Current challenges of hematologic complications due to immune checkpoint blockade: a comprehensive review.
Immune checkpoint blockade has demonstrated durable clinical benefits in a variety of malignancies. These immune checkpoint inhibitors (ICIs) produce unwanted autoimmune reactions due to an impaired self-tolerance. Hematologic immune-related adverse events (heme-irAEs) have been increasingly reported in the literature with a reported fatality rate of 12%. In this review, we illustrate 3 cases treated at Johns Hopkins Hospital for ICI-induced agranulocytosis, aplastic anemia, and thrombocytopenia. We then summarize the available evidence regarding the incidence and prevalence of heme-irAEs. We identified immune thrombocytopenia and hemolytic anemia as the most commonly reported heme-irAEs which are more commonly observed with nivolumab therapy. Median time to onset of heme-irAEs varies between patients but occurs earlier with CTLA-4 inhibitors than with anti-PD-L1/PD-1 agents. We also describe the current challenges regarding the recurrence of heme-irAEs despite immune checkpoint blockade termination. We provide the available evidence supporting a mixed T-cell and B-cell immune-mediated response. Finally, we review the treatment algorithm of these complications and provide treatment alternatives to steroid-refractory cases.


Cholesterol partially rescues the inhibition effect of pravastatin on keratinocytes proliferation by regulating cell cycle relative proteins through AKT and ERK pathway.
Mevalonate pathway plays a key role in skin physiological process in human. Recently, it has been reported that mutation of some genes in the mevalonate pathway cause disseminated superficial actinic porokeratosis (DSAP). But the pathogenesis is still unknown. Pravastatin (PRA), one of HMG-CoA reductase (HMGCR) inhibitors, has been found to inhibit cells proliferation, including keratinocytes (KCs). In this study, we use PRA to block the mevalonate pathway in KCs with or without the down-stream intermediate products replenishment. The results demonstrated that PRA strongly inhibited proliferation of KCs and caused the G0 /G1 arrest. When some down-stream intermediate products were added, only cholesterol (CH) could partially rescue the inhibition effect of PRA on KCs proliferation, but not other products, such as mevalonic acid, farnesyl pyrophosphate or geranylgeranyl pyrophosphate. Mechanistic analysis revealed that PRA down-regulated expression of cyclin B1, but up-regulated cyclin E and p21 expression. And PRA increased the phosphorylation level of Protein Kinase B (AKT) but decreased the phosphorylation level of Extracellular Signal Regulated Kinase (ERK1/2). CH could attenuate the elevated cyclin E and activated AKT induced by PRA. These results indicated that CH could rescue the proliferation inhibition of KCs caused by PRA, which laid a foundation for elucidating the pathogenesis of DSAP clearly.


Clinical and radiologic correlates of insomnia symptoms in ischemic stroke patients.
Insomnia is a common complaint in stroke survivors. The purpose of this study was to investigate the clinical and magnetic resonance imaging (MRI) correlates of insomnia symptoms in Chinese ischemic stroke survivors. A comprehensive psychiatric assessment was performed involving 508 ischemic stroke patients 3 months after their first-ever or recurrent acute stroke. Insomnia symptoms were evaluated with a standard insomnia questionnaire. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS).The evaluation of the MRI scans focused on infarctions, white matter lesions, and microbleeds. One hundred and eight-six patients (36.6% of the sample) had insomnia symptoms. Sixty-four patients (12.6%) had insomnia symptoms with daytime consequences. In the multivariate logistic regression analysis, GDS score (OR = 1.157, p < 0.001) and acute frontal lobe infarction (OR = 1.933, p = 0.039) were significant predictors of insomnia symptoms, while the GDS score (OR = 1.251, p < 0.001) and diabetes mellitus (OR = 1.959, p = 0.017) were significant predictors of insomnia symptoms with daytime consequences. Insomnia symptoms have a multi-factorial origin in stroke. Besides depressive symptoms, frontal lobe infarction and diabetes mellitus predict insomnia symptoms.


The effects of laminin-1 on spiral ganglion neurons are dependent on the MEK/ERK signaling pathway and are partially independent of Ras.
Laminin-1 (LN) is expressed along the route of neural growth from spiral ganglion (SG) neurons towards the developing organ of Corti, and has been shown to enhance neurite outgrowth from SG neurons in vitro. Signal transduction pathways linking LN signaling at the cell membrane to the cell nucleus can involve a variety of signaling molecules. Data from other systems suggest the potential involvement of the small G protein Ras, and the mitogen-activated protein kinases (MAPKs) Erk and/or p38. To assess these possibilities, the length and number of processes extending from SG explants cultured on LN-coated surfaces were evaluated after treatment with the Ras inhibitor FTI-277, the p38 inhibitor SB203580 and MAPK kinase (MEK) inhibitor U0126, which operates immediately upstream of the Erk MAPK. Treatment with the Ras inhibitor at levels known to inhibit the H- and N-Ras isoforms had no effect, while FTI-277 levels known to inhibit K-Ras reduced only neurite length. Suppression of MEK resulted in a decrease of both parameters, while incubation with the p38 inhibitor had no effect. The results of this study suggest that MEK plays a central role in LN signaling in SG neurites. While K-Ras signaling may participate in MEK-dependent increases in neurite length, the MEK-dependent increase in neurite number appears to be activated by a different intracellular pathway.


Nanoscale resonant-cavity-enhanced germanium photodetectors with lithographically defined spectral response for improved performance at telecommunications wavelengths.
We demonstrate the use of a subwavelength planar metal-dielectric resonant cavity to enhance the absorption of germanium photodetectors at wavelengths beyond the material's direct absorption edge, enabling high responsivity across the entire telecommunications C and L bands. The resonant wavelength of the detectors can be tuned linearly by varying the width of the Ge fin, allowing multiple detectors, each resonant at a different wavelength, to be fabricated in a single-step process. This approach is promising for the development of CMOS-compatible devices suitable for integrated, high-speed, and energy-efficient photodetection at telecommunications wavelengths.


National outcomes and uptake of laparoscopic gastrectomy for cancer in England.
Gastrectomy remains the mainstay of curative treatment for gastric cancer, yet it is associated with significant postoperative mortality. The laparoscopic approach has been introduced in an attempt to improve surgical outcomes. This study examines the uptake of laparoscopic gastrectomy in England and quantifies postoperative mortality and morbidity following gastrectomy for cancer. A population-based study of a national administrative database was undertaken. Patients undergoing gastrectomy for cancer in any National Health Services hospital in England between April 2000 and March 2010 were included. The main outcome measures were mortality, morbidity and length of stay. A total of 10,713 patients underwent gastrectomy, of which 10,233 (95.5%) underwent open gastrectomy (OG), and 480 (4.5%) underwent laparoscopic gastrectomy (LG). There was no significant difference in 30-day in-hospital mortality between OG and LG (5.6% vs. 4.8%; p = 0.461). Medical complications occurred in 2,311 (22.6%) and 120 (25%) patients from OG and LG groups respectively (p = 0.217). Patients in the LG groups had a shorter hospital stay than OG with median (interquartile range) of 11 (8-17) versus 14 (11-19) days respectively (p < 0.001). Readmission and reoperation rates were 10.2 versus 12.1% (p = 0.175) and 4 versus 4.6% (p = 0.523) for OG and LG respectively. LG is increasingly being performed in England. Postoperative morbidity and mortality of LG is similar to that of OG, but it is associated with a shorter hospital stay. Data from randomised controlled trials evaluating long term survival and patients' reported outcomes are essential before the final judgement on the value of LG in the management of gastric cancer.


Problems with the definition of renormalized Hamiltonians for momentum-space renormalization transformations.
For classical lattice systems with finite (Ising) spins, we show that the implementation of momentum-space renormalization at the level of Hamiltonians runs into the same type of difficulties as found for real-space transformations: Renormalized Hamiltonians are ill-defined in certain regions of the phase diagram.


The effect of fibrinolytic enzyme FIIa from Agkistrodon acutus venom on disseminated intravascular coagulation in rabbits.
A novel fibrinolytic enzyme, FII(a), was isolated from Agkistrodon acutus venom, which can degrade fibrin/fibrinogen and dissolve thrombus without activating plasminogen or influencing the activities of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type-1 (PAI-1). In this study, we evaluated the effect of FII(a) on lipopolysaccharide (LPS)-induced experimental disseminated intravascular coagulation (DIC) in rabbits, through the continuous infusion of 100-microg/kg/h LPS for a period of 6 h. Seven groups were established: LPS control, FII(a) (0.1, 0.3, and 0.6 mg/kg/h, respectively), heparin control (100 IU/kg/h), heparin + FII(a) (heparin 100 IU/kg/h associated with FII(a) 0.3 mg/kg/h), and a saline control group. A continuous injection of LPS induced a gradual impairment in hemostatic parameters, kidney fibrin deposition, and a high mortality rate. The intravenous administration of FII(a) improved the concentration of fibrinogen, the activities of protein C, plasminogen, t-PA, antithrombin III (ATIII), and PAI-1. Kidney fibrin deposition and the mortality also decreased. In the in vitro experiments, FII(a) can degrade fibrin/fibrinogen and high-dose FII(a) enhanced the activity of protein C. These findings suggest that the effects of FII(a) on LPS-induced DIC were from fibrinogen degradation and enhanced protein C activity. The simultaneous administration of FII(a) and heparin further improved all the hemostatic parameters, including decreased kidney fibrin deposition, and none of the rabbits died within 24 h, which indicates that the effects were mediated by degradation of fibrin/fibrinogen together with thrombin inhibition. We conclude that FII(a) may be useful in the treatment of DIC.


Differential contribution of velocity and distance to time estimation during self-initiated time-to-collision judgment.
To successfully intercept/avoid a moving object, human brain needs to precisely estimate the time-to-collision (TTC) of the object. In real life, time estimation is determined conjointly by the velocity and the distance of a moving object. However, surprisingly little is known concerning whether and how the velocity and the distance dimensions contribute differentially to time estimation. In this fMRI study, we demonstrated that variations of velocity evoked substantially different behavioral and neural responses than distance during self-initiated TTC judgments. Behaviorally, the velocity dimension induced a stronger time dilation effect than the distance dimension that participants' responses were significantly more delayed by increasing velocity than by decreasing distance, even with the theoretical TTC being equated between the two conditions. Neurally, activity in the dorsal fronto-parietal TTC network was parametrically modulated by variations in TTC irrespective of whether the variations in TTC were caused by velocity or distance. Importantly, even with spatial distance being equated, increasing velocity induced illusory perception of longer spatial trajectory in early visual cortex. Moreover, as velocity increased, the early visual cortex showed enhanced connectivity with the TTC network. Our results thus implied that with increasing velocity, TTC judgments depended increasingly on the velocity-induced illusory distance information from early visual cortex and was eventually tampered.


