptor antagonist L-161,982 had direct growth-inhibitory effects on S. aureusin vitro at the physiological concentration required to block the PGE2 interaction with EP4 This antimicrobial activity was observed with methicillin-sensitive S. aureus and methicillin-resistant S. aureus (MRSA) strains, with the MIC and minimum bactericidal concentration values for planktonic cells being 50 μg/ml and 100 μg/ml, respectively. In addition, L-161,982 inhibited S. aureus biofilm formation and had activity against preformed mature biofilms. More importantly, treatment of mice with L-161,982 following intraperitoneal inoculation with a lethal dose of MRSA significantly reduced the bioburden and enhanced survival. Furthermore, L-161,982 protected mice against the synergistic lethality induced by coinfection with C. albicans and S. aureus The antimicrobial activity of L-161,982 is independent of EP4 receptor inhibitory activity; an alternative EP4 receptor antagonist exerted no antimicrobial or protective effects. Taken together, these findings demonstrate that L-161,982 has potent antimicrobial activity against MRSA and may represent a significant therapeutic alternative in improving the prognosis of mono- or polymicrobial infections involving MRSA.


Oligomeric structure of a prototype retrovirus glycoprotein.
The structure of the Rous sarcoma virus envelope glycoprotein complex was studied by sedimentation gradient centrifugation analyses of detergent-solubilized wild-type and mutant envelope (env) gene products. These studies show that the envelope glycoprotein forms an oligomer during biosynthesis, which is most likely a trimer, and that this is the form of the complex found in virions. Our results are consistent with oligomer formation and transport out of the endoplasmic reticulum being closely linked. From analyses of mutant envelope proteins we conclude that the extracellular domain of the glycoprotein is sufficient for oligomer formation but that the transmembrane domain is required to stabilize this complex. Additional experiments suggest that interactions between external domains of the membrane-spanning, gp37 polypeptides are those most important for the formation of trimers. The significance of these observations to retroviral replication and implications for antiviral drug development are discussed.


Genetic diversity of Echinococcus vogeli in the western Brazilian Amazon.
Human polycystic echinococcosis is a parasitic infection caused by the larval stage of Echinococcus vogeli, which occurs in rural areas of Central and South America. Until now, little information on the genetic variability of E. vogeli is available. Here, 32 samples from human-excised E. vogeli cysts had a 396-bp sequence of the mitochondrial cytochrome oxidase I (COI) gene sequenced and compared to another 17 COI sequences representing nine Echinococcus species. A Bayesian COI tree revealed that all E. vogeli sequences formed a monophyletic and well-supported clade with an E. vogeli reference sequence. The occurrence of geographically restricted E. vogeli COI haplotypes suggests retention of ancestral polymorphisms with little migration in Acre, Brazil.


Deuterium induces a distinctive Escherichia coli proteome that correlates with the reduction in growth rate.
Substitution of protium (H) for deuterium (D) strongly affects biological systems. Whereas higher eukaryotes such as plants and mammals hardly survive a deuterium content of >30%, many microorganisms can grow on fully deuterated media, albeit at reduced rates. Very little is known about how the H/D replacement influences life at the systems level. Here, we used MS-based analysis to follow the adaptation of a large part of the Escherichia coli proteome from growth on a protonated full medium, over a protonated minimal medium, to a completely deuterated minimal medium. We could quantify >1800 proteins under all conditions, several 100 of which exhibited strong regulation during both adaptation processes. The adaptation to minimal medium strongly up-regulated amino acid synthesis and sugar metabolism and down-regulated translational proteins on average by 9%, concomitant with a reduction in growth rate from 1.8 to 0.67 h-1 In contrast, deuteration caused a very wide proteomic response over many cell functional categories, together with an additional down-regulation of the translational proteins by 5%. The latter coincided with a further reduction in growth rate to 0.37 h-1, revealing a clear linear correlation between growth rate and abundance of translational proteins. No significant morphological effects are observed under light and electron microscopies. Across all protein categories, about 80% of the proteins up-regulated under deuteration are enzymes with hydrogen transfer functions. Thus, the H/D kinetic isotope effect appears as the major limiting factor of cellular functions under deuteration.