Change in pain severity with open label venlafaxine use in patients with a depressive symptomatology: an observational study in primary care.
Venlafaxine has shown benefit in the treatment of depression and pain. Worldwide data are extensively lacking investigating the outcome of chronic pain patients with depressive symptoms treated by venlafaxine in the primary care setting. This observational study aimed to elucidate the efficacy of venlafaxine and its prescription by Swiss primary care physicians and psychiatrists in patients with chronic pain and depressive symptomatology. We studied 505 patients with depressive symptoms suffering from chronic pain in a prospective naturalistic Swiss community based observational trial with venlafaxine in primary care. These patients have been treated with venlafaxine by 122 physicians, namely psychiatrists, general practitioners, and internists. On average, patients were treated with 143+/-75 mg (0-450 mg) venlafaxine daily for a follow-up of three months. Venlafaxine proved to be beneficial in the treatment of both depressive symptoms and chronic pain. Although side effects were absent in most patients, physicians might have frequently omitted satisfactory response rate of depression by underdosing venlafaxine. Our results reflect the complexity in the treatment of chronic pain in patients with depressive symptoms in primary care. Further randomized dose-finding studies are needed to learn more about the appropriate dosage in treating depression and comorbid pain with venlafaxine.


Plasma corticosterone responses to electrical stimulation of the bed nucleus of the stria terminalis.
The effect of ventral septal stimulation on pituitary-adrenal function was assessed by evaluating plasma corticosterone obtained prior to and following sham or electrical stimulation of the bed nucleus of the stria terminalis (BNST) of female rats anesthetized with urethane (1.3 g X kg-1). Hippocampal EEG, ECG, heart rate, blood pressure and respiration were routinely monitored; timed blood samples (0.2 ml) for determining plasma corticosterone (RIA) were obtained from a catheterized tail artery. Samples were taken at 0.5 min prior to and at 5, 10, 15 and 30 min after initiation of stimulation. Whereas increased plasma corticosterone levels followed stimulation of the medial aspect of the BNST, lateral stimulation resulted in decreased plasma corticosterone levels. The overall increase in plasma corticosterone following medial stimulation was 24%; the overall decrease was 13%. The largest increase in plasma corticosterone (36%) occurred at 30 min poststimulation; the largest decrease (22%) occurred at 15 min. Stimulation of the most rostral aspect of the BNST produced plasma corticosterone responses similar to that observed following medial stimulation. In contrast, no changes in corticosterone levels were observed following either sham stimulation or stimulation of the corpus callosum, fornix or anterior commissure.


Simultaneous determination of naproxen and related compounds by HPLC using porous graphitic carbon column.
A simple, selective and sensitive high performance liquid chromatographic (HPLC) method has been developed for the simultaneous determination of naproxen and its main degradation products such as 1-(6-methoxy-2-naphthyl) ethanol (MNE), 2-methoxy-6-ethyl naphthalene (MEN) and 2-acetyl-6-methoxy naphthalene (AMN). The separation of these compounds was achieved on porous graphitic carbon (PGC) column using tetrahydrofuran-methanol as the mobile phase, and the effluent from the column was monitored at 272 nm. At a flow rate of 1 ml min(-1), the retention time of the last eluting compound was less than 10 min. Correlation coefficient for calibration curves in the ranges 2-25 microg ml(-1) for all compounds studied were greater than 0.999. The sensitivity of detection is 0.05 microg l(-1) for naproxen, MNE and MEN and 0.20 microg ml(-1) for AMN. The reproducibility of the peak area of these compounds using isocratic elution were quite high, and the standard deviations (S.D.) were below 2% (n=5). The reproducibility of retention times of these compounds was within 1% (n=5). The proposed liquid chromatographic method was successfully applied to the analysis of commercially available naproxen sodium (NS) dosage forms with recoveries of 98.8-102%. A comparative study shows that the selectivity of these compounds on PGC column was different to that obtained with octadecyl silica (ODS) columns.


Contribution of muscular weakness to osteoporosis: computational and animal models.
Chronic weakness of the femoral musculature with old age may result in prolonged exposure of bone to critical understressing and, thus, cause osteoporotic changes. This study aims at quantifying long-term changes in thickness and mechanical properties of trabecular bone at the proximal femur due to muscular weakness. We utilized computational models of typical planar trabecular lattices at the proximal femur for simulating long-term changes in morphological and mechanical properties of trabecular bone. Incorporating cellular communication network with osteocytes as mechanosensors, the models were able to mimic mechanotransduction and consequent thickening and/or thinning of individual trabeculae in response to altered gluteus muscle and hip joint loads. We also studied a rat model (n=14) in which we surgically detached the gluteus muscle, to approximately 50% or completely. The computational simulations showed that when the force of the gluteus decreased (with or without simultaneous decrease in hip joint load), the most dramatic degradation in bone density, strength and stiffness occurred at the greater trochanter. Animal studies also demonstrated significant thinning of femoral trabeculae after 19 weeks of adaptation. Specifically, Tukey-Kramer analysis showed that rats subjected to partial surgical detachment of the gluteus had femoral trabeculae that were 22% thinner than controls (P<0.05). The present study showed that in both the computer and animal models, manipulation of muscle loading produced a significant stimulus for bone to adapt, i.e., a stimulus that is beyond its irresponsive 'lazy zone'. Accordingly, the results obtained herein indicate that muscular weakness may be an important factor contributing to osteoporosis.


Elimination of energy-consuming mechanical stirring: Development of auto-suspending ZnO-based photocatalyst for organic wastewater treatment.
Powdered-photocatalysis of organic wastewater is widely investigated, unfortunately not industrially implemented due to its high energy requirement. Interestingly, such issue may be alleviated via the elimination of mechanical stirring required. Core-shell ZnO-based photocatalysts were developed herein, subsequently demonstrated efficient photocatalytic activities in the absence of mechanical stirring. Results show that the developed SiO2-cored ZnO photocatalyst are highly crystalline, while significantly smaller than coreless, pure ZnO due to the multi-point crystallization prompted. Additionally, it is also inherited with considerable buoyancy ability from SiO2-core in the absence of mechanical stirring, concurrently rendered with UV-active properties due to its ZnO-shell. Experimentally, 55% of particles of ZnO_0.0025 (0.0025 mol of ZnO-deposition) were found stably suspended for 60 min in liquid substrate, as opposed to the instant-settling of pure ZnO particles. In term of photocatalytic activity, ZnO_0.01 manifested the best methylene blue (MB) degradation with 150 mL/min of O2-bubbling. 67.63% of MB was degraded with photocatalyst loading of 0.2 g/L after 120 min UV-irradiation, simultaneously recorded the highest pseudo-first order reaction constant of 9.636 × 10-3 min-1. As summary, the auto-suspending photocatalysis conceptualized in current study offers a high possibility in reducing energy requirement for photo-treatment of wastewater, hence advocating its industrialization potential in near future.


Sex-dependent difference in the relationship between thyroid hormones and gallstone disease in euthyroid subjects.
The relationship between thyroid dysfunction and gallstone disease (GSD) has been examined by some observational studies. However, evidence about the relationship between thyroid function and GSD among euthyroid subjects was scarce. The aim of this study was to investigate the association between thyroid function and the presence of GSD in a large-sample euthyroid subjects. A total of 5476 euthyroid subjects who underwent health checkup were included. GSD was diagnosed by hepatic ultrasonography. Conventional risk factors for GSD were assessed as well as serum levels of TSH, TT3, TT4 and Log-transformed TT3/TT4 ratio. A total of 4958 subjects were finally included. Levels of TSH, TT3, TT4, and ln (TT3/TT4) were comparable between GSD and non-GSD group (TSH: 1.73 ± 1.07 vs 1.74 ± 1.07 mIU/L, P = .931; TT3: 1.55 ± 0.40 vs 1.54 ± 0.39 ng/mL, P = .797; TT4: 9.37 ± 2.07 vs 9.49 ± 2.06 ug/dL, P = .245, ln (TT3/TT4): -1.80 ± 0.23 vs -1.83 ± 0.23, P = .130, respectively). Multivariate logistic regression analysis among all subjects revealed that the thyroid function parameters did not reach significant difference. Subgroup analyses showed that the relationship between thyroid function and GSD was different according to gender, with negative association for ln (TT3/TT4) and (odds ratio:0.551, 95% CI: 0.306-0.992, P = .047) and positive association for TT4 (odds ratio:1.077, 1 95% CI: .001-1.158, P = .046) in men. None of the thyroid function parameters was significantly associated with GSD in women. Our findings indicated that low levels of TT3-to-TT4 ratio and high levels of TT4 were significantly and independently associated with GSD among euthyroid male subjects, but not female subjects.


Two novel fish paralogs provide insights into the Rid family of imine deaminases active in pre-empting enamine/imine metabolic damage.
Reactive Intermediate Deaminase (Rid) protein superfamily includes eight families among which the RidA is conserved in all domains of life. RidA proteins accelerate the deamination of the reactive 2-aminoacrylate (2AA), an enamine produced by some pyridoxal phosphate (PLP)-dependent enzymes. 2AA accumulation inhibits target enzymes with a detrimental impact on fitness. As a consequence of whole genome duplication, teleost fish have two ridA paralogs, while other extant vertebrates contain a single-copy gene. We investigated the biochemical properties of the products of two paralogs, identified in Salmo salar. SsRidA-1 and SsRidA-2 complemented the growth defect of a Salmonella enterica ridA mutant, an in vivo model of 2AA stress. In vitro, both proteins hydrolyzed 2-imino acids (IA) to keto-acids and ammonia. SsRidA-1 was active on IA derived from nonpolar amino acids and poorly active or inactive on IA derived from other amino acids tested. In contrast, SsRidA-2 had a generally low catalytic efficiency, but showed a relatively higher activity with IA derived from L-Glu and aromatic amino acids. The crystal structures of SsRidA-1 and SsRidA-2 provided hints of the remarkably different conformational stability and substrate specificity. Overall, SsRidA-1 is similar to the mammalian orthologs whereas SsRidA-2 displays unique properties likely generated by functional specialization of a duplicated ancestral gene.


PAR-1 for the course of neurodegeneration.
The large number of kinases that phosphorylate the microtubule binding protein tau has posed a challenge to understanding their individual roles in turning this protein into a killer of neurons. A study in this issue of Cell (Nishimura et al., 2004) uses an elegant fusion of loss-of-function genetics and transgenic overexpression to make the case that the PAR-1 kinase stands at the head of a temporally ordered series of tau phosphorylations.


Replicator dynamics for the game theoretic selection models based on state.
The paper presents an attempt to integrate the classical evolutionary game theory based on replicator dynamics and the state-based approach of Houston and McNamara. In the new approach, individuals have different heritable strategies; however, individuals carrying the same strategy can differ in terms of state, role or the situation in which they act. Thus, the classical replicator dynamics is completed by the additional subsystem of differential equations describing the dynamics of transitions between different states. In effect, the interactions described by game structure, in addition to the demographic payoffs (constituted by births and deaths), can lead to the change in state of the competing individuals. Special cases of reversible and irreversible incremental stage-structured models, where the state changes can describeenergy accumulation, developmental steps or aging, are derived for discrete and continuous versions. The new approach is illustrated using the example of the Owner-Intruder game with explicit dynamics of the role changes. The new model presents a generalization of the demographic version of the Hawk-Dove game,with the difference being that the opponents in the game are drawn from two separate subpopulations consisting of Owners and Intruders. Here, the Intruders check random nest sites and play the Hawk-Dove game with the Owner if they are occupied. Meanwhile, the Owners produce newborns that become Intruders, since they must find a free nest site to reproduce. An interesting feedback mechanism is produced via the fluxes of individuals between the different subpopulations. In addition, the population growth suppression mechanism resulting from the fixation Bourgeois strategy is analyzed.


Detection of the nuclear poly(ADP-ribose)-metabolizing enzymes and activities in response to DNA damage.
Poly(ADP-ribosyl)ation is a posttranslational modification of proteins in higher eukaryotes mediated by poly(ADP-ribose) polymerases (PARPs) that is involved in many physiological processes such as DNA repair, transcription, cell division, and cell death. Biochemical studies together with PARP-1- or PARP-2-deficient cellular and animal models have revealed the redundant but also complementary functions of the two enzymes in the surveillance and maintenance of genome integrity. Poly(ADP-ribose) is degraded by the endo- and exo-glycosidase activities of poly(ADP-ribose) glycohydrolase (PARG). In this chapter, biochemical and immunofluorescence methods are described for detecting and assaying PARPs and PARG.


Minimal polyketide pathway expression in an actinorhodin cluster-deleted and regulation-stimulated Streptomyces coelicolor.
Along with traditional random mutagenesis-driven strain improvement, cloning and heterologous expression of Streptomyces secondary metabolite gene clusters have become an attractive complementary approach to increase its production titer, of which regulation is typically under tight control via complex multiple regulatory networks present in a metabolite low-producing wild-type strain. In this study, we generated a polyketide non-producing strain by deleting the entire actinorhodin cluster from the chromosome of a previously generated S. coelicolor mutant strain, which was shown to stimulate actinorhodin biosynthesis through deletion of two antibiotic downregulators as well as a polyketide precursor flux downregulator (Kim et al. in Appl Environ Microbiol 77:1872-1877, 2011). Using this engineered S. coelicolor mutant strain as a surrogate host, a model minimal polyketide pathway for aloesaponarin II, an actinorhodin shunt product, was cloned in a high-copy conjugative plasmid, followed by functional pathway expression and quantitative metabolite analysis. Aloesaponarin II production was detected only in the presence of a pathway-specific regulatory gene, actII-ORF4, and its production level was the highest in the actinorhodin cluster-deleted and downregulator-deleted mutant strain, implying that this engineered polyketide pathway-free and regulation-optimized S. coelicolor mutant strain could be used as a general surrogate host for efficient expression of indigenous or foreign polyketide pathways derived from diverse actinomycetes in nature.


Economy of locomotion in high-altitude Tibetan migrants exposed to normoxia.
High-altitude Tibetans undergo a pattern of adaptations to chronic hypoxia characterized, among others, by a more efficient aerobic performance compared with acclimatized lowlanders. To test whether such changes may persist upon descent to moderate altitude, oxygen uptake of 17 male Tibetan natives lifelong residents at 3500-4500 m was assessed within 1 month upon migration to 1300 m. Exercise protocols were: 5 min treadmill walking at 6 km h(-1) on increasing inclines from +5 to +15% and 5 min running at 10 km h(-1) on a +5% grade. The data (mean +/- S.E.M.) were compared with those obtained on Nepali lowlanders. When walking on +10, +12.5 and +15% inclines, net V(O2) of Tibetans was 25.2 +/- 0.7, 29.1 +/- 1.1 and 31.3 +/- 0.9 ml kg(-1) min(-1), respectively, i.e. 8, 10 and 13% less (P < 0.05) than that of Nepali. At the end of the heaviest load, blood lactate concentration was lower in Tibetans than in Nepali (6.0 +/- 0.9 versus 8.9 +/- 0.6 mM; P < 0.05). During running, V(O2) of Tibetans was 35.1 +/- 0.8 versus 39.3 +/- 0.7 ml kg(-1) min(-1) (i.e. 11% less; P < 0.01). In conclusion, during submaximal walking and running at 1300 m, Tibetans are still characterized by lower aerobic energy expenditure than control subjects that is not accounted for by differences in mechanical power output and/or compensated for by anaerobic glycolysis. These findings indicate that chronic hypoxia induces metabolic adaptations whose underlying mechanisms still need to be elucidated, that persist for at least 1 month upon descent to moderate altitude.


A large population histology study showing the lack of association between ALT elevation and significant fibrosis in chronic hepatitis B.
We determined the association between various clinical parameters and significant liver injury in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients. From 1994 to 2008, liver biopsy was performed on 319 treatment-naïve CHB patients. Histologic assessment was based on the Knodell histologic activity index for necroinflammation and the Ishak fibrosis staging for fibrosis. 211 HBeAg-positive and 108 HBeAg-negative patients were recruited, with a median age of 31 and 46 years respectively. 9 out of 40 (22.5%) HBeAg-positive patients with normal ALT had significant histologic abnormalities (necroinflammation grading ≥ 7 or fibrosis score ≥ 3). There was a significant difference in fibrosis scores among HBeAg-positive patients with an ALT level within the Prati criteria (30 U/L for men, 19 U/L for women) and patients with a normal ALT but exceeding the Prati criteria (p = 0.024). Age, aspartate aminotransferase and platelet count were independent predictors of significant fibrosis in HBeAg-positive patients with an elevated ALT by multivariate analysis (p = 0.007, 0.047 and 0.045 respectively). HBV DNA and platelet count were predictors of significant fibrosis in HBeAg-negative disease (p = 0.020 and 0.015 respectively). An elevated ALT was not predictive of significant fibrosis for HBeAg-positive (p = 0.345) and -negative (p = 0.544) disease. There was no significant difference in fibrosis staging among ALT 1-2 × upper limit of normal (ULN) and > × 2 ULN for both HBeAg-positive (p = 0.098) and -negative (p = 0.838) disease. An elevated ALT does not accurately predict significant liver injury. Decisions on commencing antiviral therapy should not be heavily based on a particular ALT threshold.


Parahiatal Hernia Sac Tumor of Localized Malignant Peritoneal Mesothelioma.
We describe an extremely rare case of a parahiatal hernia sac tumor. A computed tomography scan showed a solitary mass located adjacent to the diaphragm and esophagus in a 72-year-old woman. Thoracoscopic surgery revealed that a tumor protruded through a diaphragmatic defect lateral to the crus and adhered to the perigastric fat in the gastric fundus. Radical resection of the tumor and herniorrhaphy of the diaphragmatic defect were performed. Pathologic and clinical findings indicated this was a parahiatal hernia sac tumor of localized malignant peritoneal mesothelioma. No recurrence was observed without adjuvant therapy 10 months after surgery.


Does the cost of care differ for patients with fee-for-service vs. capitation of payment? A case-control study in gastroenterology.
There is growing evidence to demonstrate overuse of medical resources in fee for service (FFS) payment models (in which physicians are reimbursed according to volume of care provided) compared to capitation payment models (in which physicians receive a fixed salary regardless of level of care provided). In this medical centre, patients with and without insurance are admitted through the same access point (emergency room) and cared for by the same physicians. Therefore, apart from insurance status, all other variables influencing delivery of care are similar for both patient groups. However, physician reimbursement differs for both groups: FFS for patients with private insurance (i.e. the admitting physician's reimbursement escalates progressively with each day that the patient spends in hospital) and base salary irrespective of care provided for patients with universal insurance (capitation payment model). All admitting physicians are aware of the patient's insurance status and the duration of hospitalization is at the discretion of the admitting physician. This study aimed to compare cost of care of patients with and without insurance admitted to a teaching hospital with a primary gastroenterology or hepatology (GIH) diagnosis. All hospital inpatients admitted between January 2008 and December 2009 with a primary GI-related diagnosis related group (DRG) were identified. Patients were classified as uninsured (state-funded) or privately insured. Only DRGs with at least five patients in both the insured and uninsured patient groups were analyzed to ensure a precise estimate of inpatient costs. Patient level costing (PLC) was used to express the total cost of hospital care for each patient; PLC comprised a weighted daily bed cost plus cost of all medical services provided (e.g. radiology, pathology tests) calculated according to an activity-based costing approach, cost of medications were excluded. An overall mean cost of care per patient was calculated for both groups. All costs were discounted to 2009 values. In total, 630 patients were admitted with one of 11 GIH DRGs, 181 (29 %) with private insurance. Pooled mean cost of care was higher for uninsured (6,781 euros/patient) compared to insured patients (6,128 euros/patient). Apart from patients with 'non-cirrhotic non-alcoholic liver disease (non-complex)' in whom mean cost was higher for insured patients, there were no significant differences in mean cost of care nor mean patient age for insured and uninsured groups for any other diagnoses. Inpatient hospital costs were equivalent for patients with and without private health insurance when care was provided in a single hospital. Provision of care for all patients in a common hospital setting regardless of health insurance status may reduce disparities in healthcare utilization.