Semi-quantitative assessment of disease risks at the human, livestock, wildlife interface for the Republic of Korea using a nationwide survey of experts: A model for other countries.
Wildlife-associated diseases and pathogens have increased in importance; however, management of a large number of diseases and diversity of hosts is prohibitively expensive. Thus, the determination of priority wildlife pathogens and risk factors for disease emergence is warranted. We used an online questionnaire survey to assess release and exposure risks, and consequences of wildlife-associated diseases and pathogens in the Republic of Korea (ROK). We also surveyed opinions on pathways for disease exposure, and risk factors for disease emergence and spread. For the assessment of risk, we employed a two-tiered, statistical K-means clustering algorithm to group diseases into three levels (high, medium and low) of perceived risk based on release and exposure risks, societal consequences and the level of uncertainty of the experts' opinions. To examine the experts' perceived risk of routes of introduction of pathogens and disease amplification and spread, we used a Bayesian, multivariate normal order-statistics model. Six diseases or pathogens, including four livestock and two wildlife diseases, were identified as having high risk with low uncertainty. Similarly, 13 diseases were characterized as having high risk with medium uncertainty with three of these attributed to livestock, six associated with human disease, and the remainder having the potential to affect human, livestock and wildlife (i.e., One Health). Lastly, four diseases were described as high risk with high certainty, and were associated solely with fish diseases. Experts identified migration of wildlife, international human movement and illegal importation of wildlife as the three routes posing the greatest risk of pathogen introduction into ROK. Proximity of humans, livestock and wildlife was the most significant risk factor for promoting the spread of wildlife-associated diseases and pathogens, followed by high density of livestock populations, habitat loss and environmental degradation, and climate change. This study provides useful information to decision makers responsible for allocating resources to address disease risks. This approach provided a rapid, cost-effective method of risk assessment of wildlife-associated diseases and pathogens for which the published literature is sparse.


Digital pHealth - Problems and Solutions for Ethics, Trust and Privacy.
The penetration of digital platforms and ecosystem based business-model together with the use algorithm and machine leaning are changing the environment where pHealth takes place. Traditional pHealth is changing to Digital pHealth. This development brings new ethical, privacy and trust problems which have to solve to make Digital pHealth successful. In this paper ethical, privacy and trust problems in Digital pHealth are studied at conceptual level. Concerns caused by the use novel ICT-technology and regulatory environment are also discussed. The starting point is that the Digital pHealth as a system and its applications and algorithms should be ethically acceptable, trustworthy and enable the service user to set own context-aware privacy policies. Mutual trust is needed between application and all stakeholders. Solution proposed for trustworthy Digital pHealth include ethical design, policy based privacy management and on-line calculation of privacy and trust levels using proven mathematical methods. In the future, novel solutions such as algorithm based access control and data sharing, and algorithm based privacy prediction together with cryptography based blockchain seems to have potential to change the way privacy is managed in Digital pHealth. Technology alone cannot solve current privacy and trust problems. New regulations which not only give users of the Digital pHealth right to set personal privacy polies but also force pHealth service providers and platform owners to prove regulatory compliance of their services are needed.


Review of Structural Features and Binding Capacity of Polyphenols to Gluten Proteins and Peptides In Vitro: Relevance to Celiac Disease.
Polyphenols have been extensively studied due to their beneficial effects on human health, particularly for the prevention and treatment of diseases related to oxidative stress. Nevertheless, they are also known to have an anti-nutritional effect in relation to protein metabolism. This effect is a consequence of its binding to digestive enzymes and/or protein substrates. Dietary gluten is the main trigger of celiac disease, a common immune-based disease of the small intestine and for which the only treatment available is the adherence to a gluten-free diet. Recent studies have addressed the use of dietary polyphenols to interact with gluten proteins and avoid its downstream deleterious effects, taking the advantage of the anti-nutritive nature of polyphenols by protein sequestering. Flavonoids, coumarins and tannins have shown the ability to form insoluble complexes with gluten proteins. One of the most promising molecules has been epigallocatechin-3-gallate, which through its binding to gliadins, was able to reduce gliadins digestibility and its ability to stimulate monolayer permeability and transepithelial transport of immunodominant peptides in cell models. This review focuses on the structural features and binding capacity of polyphenols to gluten proteins and peptides, and the prospects of developing an adjuvant therapy in celiac disease.