Nonsense and missense mutation of mitochondrial ND6 gene promotes cell migration and invasion in human lung adenocarcinoma.
Previous study showed that mitochondrial ND6 (mitND6) gene missense mutation resulted in NADH dehydrogenase deficiency and was associated with tumor metastasis in several mouse tumor cell lines. In the present study, we investigated the possible role of mitND6 gene nonsense and missense mutations in the metastasis of human lung adenocarcinoma. The presence of mitND6 gene mutations was screened by DNA sequencing of tumor tissues from 87 primary lung adenocarcinoma patients and the correlation of the mutations with the clinical features was analyzed. In addition, we constructed cytoplasmic hybrid cells with denucleared primary lung adenocarcinoma cell as the mitochondria donor and mitochondria depleted lung adenocarcinoma A549 cell as the nuclear donor. Using these cells, we studied the effects of mitND6 gene nonsense and missense mutations on cell migration and invasion through wounding healing and matrigel-coated transwell assay. The effects of mitND6 gene mutations on NADH dehydrogenase activity and ROS production were analyzed by spectrophotometry and flow cytometry. mitND6 gene nonsense and missense mutations were detected in 11 of 87 lung adenocarcinoma specimens and was correlated with the clinical features including age, pathological grade, tumor stage, lymph node metastasis and survival rate. Moreover, A549 cell containing mitND6 gene nonsense and missense mutation exhibited significantly lower activity of NADH dehydrogenase, higher level of ROS, higher capacity of cell migration and invasion, and higher pAKT and pERK1/ERK2 expression level than cells with the wild type mitND6 gene. In addition, NADH dehydrogenase inhibitor rotenone was found to significantly promote the migration and invasion of A549 cells. Our data suggest that mitND6 gene nonsense and missense mutation might promote cell migration and invasion in lung adenocarcinoma, probably by NADH dehydrogenase deficiency induced over-production of ROS.


Increases in institutionalization, healthcare resource utilization, and mortality risk associated with Parkinson disease psychosis: Retrospective cohort study.
Patients with Parkinson disease (PD) often develop psychosis (P). The association of PDP with death and long-term custodial care (CC) has not been well studied. Medicare Parts A, B, and D data, 2007-2015, were used to define cohorts of PD and PDP patients. PD was defined by ≥ 2 ICD-9-CM codes (332.0x) at least 30, but no more than 365, days apart, and PDP by ≥ 2 codes for psychotic symptoms. Outcomes were CC use, defined as nursing home stays of >100 consecutive days, and death. To compare the association of PDP with outcomes, PDP patients were matched to PD patients without psychosis. Within 1 year of PDP diagnosis, 12.1% of PDP patients used CC, versus 3.5% of non-PDP patients 1 year after the matching date; corresponding percentages at 5 years were 25.8% and 10.0%. Cumulative incidence curves for CC and for death differed significantly (P < 0.0001). PDP was associated with RRs of 3.38 (95% CI, 2.93-3.90) for CC and 1.34 (1.23-1.45) for death. Other factors associated with CC were age (3.57, 2.08-6.14, age ≥90 versus ≤70 years) and female sex (1.37, 1.18-1.58). Female sex was associated with a lower RR for death (0.76, 0.70-0.82). Health care utilization and costs were substantially higher for PDP than for non-PDP patients. In PD patients, psychosis was associated with a more than 3-fold increased risk of CC and a nearly one-third increased risk of death. Women entered CC more often than men, likely because they lived longer in the setting of PD.


Arthroscopic anatomy of the middle glenohumeral ligament.
The middle glenohumeral ligament (MGHL) has seldom been studied and its function is unknown. The aim of this study was to describe its anatomical presentations. A prospective study was conducted of MGHL anatomy in 107 arthroscopies, with a description of its shape and superior and inferior insertion in the articular surface of the subscapularis tendon. The MGHL was investigated dynamically during internal rotation of the glenohumeral joint. Sixty-three percent (68/107) of the MGHLs were found to be leaf-like, and 27% (28/107) cord-like, 5.5% (6/107) vestigial, and 2% (2/107) had several strands. The MGHL was absent for 2% of patients (2/107). The inferior insertion point of the MGHL was lateral, masked by the humeral head, in 34% of cases (36/105), intermediate, in front of the glenohumeral joint line, in 57% of cases (60/105), and medial, in front of the labrum, in 9% of cases (9/105). During internal rotation, 46% (48/105) of the MGHLs were observed to retract medially, the subscapularis tendon moving away from the anterior glenoid rim, while 54% (57/105) remained visible in front of the glenohumeral joint and came into contact with the articular surface of the subscapularis tendon. The MGHL has many anatomical variations.


Integrating McGill Wetland Model (MWM) with peat cohort tracking and microbial controls.
Peatlands store a large amount of organic carbon and are vulnerable to climate change and human disturbances. However, ecosystem-scale peatland models often do not explicitly simulate the decrease in peat substrate quality, i.e., decomposability or the dynamics of decomposers during peat decomposition, which are key controls in determining peat carbon's response to a changing environment. In this paper, we incorporated the tracking of each year's litter input (a cohort) and controls of microbial processes into the McGill Wetland Model (MWMmic) to address this discrepancy. Three major modifications were made: (1) the simple acrotelm-catotelm decomposition model in MWM was changed into a time-aggregated cohort model, to track the decrease in peat quality with decomposition age; (2) microbial dynamics: growth, respiration and death were incorporated into the model and decomposition rates are regulated by microbial biomass; and (3) vertical and horizontal transport of the dissolved organic carbon (DOC) were added and used to regulate the growth of microbial biomass. MWMmic was evaluated against measurements from the Mer Bleue peatland, a raised ombrotrophic bog located in southern Ontario, Canada. The model was able to replicate microbial and DOC dynamics, while at the same time reproduce the ecosystem-level CO2 and DOC fluxes. Sensitivity analysis with MWMmic showed increased peatland resilience to perturbations compared to the original MWM, because of the tracking of peat substrate quality. The analysis revealed the most important parameters in the model to be microbial carbon use efficiency (CUE) and turnover rate. Simulated microbial adaptation with those two physiological parameters less sensitive to disturbances leads to a significantly larger peat C loss in response to warming and water table drawdown. Thus, the rarely explored peatland microbial physiological traits merit further research. This work paves the way for further model development to examine important microbial controls on peatland's biogeochemical cycling.


Feasibility, safety and effectiveness of mapping system assisted conduction system pacing: a single-center prospective study.
To assess pacing and electrophysiological parameters, as well as mid-term outcomes, among patients undergoing His bundle pacing (HBP) guided by KODEX-EPD (a novel mapping system). Consecutive patients undergoing conduction system pacing (CSP) for bradycardia indications were evaluated. Procedural and fluoroscopic times and pacing characteristics were compared between conventional fluoroscopy (the standard group, N = 20 cases) and KODEX-EPD mapping system guided group (the KODEX group, N = 20cases) at CSP implantation and all patients were followed at 6-month. HBP was achieved in all patients (the standard group 20/20 and the KODEX group 20/20). There was no difference in the mean procedure time between the two groups (63.7 ± 9.3 vs. 78.2 ± 25.1 min, p = 0.33). Compared with the standard group, the KODEX group significantly reduced the intraoperative X-ray exposure time (3.8 ± 0.5 vs. 19.3 ± 5.1 min, p < 0.05) and X-ray dose (23.6 ± 5.4 vs. 120.2 ± 38.3 mGy, p < 0.05). There were no significant differences in atrial impedance (643.0 ± 98.8 vs. 591.5 ± 92.1 Ω, p = 0.09), atrial sensing (2.9 ± 0.8 vs. 2.5 ± 0.8 mV, p = 0.08), ventricular sensing (12.8 ± 2.4 vs. 13.3 ± 3.3 mV, p = 0.63),atrial pacing threshold (1.0 ± 0.2 vs. 1.0 ± 0.1 V/0.4 ms, p = 0.81) and ventricular pacing threshold (1.0 ± 0.2 vs. 0.9 ± 0.1 V/0.4 ms, p = 0.63) between two groups, There were statistical differences in ventricular impedance (640.0 ± 80.3 vs. 702.0 ± 86.1 Ω, p < 0.05). There was no statistical significance in pacing parameters between the two groups at 6 months after procedure (p > 0.05). During the 6-months follow-up period, no adverse events occurred in the two groups. It can be concluded that KODEX-EPD can safely guide His bundle branch pacing lead implantation with reduced fluoroscopic time and dose without lengthening the procedure time.


Modulation of noradrenergic transmission in the rabbit ear artery by dopamine.
1. The effects of dopamine on vasoconstrictor responses to field stimulation of sympathetic nerves and to exogenous noradrenaline were studied in the isolated ear artery of the rabbit. Responses to noradrenaline were unchanged at the start of the dopamine infusions but were enhanced as the infusions continued and also after cessation of the infustion. 2 Dopamine (0.5 muM) reduced the stimulation-induced efflux of tritium from segments of ear artery labelled with [3H]-noradrenaline. The reduction persisted during 65 min of dopamine infusion, after which time the vasoconstrictor responses had generally recovered to 93% of control level. On ceasing the infusion, the stimulation-induced efflux and the vasoconstrictor responses were enhanced. 3 Metoclopramide, haloperidol and ergometrine, each in a concentration of 0.2 muM, prevented the inhibitory effect of 0.5 muM dopamine on the stimulation-induced tritium release, but not the inhibitory effect of 0.5 muM noradrenaline. Phenoxybenzamine (0.2 and 1 muM) and phentolamine (1 muM) prevented the inhibitory effects of both noradrenaline and dopamine on the stimulation-induced efflux, and phentolamine (0.2 muM) prevented the inhibition of the stimulation-induced release by noradrenaline but only partially prevented the inhibitory effect of dopamine on the stimulation-induced efflux. 4 A possible role for dopamine in the modulation of noradrenergic transmission is suggested.


Quantitative three-dimensional reconstruction: feasibility for studies of sexually dimorphic hypothalamic development in rats.
The adult rat brain develops through an interplay of neuronal proliferation with programmed cell death. Sensory stimulation, as well as growth factors and steroids, may alter the balance between these competing processes. "Endocrine disrupters" (EDs) may do the same by mimicry or modulation of endogenous hormones. The sexually dimorphic nucleus (SDN) of the medial preoptic hypothalamus contains a high concentration of estrogen receptors (ERs). The SDN develops to a final adult volume, which may be used as an indication of the hormonal conditions during perinatal development. Although male rats have been repeatedly observed to have a greater adult SDN volume than female rats, variability between the actual measurements reported (both within and between laboratories) have been rather large. Exposure of female rats to testosterone (or excessive estradiol, beyond the binding capacity of alpha-fetoprotein) has been shown to masculinize them through a P450 aromatase that converts testosterone to estrogen in the SDN. Exposure of males to estradiol may feminize them at low doses through interference with the synthesis of their endogenous testosterone, which normally acts on SDN ERs following aromatization. We have employed computer-assisted reconstruction methods in order to render the SDN within the surrounding hypothalamus in 3-D for computation of its volume. Ongoing studies are investigating whether exposure through the diet to estrogenic endocrine disruptors such as genistein, nonylphenol, and ethinyl estradiol might produce effects similar to those of estradiol itself on the adult SDN.