Deviance-elicited changes in event-related potentials are attenuated by ketamine in mice.
People with schizophrenia exhibit reduced ability to detect change in the auditory environment, which has been linked to abnormalities in N-methyl-D-aspartate (NMDA) receptor-mediated glutamate neurotransmission. This ability to detect changes in stimulus qualities can be measured with electroencephalography using auditory event-related potentials (ERPs). For example, reductions in the N100 and mismatch negativity (MMN), in response to pitch deviance, have been proposed as endophenotypes of schizophrenia. This study examines a novel rodent model of impaired pitch deviance detection in mice using the NMDA receptor antagonist ketamine. ERPs were recorded from unanesthetized mice during a pitch deviance paradigm prior to and following ketamine administration. First, N40 amplitude was evaluated using stimuli between 4 and 10 kHz to assess the amplitude of responses across the frequency range used. The amplitude and latency of the N40 were analyzed following standard (7 kHz) and deviant (5-9 kHz) stimuli. Additionally, we examined which portions of the ERP are selectively altered by pitch deviance to define possible regions for the mouse MMN. Mice displayed increased N40 amplitude that was followed by a later negative component between 50 and 75 msec in response to deviant stimuli. Both the increased N40 and the late N40 negativity were attenuated by ketamine. Ketamine increased N40 latency for both standard and deviant stimuli alike. The mouse N40 and a subsequent temporal region have deviance response properties similar to the human N100 and, possibly, MMN. Deviance responses were abolished by ketamine, suggesting that ketamine-induced changes in mice mimic deviance detection deficits in schizophrenia.


Adaptations Associated With an After-School Strength and Conditioning Program in Middle-School-Aged Boys: A Quasi-Experimental Design.
High-intensity strength and conditioning programs aimed at improving youth performance are becoming increasingly prevalent. The purpose of this study was to investigate the effects of a 16-week after-school strength and conditioning program on performance and body composition in middle-school-aged boys. Subjects in the training group (n = 16, mean age = 11.8 years) performed 90 minutes of supervised plyometric and resistance training twice weekly for 16 weeks. A group of control subjects (n = 9, age = 12.1 years) maintained their current activity levels. Sprint speed, 5-10-5 proagility, jump height, isometric peak torque of the leg extensors and flexors, and dual energy x-ray absorptiometry-derived body composition were examined during pretesting and posttesting. Data were analyzed by performing independent samples t-tests on the absolute change scores between groups. The primary findings were that the training intervention elicited significant improvements in 20-m sprint times (p = 0.03; mean change for training group = -0.17 seconds) and body-fat percentage (p = 0.03; 2.5% absolute improvement), the latter of which was a function of reduced fat mass (p = 0.06; -0.84 kg). Between-group differences were not noted for agility, jump height, lean mass, or strength measures; however, effect sizes generally showed greater improvements for the training group. In contrast to findings in longitudinal studies performed in collegiate athletes, sprint speed may be particularly adaptable during adolescence. In addition to potentially improving sport performance, high-intensity plyometric and resistance training programs offer the added benefit of improved body composition. These programs appear less effective for agility and jump performance and do not elicit substantial improvements in muscle mass above maturation.


Dental anomalies of number in the permanent dentition of patients with bilateral cleft lip: radiographic study.
To radiographically evaluate the prevalence of dental anomalies in patients with complete and incomplete bilateral cleft lip, comparing the prevalence of anomalies between genders and cleft types. Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo (HRAC/USP), Bauru, São Paulo, Brazil. 150 randomly selected panoramic radiographs of individuals with complete or incomplete bilateral cleft lip; patient age 12 to 25 years (mean age 13.8 years). Data were statistically analyzed to compare the possible association between presence of hypodontia and supernumerary teeth, according to gender and cleft type. Among the 150 patients evaluated, 80 (53.3%) were male and 70 (46.6%) were female. Since no statistically significant difference was found in hypodontia between genders, data were grouped for analysis, revealing prevalence of 31.6% for complete clefts and 26.8% for incomplete clefts. Concerning supernumerary teeth, the prevalence for the male patients was 28.2% for complete cleft lip and 29.2% for incomplete cleft lip. For female patients, the prevalence was significantly (p = .006) lower for complete cleft lip (17.5%) than for incomplete cleft lip (46.6%). The present results suggest that the prevalence of hypodontia was higher in patients with complete cleft lip, and the prevalence of supernumerary teeth was higher in patients with incomplete cleft lip, in agreement with previous studies.


Intraocular concentrations of cytokines and chemokines in rhegmatogenous retinal detachment and the effect of intravitreal triamcinolone acetonide.
To investigate the role of intravitreal injection of triamcinolone acetonide (IVTA) in preventing photoreceptor apoptosis in eyes with rhegmatogenous retinal detachment (RRD) by measuring cytokine levels in the aqueous humor before and after IVTA. Prospective, nonrandomized, interventional case series. setting: Institutional. patients: Nineteen eyes of 19 consecutive patients with RRD. intervention: All 19 eyes underwent IVTA 1 day before 25-gauge vitrectomy. Seventeen eyes free of retinal vascular disease served as controls. main outcome measure: Both baseline and 1 day post-IVTA measurements were made of the relative concentrations of 15 soluble factors (3 cytokines, 7 chemokines, and 5 growth factors). The associations with clinical findings, including macular status, were then analyzed. Elevated monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1β (MIP-1β), and interferon γ-induced protein 10 (IP-10) in eyes with RRD were significantly reduced after IVTA. MCP-1 levels were significantly correlated with MIP-1β and IP-10 before and after IVTA. The decreases in MCP-1, MIP-1β, and IP-10 were also closely correlated to each other. Both before and after IVTA, MCP-1 was higher in eyes with macula-off RRD than in eyes with macula-on RRD. IVTA suppressed elevated levels of intraocular MCP-1, MIP-1β, and IP-10 in eyes with RRD. The decrease in the aqueous levels of each of these factors was significantly correlated with the others. In addition to MCP-1, MIP-1β and IP-10 might potentially be additional target molecules for RRD therapy.


Targeted Interleukin-22 Gene Delivery in the Liver by Polymetformin and Penetratin-Based Hybrid Nanoparticles to Treat Nonalcoholic Fatty Liver Disease.
Nonalcoholic fatty liver disease (NAFLD) is now a leading cause of chronic liver disease, and there is currently no available treatment strategy. Interleukin-22 (IL-22) has been recognized as a promising agent for alleviating NAFLD, but the efficacy of IL-22 is far from satisfactory because safe dose of IL-22 elicited limited improvement, whereas higher concentration might induce serious side effects and off-target toxicities. Thus, targeted and sustained expression of IL-22 in the liver is necessary. To meet the challenge, we elaborately developed a novel polymetformin carrier by conjugating biguanide to chitosan, termed chitosan-metformin (CM), which could exert advanced gene delivery efficiency and possess intrinsic therapeutic efficacy from metformin for NAFLD. CM accompanied with penetratin and DSPE-PEG2000 could self-assemble to form stable nanocomplexes with IL-22 gene via electrostatic interaction. This nanoparticle (CDPIA) exerted desirable particle size at ∼100 nm, fine morphology, and efficient cellular internalization. Furthermore, CDPIA also demonstrated a unique superiority in endosomal escape capacity and satisfactory biocompatibility as well as predominant liver accumulation. Most importantly, CDPIA distinctly alleviated hepatic steatosis, restored insulin sensitivity, and improved metabolic syndrome in high-fat-diet-fed mice model. This liver-targeted delivery of IL-22 activated STAT3/Erk1/2 and Nrf2/SOD1 signaling transductions as well as modulated lipid-metabolism-related gene expression. These findings altogether demonstrated that the polymetformin and penetratin-based hybrid nanoparticles could be exploited as a novel safe and efficient strategy for the improvement of NAFLD.


5-Hydroxytryptamine depolarizes neurons of cat pancreatic ganglia.
Pancreatic ganglia contain 5-hydroxytryptamine (5-HT)-immunoreactive axons, some of which are extensions of myenteric neurons located in the pyloric antrum and proximal duodenum. The present study investigated the effect of 5-HT on the membrane potential of cat pancreatic ganglion neurons by means of intracellular recordings in vitro. Pressure application of 5-HT evoked a fast depolarization in 29 of 147 neurons and a slow depolarization in 89 of 147 neurons. A biphasic response was observed in 10 of 108 neurons. The 5-HT-induced slow depolarizing response was not altered in a low Ca2+ (0.1 mM), high Mg2+ (15 mM) solution nor by hexamethonium (10(-4) M) or atropine (10(-6) M). The fast depolarizing response was associated with a decrease of membrane input resistance (-17.2%). The slow depolarizing response was associated with either a decrease (-19.6%) in 24, an increase (+25.0%) in 20, or without a detectable change of membrane input resistance in 10 out of 54 neurons tested. Conditioning hyperpolarization increased the amplitude of both fast and slow depolarizing responses. A low Na+ (68.5 mM) solution and a high K+ (23.5 mM) solution significantly reduced the amplitude of the slow depolarizing response. A low Cl- (9.6 mM) solution had no significant effect on the slow depolarization. The 5-HT3 receptor antagonist MDL 72222 (Bemesetron) blocked the 5-HT-evoked fast depolarizing response. BRL 24924 (Renzapride) and 5 HT-DP, antagonists for the putative 5-HT1P receptor, blocked the slow depolarizing response. The 5-HT3 receptor agonist 2-methyl-5-HT evoked a fast depolarizing response and MCPP, an agonist for the putative 5-HT1P receptor, evoked a slow depolarizing response. Spiperone (a 5-HT1A receptor antagonist) and mianserin (a 5-HT2 receptor antagonist) had no effect on either depolarizing response to 5-HT. The results show that pancreatic ganglion neurons responded to 5-HT with fast and slow depolarizing responses. The data suggest that these responses were mediated by the 5-HT3 receptor and the putative 5-HT1P receptor, respectively.