Dependency on the TYK2/STAT1/MCL1 axis in anaplastic large cell lymphoma.
TYK2 is a member of the JAK family of tyrosine kinases that is involved in chromosomal translocation-induced fusion proteins found in anaplastic large cell lymphomas (ALCL) that lack rearrangements activating the anaplastic lymphoma kinase (ALK). Here we demonstrate that TYK2 is highly expressed in all cases of human ALCL, and that in a mouse model of NPM-ALK-induced lymphoma, genetic disruption of Tyk2 delays the onset of tumors and prolongs survival of the mice. Lymphomas in this model lacking Tyk2 have reduced STAT1 and STAT3 phosphorylation and reduced expression of Mcl1, a pro-survival member of the BCL2 family. These findings in mice are mirrored in human ALCL cell lines, in which TYK2 is activated by autocrine production of IL-10 and IL-22 and by interaction with specific receptors expressed by the cells. Activated TYK2 leads to STAT1 and STAT3 phosphorylation, activated expression of MCL1 and aberrant ALCL cell survival. Moreover, TYK2 inhibitors are able to induce apoptosis in ALCL cells, regardless of the presence or absence of an ALK-fusion. Thus, TYK2 is a dependency that is required for ALCL cell survival through activation of MCL1 expression. TYK2 represents an attractive drug target due to its essential enzymatic domain, and TYK2-specific inhibitors show promise as novel targeted inhibitors for ALCL.


Influence of progressive renal dysfunction in chronic heart failure.
Chronic heart failure (CHF) is often associated with impaired renal function due to hypoperfusion. Such patients are very sensitive to changes in renal perfusion pressure, and may develop acute tubular necrosis if the pressure falls too far. The situation is complicated by the use of diuretics, ACE inhibitors and spironolactone, all of which may affect renal function and potassium balance. Chronic renal failure (CRF) may also be associated with fluid overload. Anaemia and hypertension in CRF contribute to the development of left ventricular hypertrophy (LVH), which carries a poor prognosis, so correction of these factors is important.


Post-activation depression in various group I spinal pathways in humans.
This investigation was designed to study the effects of post-activation depression in different spinal pathways fed by group I afferents available to investigation in human subjects. It was precipitated by a recent investigation in the cat showing that-contrary to the general assumption-post-activation depression is not a widespread phenomenon in the spinal cord. In 24 healthy subjects comparison was made between the effects of low and high-test stimulus rates on the monosynaptic Ia excitation, known to be subject to post-activation depression, and on oligosynaptic pathways fed by group I afferents. Both the amplitude of monosynaptic H reflexes and the amount of heteronymous monosynaptic Ia facilitation were significantly smaller at high than at low-test stimulus rates (1-2 s compared with 6-8 s between two consecutive stimuli). So was the amount of reciprocal Ia inhibition of tibialis anterior motoneurones. In contrast, the amount of other non-monosynaptic group I effects directed to the same motor nuclei (peroneal-induced excitation of quadriceps motoneurones, disynaptic non-reciprocal group I inhibition of flexor carpi radialis motoneurones, and D1 inhibition of flexor carpi radialis and soleus H reflexes) were enhanced at high stimulus rates. Results in humans confirm that post-activation depression depends on the type of group I afferents, and/or on the target neurones. The functional significance of the discrepancy between post-activation depression in pure Ia pathways and in other group I pathways is discussed with regard to the fusimotor-driven servo-assistance from Ia afferent discharges.


A first glance into the black box of life satisfaction surrounding childbearing.
The vast majority of studies looking into the relationship between childbearing and subjective well-being use overall measures where respondents either report their general level of happiness or their life satisfaction, leaving substantial doubt about the underlying mechanisms. However, life satisfaction and happiness are intuitively multidimensional concepts, simply because there cannot be only one aspect that affects individuals' well-being. In this study, by considering seventeen specific life satisfaction domains, these features come out very clearly. Whereas all the domains considered matter for the overall life satisfaction, only three of them, namely satisfaction with leisure, health and satisfaction with the partnership, change dramatically surrounding childbearing events. Even though we cannot generalise (since these results stem from one particular panel survey, i.e., Household Income and Labour Dynamics in Australia data), it appears that the typical anticipation and post-child decrease of life satisfaction, so often found in existing studies, stems from changes in these three domains.


"We've Really Built Something": Why Family Medicine Program Directors Stay in Their Positions-A Qualitative Study.
Program directors (PDs) are essential to more than 12 000 residency and fellowship programs accredited in the United States. Short PD tenure may affect overall program quality. Reasons why PDs leave the position are multifactorial, and little is known about the reasons why PDs stay in the position. The authors explored factors related to retention and why family medicine PDs have stayed in their positions long term. This was a qualitative study of PDs in their roles for 12 or more years drawn from a national sample of family medicine residency PDs. Interviews with semi-structured and structured questions about long-term PD experience were conducted in October and November 2020. Multiple cycles of comparative coding and code network analysis produced constructs describing reasons why some PDs stay in the position long term. Among 17 respondents with a mean tenure of 17.4 years, 3 interrelated constructs consistently emerged that supported PDs: developing the program, support systems, and job rewards. Program development reinforces internal and external support systems and enhances experiencing rewards of the job. Strong support systems enable further program development and job rewards. Family medicine residency PDs who have been in the role 12 or more years continuously work to develop the program, benefit from strong internal and external support systems, and describe many important rewards of the position that help sustain them in the role.


Clinical significance of glycated hemoglobin in acute coronary syndrome patients from the CCC-ACS project : Findings from a multicenter retrospective observational study.
Blood glucose levels are associated with the prognosis of patients with acute coronary syndrome (ACS). Glycated hemoglobin (HbA1c) reflects the average blood glucose level. The purpose of the study was to evaluate HbA1c as a prognostic indicator for ACS. In total, 27,337 ACS patients from the CCC-ACS (Improving Care for Cardiovascular Disease in China - Acute Coronary Syndrome) project were enrolled in this study and divided into three groups according to HbA1c level: Group I, HbA1c level <5.7%; Group II, HbA1c level 5.7-6.4%; Group III, HbA1c level ≥6.5%. The primary outcome was an in-hospital major adverse cardiovascular event (MACE), such as all-cause death, recurrent myocardial infarction, acute or subacute stent thrombosis, heart failure, cardiogenic shock, or cardiac arrest. Baseline data and effectiveness outcome were compared among patients in the three groups. Group III had the highest MACE incidence (13.4% [Group III] vs. 8.7% [Group I] and 10.5% [Group II], p < 0.001). In the logistic regression, there was a statistically significant difference in HbA1c level between the groups (odds ratio [OR]: 1.110, 95% confidence interval [CI]: 1.008-1.133, p < 0.001). In the receiver operating characteristic curve, the area under the curve for MACE was 0.560 (95% CI: 0.550-0.571, p < 0.001); the cut-off value for the HbA1c level was 6.38%. The HbA1c level was associated with the risk of MACEs in ACS patients with or without diabetes. Trial Registration clinicaltrials.gov, NCT02306616. Registered 3 December 2014-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02306616 .


Marriage trends among Americans with childhood-onset disabilities, 1997-2013.
People with disabilities are less likely to marry than people without disabilities. Trends in marriage and assortative mating among people with disabilities have not been investigated. This study tested if marriage likelihood converged between adults with childhood-onset disabilities and their peers, and if married adults with childhood-onset disabilities became more likely to have a spouse without disabilities. U.S. data from annual National Health Interview Surveys were used to identify adults ages 18-44 surveyed between 1997 and 2013 (N = 562,229). Childhood-onset disability was defined by self-report of physical conditions limiting the respondent's activities since age <18 years. Weighted multivariate logistic regressions were used to compare trends in ever marrying and current marriage to a spouse without reported disabilities between adults with childhood-onset disabilities and adults without childhood-onset disabilities. Across survey years, the decline in odds of having ever married was stronger among adults with childhood-onset disabilities (OR = 0.94; 95% CI: 0.93, 0.95; p < 0.001) than among adults without childhood-onset disabilities (OR = 0.96; 95% CI: 0.96, 0.96; p < 0.001), and divergence in these trends was statistically significant (p = 0.001). Employment and college attendance were positively correlated with marriage among people with childhood-onset disabilities. Among adults married at the time of the survey, those with childhood-onset disabilities were less likely to have a spouse without reported disabilities. The American retreat from marriage has been accelerated among adults with childhood-onset disabilities, with high rates of in-marriage to other people with disabilities persisting in this group.


Mean geometry of the thiopeptide unit and conformational features of dithiopeptides and polythiopeptides.
The mean geometry of the thiopeptide [Ca-N-C(=S)-Ca] unit has been derived from an analysis of X-ray crystal structure data, as well as MM2 and Gaussian 80/82 calculations. The conformational flexibilities of dithiopeptides with glycl- and alanyl-side chains have been investigated by molecular mechanics. Minimum energy conformations were examined using interactive computer graphics molecular modeling techniques. Alanyl-dithiopeptide substitution within an oligopeptide results in considerable restriction of conformational freedom whereas the effect is minimal for glycyl-dithiopeptide substitution. Polyglycyl-thiopeptide adopts a left-handed three or fourfold or right-handed threefold helical structure with favorable interchain C = S...H-N hydrogen bond interactions. A poly-L-alanyl-thiopeptide prefers a left-handed threefold poly-L-proline-like helical structure.


Successful treatment of pulmonary haemorrhage and acute respiratory distress syndrome caused by fulminant Stenotrophomonas maltophilia respiratory infection in a patient with acute lymphoblastic leukaemia - case report.
Stenotrophomonas maltophilia-induced pulmonary haemorrhage is considered a fatal infection among haematological patients. The outcome can be explained by the patients' immunity status and late diagnosis and treatment. We present the rare case of successful outcome in a 61-year-old female who developed alveolar haemorrhage and acute respiratory distress syndrome 8 days after a chemotherapy session for her acute lymphoblastic leukaemia, in the context of secondary bone marrow aplasia. Stenotrophomonas maltophilia was isolated in sputum culture. The patient benefitted from early empirical treatment with colistin followed by trimethoprim/sulfamethoxazole, according to the antibiogram. Despite a severe initial clinical presentation in need of mechanical ventilation, neuromuscular blocking agents infusion, and ventilation in prone position, the patient had a favourable outcome and was discharged from intensive care after 26 days. Stenotrophomonas maltophilia severe pneumonia complicated with pulmonary haemorrhage is not always fatal in haematological patients. Empirical treatment of multidrug-resistant Stenotrophomonas maltophilia in an immunocompromised haematological patient presenting with hemoptysis should be taken into consideration.