Renal pathology of the fowl--a review.
On the basis of published literature and some original observations a comprehensive review is presented of the current concept of renal diseases in the fowl. All aspects of this important but much neglected subject are considered including autolysis, intoxications, inflammatory and degenerative conditions, specific viral diseases, gout, congenital abnormalities and neoplasms. The aetiology and pathogenesis of some forms of avian kidney disease are well understood but there are large gaps in our knowledge on others.


Constitutive hydrogen inhalation prevents vascular remodeling via reduction of oxidative stress.
Molecular hydrogen is thought to have an inhibitory effect on oxidative stress, thereby attenuating the onset and progression of various diseases including cardiovascular disease; however, few reports have assessed the preventive effect of constitutive inhalation of hydrogen gas on of vascular remodeling. Here, we investigated the effect of constitutive inhalation of hydrogen gas on vascular neointima formation using a cuff-induced vascular injury mouse model. After constitutive inhalation of compressed hydrogen gas (O2 21%, N2 77.7%, hydrogen 1.3%) or compressed air only (O2 21%, N2 79%) by C57BL/6 mice for 2 weeks from 8 weeks of age in a closed chamber, inflammatory cuff injury was induced by polyethylene cuff placement around the femoral artery under anesthesia, and hydrogen gas administration was continued until sampling of the femoral artery. Neointima formation, accompanied by an increase in cell proliferation, was significantly attenuated in the hydrogen group compared with the control group. NADPH oxidase NOX1 downregulation in response to cuff injury was shown in the hydrogen group, but the expression levels of NADPH oxidase subunits, p40phox and p47phox, did not differ significantly between the hydrogen and control groups. Although the increase in superoxide anion production did not significantly differ between the hydrogen and control groups, DNA damage was decreased as a result of reduction of reactive oxygen species such as hydroxyl radical (⋅OH) and peroxynitrite (ONOO-) in the hydrogen group. These results demonstrate that constitutive inhalation of hydrogen gas attenuates vascular remodeling partly via reduction of oxidative stress, suggesting that constitutive inhalation of hydrogen gas at a safe concentration in the living environment could be an effective strategy for prevention of vascular diseases such as atherosclerosis.


Serial Follow-Up Evaluation With Computed Tomography After Conservative Medical Treatment in Patients With Symptomatic Spontaneous Isolated Superior Mesenteric Artery Dissection.
There is no detailed information available about trend in the morphological change after conservative medical treatment in patients with symptomatic spontaneous isolated superior mesenteric artery dissection (SISMAD). We enrolled 27 consecutive patients with symptomatic SISMAD who underwent conservative medical treatment between 2006 and 2015. The long-term prognosis, natural history, and serial follow-up computed tomography (CT) findings of risk factors of rupture such as arterial diameter and false lumen enhancement were retrospectively assessed. Spontaneous isolated superior mesenteric artery dissection usually developed in middle-aged men around 50 years old who had a history of smoking. Follow-up CT was performed at 1 to 6 months, 7 to 12 months, and after 12 months. Superior mesenteric artery (SMA) maximum diameter was 10.3 mm (quartile 9.5-11.3) on initial CT and expanded in 47.1% patients during 1- to 6-month follow-up, which decreased over time ( P < .001 at 7- to 12-month follow-up, P = .001 after 12-month follow-up). On the other hand, false lumen enhancements were revealed in 9 (33.3%) patients on initial CT. The size of false lumen enhancement was expanded in the longest diameter in 35.3% patients and in shortest diameter in 29.4% during 1- to 6-month follow-up. However, the size of false lumen decreased in all patients after 12-month follow-up. All patients were alive without arterial aneurysm rupture and hospital readmission during the median of 523 days (170-799) study period. We demonstrated that both SMA maximum diameter and false lumen enhancement were transiently expanded in some patients during 6-month follow-up, but no longer expanded after 12-month follow-up. Patients with symptomatic SISMAD could be treated medically with scheduled careful follow-up CT evaluations.