Surgical management of osteomas of the frontal recess and sinus: extending the limits of the endoscopic approach.
Osteomas are among the most common benign tumors of the paranasal sinuses. Symptomatic osteomas are most often found in the frontal recess and the frontal sinus. While the extranasal approach is still a part of the treatment concept for removing osteomas at this localization, over the last years the endoscopically controlled endonasal approach has greatly gained in importance due to the improved surgical equipment. We retrospectively analyzed the surgical indication, surgical approach and outcome of the removal of osteomas of the frontal recess and the frontal sinus performed at our hospital between 1996 and 2010. The exact surgical technique, intra- and postoperative complications, the duration of the hospital stay and the follow-up and subjective contentment of the patients were evaluated. With a total of 24 patients being included, the study comprises one of the largest groups of patients with osteomas of the frontal recess and sinus. Over the study period, the frequency of the endoscopic approach clearly increased. Previously suggested guidelines for the endoscopic resection of a frontal sinus osteoma turned out to be superseded. Endoscopically controlled resection even of large, adversely located osteomas of the frontal recess and the frontal sinus is becoming increasingly possible, but is still naturally limited by the individual anatomic conditions and the need for experienced surgeons.


Anesthesia and surgical trauma: their influence on the guinea pig compound action potential.
A chronic implant consisting of a fine thermocouple placed on the round window permitted measurement of temperature and of the compound action potential (CAP) of the cochlear nerve in guinea pigs. Thresholds and latencies of the CAP, in response to tone bursts (2-40 kHz), were measured when the animal was awake and unrestrained, and again after several hours of anesthesia. The CAP remained unchanged with a variety of common anesthetics when precise control of round window temperature was maintained. However, when anesthesia was accompanied by several hours of slight cochlear cooling, thresholds were elevated for CAPs evoked by frequencies above 24 kHz and latencies were increased for CAPs evoked by all frequencies tested. The effects of surgery on CAP threshold and latency were also examined. Guinea pigs were tested while still anesthetized at the conclusion of the implantation procedure, and then again several days later while awake. Thresholds and latencies were unchanged. In two anesthetized guinea pigs already implanted with thermocouples, ventral and post-auricular surgery to expose the middle ear had no effect on the CAP, when low-speed drilling was used to open the auditory bulla. However, when small portions of the bulla were broken away with forceps, the CAP in response to high-frequency tone bursts immediately showed elevated thresholds. This alteration of the CAP was clearly different from that produced by lowered temperature, since the latencies at threshold were significantly decreased.


Correction: Improvement of the reduction in catastrophic health expenditure in China's public health insurance.
[This corrects the article DOI: 10.1371/journal.pone.0194915.].


Direct observation of molecular images of lanthanide phthalocyanines: III. Structural defects.
The crystal imperfections in thin films of lanthanide phthalocyanines (LnPc2H, Ln = Nd, Tb, Er, Tm, Yb, and Lu) grown expitaxially on KCl have been observed by molecular imaging. Grain and twin boundaries, stacking faults, point defects, vacancies, mosaic structures, and sometimes even some amorphous islands exist in the well-crystallized specimens. Combined with the results reported earlier, the packing characteristics of planar LnPc2H molecules can be well understood.


miR-21 and miR29-a: Potential Molecular Biomarkers for HPV Genotypes and Cervical Cancer Detection.
This study aimed to assess miR21 and miR-29a diagnostic usefulness for HPV infection and Cervical Cancer (CC) detection. miRs extraction has been performed on HPV-positive, CC and negative control of 43, 50 and 46 individuals, respectively. The expression level of miRs has been analyzed using Real-Time RT-PCR. There was a correlation between the expression of miRs and the Receiver Operating Characteristic (ROC) analysis in CC and HPV-positive patients. The correlation between expressions of miRs is notable. ROC curve analysis could be applied in molecular diagnostic exposure for CC related to HPV infections.


The effect of scleral exoplant removal on strabismus following retinal detachment repair.
Scleral buckling for retinal detachment is a well-reported cause of secondary strabismus. We analyzed the effects on motility of removal of the exoplant alone to determine whether this is warranted as a separate step in the surgical management of these patients. A retrospective case series of patients who underwent scleral exoplant removal due to symptomatic strabismus development following retinal detachment repair from 2007 to 2009 was conducted. Manifest horizontal and vertical deviations were treated as vectors of a single combined deviation (|dev|). Pre- and postoperative manifest |dev| in the primary position (|dev|(pp)) and in the gaze position of maximal deviation (|dev|(max)) were analyzed. Five patients were identified, all with symptomatic, binocular diplopia in the primary position prior to exoplant removal. Median |dev|(pp) prior to exoplant removal was 21(Δ) and following removal was 21(Δ) (P = 0.81). The median |dev|(max) prior to exoplant removal was 33(Δ) and following removal, 22(Δ) (P = 0.82). Median follow-up was 8 months. There were no cases of retinal redetachment following the exoplant removal. No patient reported any subjective improvement of their diplopia. All 5 patients went on to have strabismus surgery as a separate procedure. Median primary position deviation was unchanged by scleral buckle removal, and Exoplant removal has minimal long-term benefit on the strabismus following scleral buckling procedures.


Adipose-derived mesenchymal stem cells enhance healing of mandibular defects in the ramus of swine.
This study investigated the effect of adipose-derived mesenchymal stem cells (ASCs) injected locally or systemically on the bone regeneration of a 10-mm-diameter cylindrical noncritical-size defect in the ramus of the pig mandible. Fifteen Yorkshire pigs, weighing 60 to 80 kg, received bilateral 10-mm-diameter cylindrical surgical defects in each ramus of the mandible. Pigs received 1) a direct injection into the defect of 2.5 million carboxy-fluorescein diacetate succinimidyl ester-labeled ASCs from 1 of 2 pig donors (n = 6); 2) an ear vein injection of 5 million carboxy-fluorescein diacetate succinimidyl ester-labeled ASCs from 1 of 2 pig donors (n = 6); or 3) an ear vein injection of culture Dulbecco's Modified Eagle's Medium without stem cells (control; n = 3). Pigs from each treatment were sacrificed at 1 hour, 2 weeks, or 4 weeks after surgery. Healing of the defect was evaluated by dual-energy x-ray absorptiometry, micro-computed tomography, fluorescent microscopy, and histology. Bone healing was accelerated in the ASC-injected treatment groups at 2 and 4 weeks after surgery compared with the control pigs. Results from this animal model provide evidence that the injection of ASC locally into a bone defect or systemically can accelerate the healing of bone.


[Fatty acid composition of lipids from the hair in psoriasis vulgaris (author's transl)].
The composition of fatty acids of hair lipids and the sum of hair and scalp lipids from subjects with Psoriasis vulgaris and a control group was determined by gas liquid chromatography. The analyses indicates that the percentage compositions of lauric acid was distinctly higher by Psoriasis vulgaris.


The AST/ALT (De Ritis) Ratio Predicts Survival in Patients with Oral and Oropharyngeal Cancer.
Aminotransaminases, including aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT), are strongly involved in cancer cell metabolism and have been associated with prognosis in different types of cancer. The purpose of the present study was to evaluate the prognostic significance of the pre-treatment AST/ALT ratio in a large European cohort of patients with oral and oropharyngeal squamous cell cancer (OOSCC). Data from 515 patients treated for OOSCC at a tertiary academic center from 2000-2017 were retrospectively analyzed. Levels of AST and ALT were measured prior to the start of treatment. Uni- and multivariate Cox regression analyses were applied to evaluate the prognostic value of the AST/ALT ratio for cancer-specific survival (CSS) and overall survival (OS), survival rates were calculated. Univariate analyses showed a significant association of the AST/ALT ratio with CSS (hazard ratio (HR) 1.71, 95% confidence interval (CI) 1.38-2.12; p < 0.001) and OS (HR 1.69, 95% CI 1.41-2.02; p < 0.001). In multivariate analysis, the AST/ALT ratio remained an independent prognostic factor for CSS and OS (HR 1.45, 95% CI 1.12-1.88, p = 0.005 and HR 1.42, 95% CI 1.14-1.77, p = 0.002). Applying receiver operating characteristics (ROC) curve analysis, the optimal cut-off level for the AST/ALT ratio was 1.44, respectively. In multivariate analysis, an AST/ALT ratio > 1.44 was an independent prognostic factor for poor CSS and OS (HR 1.64, 95% CI 1.10-2.43, p = 0.014 and HR 1.55, 95% CI 1.12-2.15; p = 0.008). We conclude that the AST/ALT ratio is a prognostic marker for survival in OOSCC patients and could contribute to a better risk stratification and improved oncological therapy decisions.


Post-tetanic potentiation at the nerve-muscle junction in the longitudinal muscle of the guinea-pig ileum. Possible role of substance P.
The effect of short tetanic stimulation (30 Hz for 25 s) on the following twitch responses of the myenteric plexus-longitudinal muscle preparation of guinea-pig ileum to electric stimulation (0.1 Hz) was investigated in the presence of naloxone and indomethacin. Post-tetanic potentiation (PTP) of the twitches observed in control experiments was abolished in preparations desensitized by substance P but it was not affected in preparations desensitized by serotonin or pretreated with methysergide. Immediately after 5 min tetanic stimulation a decreased sensitivity to substance P but unchanged sensitivity to serotonin were observed. Electromyogram (EMG) of the longitudinal muscle layer was picked up 4 and 10 mm aborally from the stimulation site in response to 1 to 16 impulse trains delivered at 100 Hz. In control conditions only the longer trains triggered this neurogenic response at the distal recording site. In the presence of substance P but not serotonin facilitation occurred so that the distal site was frequently recruited to respond with an EMG even to single impulses. A substance P-like compound rather than serotonin may be a candidate for the neuromodulator or neurotransmitter substance involved in PTP and changes in the response topography of muscarinic transmission.


Asymmetric total synthesis and identification of tetrahydroprotoberberine derivatives as new antipsychotic agents possessing a dopamine D(1), D(2) and serotonin 5-HT(1A) multi-action profile.
An effective and rapid method for the microwave-assisted preparation of the key intermediate for the total synthesis of tetrahydroprotoberberines (THPBs) including l-stepholidine (l-SPD) was developed. Thirty-one THPB derivatives with diverse substituents on A and D ring were synthesized, and their binding affinity to dopamine D(1), D(2) and serotonin 5-HT(1A) and 5-HT(2A) receptors were determined. Compounds 18k and 18m were identified as partial agonists at the D(1) receptor with K(i) values of 50 and 6.3nM, while both compounds act as D(2) receptor antagonists (K(i)=305 and 145nM, respectively) and 5-HT(1A) receptor full agonists (K(i)=149 and 908nM, respectively). These two THPBs compounds exerted antipsychotic actions in animal models. Further electrophysiological studies employing single-unit recording in intact animals demonstrated that 18k-excited dopaminergic (DA) neurons are associated with its 5-HT(1A) receptor agonistic activity. These results suggest that these two compounds targeted to multiple neurotransmitter receptors may present novel lead drugs with new pharmacological profiles for the treatment of schizophrenia.


Slow-release lubrication effect of graphene oxide/poly(ethylene glycol) wrapped in chitosan/sodium glycerophosphate hydrogel applied on artificial joints.
The artificial joints would go through serious wear after implantation surgery due to the poor lubrication of the body fluid, and the biomimetic lubricants directly injected in vitro is easy to be absorbed by human tissues, and after a period of time, it will lose its lubrication effect. However, the composite hydrogel with slow-release lubrication effect provides a new way for the lubrication of artificial joints. In this study, Graphene oxide/Poly(ethylene glycol) (GO/PEG) composites were prepared to improve the artificial joint lubrication, and through wrapped in the Chitosan/Sodium glycerophosphate (CS/GP) hydrogel, the GO/PEG lubricant will be released under the squeezing action, thus to prolong the service time of biomimetic lubricants. The friction experimental results showed that GO/PEG had better lubrication effect, and the average friction coefficient of the slow-release solution was below 0.03, especially with the pressure increasing. GO, PEG and small molecule GP in the slow-release solution through hydrogen-bond interaction might form a particular structure, which led to the good lubricating effect. The experiments of cell and acute toxicity in vivo showed that GO and its composite hydrogel had good biocompatibility.


Comparative effectiveness and safety of cefotetan and cefoxitin as prophylactic agents in patients undergoing abdominal or vaginal hysterectomy.
In a multicenter, randomized clinical trial, 282 women who underwent abdominal or vaginal hysterectomy were given a single preoperative 2 g dose of cefotetan (171 evaluable patients) or three perioperative 2 g doses of cefoxitin (84 evaluable patients) as antibiotic prophylaxis. A successful clinical response occurred in 92 percent of those receiving cefotetan and 90 percent of those receiving cefoxitin who underwent abdominal hysterectomy, and in 94 percent of those receiving cefotetan and 93 percent of those receiving cefoxitin who underwent vaginal hysterectomy. The incidence of vaginal cuff cellulitis was 3.4 percent and 5 percent for cefotetan and cefoxitin patients, respectively, who underwent abdominal hysterectomy, and 4.8 percent and 4.5 percent, respectively, for those who underwent vaginal hysterectomy. The incidence of major wound infection was 3.4 percent and 2.5 percent for cefotetan and cefoxitin, respectively, in the abdominal hysterectomy group. Postoperative changes in oral body temperature, duration of hospitalization, and postoperative grading of surgical wounds were similar. Both drugs were well tolerated. These results suggest that a single dose of cefotetan is equally effective and as safe as multiple-dose cefoxitin for prophylaxis in patients undergoing hysterectomy.


Sensory perception and neuroanatomical structures in normal and grafted skin of burn survivors.
This study compared the neural structures found in grafted skin of burn survivors with neural structures found in site-matched normal skin and correlated these structures with psychophysical measures of sensation. Fifteen skin-grafted male burn survivors (47.7+/-10.4 years old) with deep partial- or full-thickness thermal burn injuries covering an average of 11+/-5.6% of their total body surface and with normal skin at a matching, unburned, contralateral site were recruited into this study. Threshold determinations and magnitude estimations for touch, cold, warmth and heat-pain were performed at sites with grafted and normal skin, using Semmes-Weinstein monofilaments and the Medoc TSA 2001 thermal stimulator. Skin biopsies from both the grafted and normal sites were stained with antibodies for protein gene product 9.5 (PGP) and neurofilament 200 kDa. Nerve fibers in the epidermis and nerve fibers or bundles of nerve fibers in the superficial and deep dermis as well as innervated blood vessels, hair follicles and sweat glands were counted. On average, the data were collected 43.1+/-10.4 months after grafting. When thresholds on grafted skin were compared to thresholds on normal skin, they showed elevated sensory thresholds [touch (p<0.003), cold (p<0.031), warmth (p<0.009)]. Magnitude estimates of touch, cold and warmth differed on the two sides with sensations elicited from grafts being smaller than those from normal skin. Heat-pain thresholds and heat-pain magnitude estimations were not statistically different on the two sites. By comparison to the normal side, and consistent with the attenuated sensory functions of the grafts, counts of neural structures showed a reduction in innervation density; PGP-immunoreactive nerve fibers/bundles were reduced in grafted epidermis (p<0.026) and superficial dermis (p<0.001). The numbers of sweat glands (p<0.006) and hair follicles (p<0.001) were also reduced. The number of innervated blood vessels did not differ significantly on the two sides. There were significant correlations between sensory thresholds and the neuroanatomical variables: thresholds of cold and touch were correlated with the number of sweat glands in both grafted and normal skin (r2=0.56 and 0.50, respectively; p<0.001), while warmth thresholds were significantly correlated with the number of innervated blood vessels in grafted skin (r2=0.62, p<0.001). Encapsulated mechanoreceptors were not encountered in this study of hairy skin. Touch, cold and warmth thresholds and magnitude estimations do not return to normal levels after skin grafting in burn survivors. The elevation of thresholds and reduction of sensory intensity is accompanied by a general decrease in the density of nerve terminals. The lack, or numerical reduction, of sweat glands and innervated blood vessels was also indicative of diminished sensation on grafted skin.


Impact of an education program on the incidence of central line-associated bloodstream infection in 2 medical-surgical intensive care units in Brazil.
An intervention study was undertaken to evaluate the impact of an education program on the incidence of central line-associated bloodstream infection (CLABSI) in 2 intensive care units. There was a nonsignificant reduction in the incidence of CLABSI (odds ratio, 0.46 [95% confidence interval, 0.21-1.02]; P=.04) despite a significant increase in knowledge of CLABSI prevention by the staff of both intensive care units after the education program.


Pain, quality of life and activity in aged evacuees living in temporary housing after the Great East Japan earthquake of 11 March 2011: a cross-sectional study in Minamisoma City, Fukushima prefecture.
The aim of this study was to clarify pain, quality of life and activity in the aged evacuees living in temporary housing after the Great East Japan Earthquake on 11 March 2011. The study was a cross-sectional study performed in Minamisoma City, Fukushima Prefecture 1 year and 6 months after the disaster. Inclusion criteria were the ability to walk independently and consent to answer questionnaires. Seventy-one evacuees who met the inclusion criteria were included in this study. There were 16 men and 55 women with a mean age of 75.9 years. Sixty evacuees were surveyed when they gathered at the assembly hall in the temporary housing (Assembled group) and 11 evacuees were surveyed through individual visits to their residences (Individual group). Evacuees in the Individual group agreed to participate in this study, but refused to visit the assembly hall to engage in exercise and recreation. Pain, quality of life (QOL) and level of activity were assessed with the Numeric Rating Scale (NRS), the MOS Short-Form 36 item Health Survey (SF-36) and a pedometer, respectively. Student's t-test, Mann-Whitney U test, and Fisher's exact test were used for statistical analysis. Forty-four (62.0 %) residents had chronic pain with a mean NRS of 2.74. Twenty-one (29.6 %) of these residents had relatively severe pain rated 5 or above on the NRS. QOL was significantly lower for the subscales of "physical functioning," "role physical", "general health", "social functioning", "role emotional" and "mental health", when compared with the national standard values. Values were also visibly lower for "physical component summary" in the summary score. On comparing the Assembled group and the Individual group, "physical function", "role physical", "social functioning" and "physical component summary" were found to be significantly lower in the Individual group. The mean daily number of steps was 1,892 in the Individual group and 4,579 in the Assembled group. The Individual group thus significantly took less mean daily number of steps compared with the Assembled group. This study quantified the state of pain, QOL and activity of aged evacuees living in temporary housing after the Great East Japan Earthquake. The evacuees frequently had chronic pain and lower physical and mental QOL scores compared to the national standard values.


Socioeconomic, geographic and climatic risk factors for canine parvovirus infection and euthanasia in Australia.
Infection of canids with canine parvovirus (CPV) can result in severe, often fatal disease. This study aimed to examine climatic, socioeconomic and geographic risk factors for CPV infection and CPV-associated euthanasia in Australia. Australian veterinary hospital responses (534; 23.5 %) to a national veterinary survey of CPV case occurrences and euthanasias in 2016 were used. Severe caseloads (>40 cases per annum) were reported by 26 (11 %) hospitals (median 60 cases; IQR 50-110). Case reporting, case numbers, and without-treatment euthanasia were significantly associated with disadvantage across all Socio-Economic Index for Areas quintiles (p < 0.0001) - the greater the disadvantage, the more reports. Strong negative correlations were found between case numbers and the Index of Relative Socioeconomic Disadvantage (rSP = -0.3357, p < 0.0001) and also between euthanasia and the Index of Education and Occupation (rSP = -0.3762, p < 0.0001). Hospitals in more remote areas were also more likely to report cases and to euthanize without treatment (p < 0.0001). Of the climate variables, temperature of the hottest month was most strongly positively correlated with case numbers (rSP = 0.421, p < 0.0001), and lower annual rainfall was associated with more case-reporting hospitals (p < 0.0001). These results confirm that socioeconomic disadvantage is a significant risk-factor for CPV infection and outcome, and high temperature may also contribute to risk.


Clinical and angiographic characteristics of acute myocardial infarction caused by vasospastic angina without organic coronary heart disease.
Vasospastic angina (VA) can occasionally cause acute myocardial infarction (AMI). From January 2003 to June 2005, coronary spastic angina was diagnosed in 292 patients by performing spasm provocation tests. Among the 292 patients, 21 (7.2% of all the VA patients) had an AMI. There were 20 patients who initially visited the emergency room for AMI without suffering prior VA. One patient with a history of VA had an AMI when he discontinued his medication. Among the 21 VA patients with AMI, 14 had experienced severe emotional stress before they visited the emergency room. The spasm provocation test showed that the VA patients with AMI had more multivessel and diffuse spasm than the VA patients without AMI (p<0.001). Clinically, the VA patients with AMI usually had their first symptom of VA as the severe chest pain of AMI. Two-thirds of the VA patients with AMI had experienced emotional stress before their AMI. Angiographically, the spasm provocation test for VA patients with AMI showed more multivessel and diffuse spasm than in VA patients without AMI.


Immunoglobulin levels in saliva in individuals with selective IgA deficiency: compensatory IgM secretion and its correlation with HLA and susceptibility to infections.
Total levels of IgA, IgM, and IgG were measured in unstimulated whole saliva and serum from 63 individuals with selective IgA deficiency. Values were compared with the incidence of upper respiratory tract infections, antibiotic treatments (necessitated by upper respiratory tract infection), and HLA antigens. A statistically significant increase in salivary IgM and IgG levels was noted in individuals with selective IgA deficiency compared to healthy normal individuals. Healthy individuals with selective IgA deficiency did not have increased concentrations of salivary IgM compared to infectious-prone patients. Nor was there any correlation found between proneness to infections and HLA antigens or between salivary IgM or IgG levels and HLA antigens in this patient material.


Minimally invasive surgery for hallux valgus: a systematic review of current surgical techniques.
The aim of this study was to systematically evaluate the available literature on minimally invasive surgical (MIS) treatment for hallux valgus and to provide an overview of the different surgical techniques. A systematic review of the literature available in MEDLINE, EMBASE, and the Cochrane database was performed including studies from January 2001 to 1 January 2018. The radiological outcomes (hallux valgus angle (HVA), intermetatarsal angle (IMA)), complication rates, and clinical outcome scores were evaluated. The MINORS scale was used to assess the methodological quality of included articles. Of 278 reviewed articles, 23 met the inclusion criteria. The included studies reported on the results of 2279 procedures in 1762 patients. The surgical techniques were divided into five categories: the Bosch technique, MIS Chevron-Akin, Reverdin-Isham procedure, Endolog system, and techniques involving distal soft tissue release and fixation. Results regarding radiological correction, clinical outcomes, and complication rate varied widely. The studies included were of too little level of evidence to allow for data pooling or meta-analysis. There were too few studies on each surgical technique category to assess whether one is more effective than the rest. However, there is some evidence that the Chevron and Akin showed the most potential for improvement of the HVA and the Endolog for the IMA. An overall complication rate of 13% was obtained among all included studies. Appropriately powered randomized controlled trials, utilizing validated outcome measures, blinded assessors, and long-term follow up are needed to assess the efficacy of MIS techniques.


Lipid abnormalities in untreated maturity-onset diabetics and the effect of treatment.
Plasma cholesterol and serum triglyceride levels and frequency of lipoprotein abnormalities were investigated in 126 untreated maturity-onset diabetics and 126 age- and sex-matched control subjects. Serum triglyceride levels were higher (mean: 1.67 mmol/l) and type IV hyperlipoproteinaemia occurred more frequently (16.7%) in the diabetic group as compared with the controls (1.29 mmol/l and 4.8% respectively). These findings were not explained by an excessive frequency of renal disease, hypertension or drug treatment amongst the diabetics. Normal men showed higher serum triglyceride (mean: 1.36 mmol/l) and lower plasma cholesterol (mean: 5.6 mmol/l) levels than normal women (1.21 mmol/l and 6.4 mmol/l respectively). No sex difference was seen amongst the diabetics. Triglyceride levels fell after one month of dietary treatment but only remained lowered in diabetics who required sulphonylureas for glycaemic control. After treatment for one year the correlation between serum triglycerides and blood glucose rose from r = 0.15 (NS) before treatment to r = 0.43 (p less than 0.001). Similarly the correlation between serum triglycerides and ponderal index rose from r = 0.19 (NS) to r = 0.28 (p less than 0.02).


Endocrine causes of bone disease.
Hyperthyroidism, glucocorticoid excess, hyperparathyroidism, hypogonadism, and acromegaly decrease bone mineral density and aggravate the osteoporotic tendencies of elderly individuals. After effective treatment of endocrinopathy, the bone attempts to return to the normal mineral density. In most circumstances, however, this attempt is incomplete. Early diagnosis and treatment of these endocrine problems in older patients helps to maintain their skeletal integrity and prevent osteoporotic fractures.


Reduction in digitalis-associated postinfarction mortality with nadolol in conscious dogs.
Previously, we have demonstrated an increased incidence of lethal ischemic arrhythmias in postinfarction dogs with clinically observable serum digoxin concentrations, and a significant reduction in digitalis-related lethal ischemic arrhythmias after subacute left stellectomy. In the present study, the protective actions of acute beta-adrenoceptor blockade with nadolol, 1.0 mg/kg administered intravenously immediately preceding the induction of posterolateral myocardial ischemia, were assessed in conscious dogs with recent, small anterior myocardial infarctions pretreated with digoxin, 0.0125 mg/kg/day intravenously, for 5 to 7 consecutive days (total n = 11). A cohort of postinfarction dogs pretreated with digoxin alone served as a control group (total n = 26). Pre vs postdigoxin electrophysiologic testing indicated reductions in myocardial refractoriness in ventricular noninfarct and infarct zones in both treatment groups, whereas the administration of nadolol tended to reverse the reductions in ventricular refractoriness. Arrhythmia-related deaths in response to posterolateral myocardial ischemia were reduced from 12 of 20 (60%) in the digoxin control group to 2 of 10 (20%) in the digoxin + nadolol group (p = 0.039). Serum digoxin concentrations (1.29 +/- 0.14 ng/ml vs 1.39 +/- 0.24 ng/ml), underlying anterior myocardial infarct size (6.9 +/- 1.5% vs 4.6 +/- 0.9% of left ventricle), and developing posterolateral myocardial infarct size (22.8 +/- 2.5% vs 17.5 +/- 3.6% of left ventricle) did not differ significantly between the digoxin and digoxin + nadolol groups. Acute beta-adrenoceptor blockade with nadolol appears to reduce digitalis-mediated ischemic postinfarction mortality, possibly because of a salutary increase in ventricular refractoriness.


MT1G serves as a tumor suppressor in hepatocellular carcinoma by interacting with p53.
Poor prognosis of hepatocellular carcinoma (HCC) patients is frequently associated with rapid tumor growth, recurrence and drug resistance. MT1G is a low-molecular weight protein with high affinity for zinc ions. In the present study, we investigated the expression of MT1G, analyzed clinical significance of MT1G, and we observed the effects of MT1G overexpression on proliferation and apoptosis of HCC cell lines in vitro and in vivo. Our results revealed that MT1G was significantly downregulated in tumor tissues, and could inhibit the proliferation as well as enhance the apoptosis of HCC cells. The mechanism study suggested that MT1G increased the stability of p53 by inhibiting the expression of its ubiquitination factor, MDM2. Furthermore, MT1G also could enhance the transcriptional activity of p53 through direct interacting with p53 and providing appropriate zinc ions to p53. The modulation of MT1G on p53 resulted in upregulation of p21 and Bax, which leads cell cycle arrest and apoptosis, respectively. Our in vivo assay further confirmed that MT1G could suppress HCC tumor growth in nude mice. Overall, this is the first report on the interaction between MT1G and p53, and adequately uncover a new HCC suppressor which might have therapeutic values by diminishing the aggressiveness of HCC cells.


Accuracy of pre-interventional computed tomography angiography post-processing software and extravascularly calibrated devices to determine vessel diameters: comparison with an intravascularly located calibrated catheter.
Background Accurate vessel sizing might affect treatment outcome of endovascular therapy. Purpose To compare accuracy of peripheral vessel diameter measurements using pre-interventional computed tomography angiography post processing software (CTA-PPS) and extravascularly located calibrated devices used during digital subtraction angiography (DSA) with an intravascular scaled catheter (SC). Material and Methods In 33 patients (28 men, mean age = 72 ± 11 years) a SC was used during DSA of the femoro-popliteal territory. Simultaneously, one scaled radiopaque tape (SRT) was affixed to the lateral thigh, one scaled radiopaque ruler (SRR) was positioned on the angiography table. For each patient, diameters of five anatomic landmarks were measured on DSA images after calibration using different scaled devices and CTA-PPS. Diameters were compared to SC (reference) and between groups of non-obese (NOB) and obese (OB) patients. Results In total, 660 measurements were performed. Compared to the reference, SRT overestimated the diameter by 1.2% (range = -10-12, standard deviation [SD] = 4.1%, intraclass correlation coefficient [ICC] = 0.992, 95% confidence interval [CI] = 0.989-0.992, P = 0.01), the SRR and CTA-PPS underestimated it by 21.3% (range = 1-47, SD = 9.4%, ICC = 0.864, 95% CI = 0.11-0.963, P = 0.08) and 3.2% (range = 17-38, SD = 9.7%, ICC = 0.976, 95% CI = 0.964-0.983, P = 0.01), respectively. Underestimation using the SRR was greatest in the proximal superficial-femoral artery (31%) and lowest at the P2 level of the popliteal artery (15%). In the NOB group, diameter overestimation of the SRT was 0.8% (range = 4-7, SD = 4.2%, B = 0.071, 95% CI = 0.293-0.435, P = 0.08) compared to the OB group of 1.6% (range = -7-4, SD = 2.9%, B = 0.010, 95% CI = 0.474-0.454, P = 0.96). Diameter underestimation of the SRR was 17.3% (range = 13-21, SD = 3.1%, B = 0.946, 95% CI = 0.486-1.405, P = 0.002) in the NOB group, 23.3% (range = 11-36, SD = 6.6%, B = 0.870, 95% CI = 0.268-1.472, P = 0.007) in the OB group. Conclusion For calibrated measurements SRT and CTA-PPS prove accurate compared to the reference, while SRR does not. Obesity has a significant impact on underestimation of diameter if SRR is used.


Functional MRI of the rat lumbar spinal cord involving painful stimulation and the effect of peripheral joint mobilization.
To examine neuronal activation in the spinal cord due to secondary hyperalgesia resulting from intrajoint capsaicin injection, and the effect of physiotherapy manipulation, using functional magnetic resonance imaging (fMRI), in alpha-chloralose anesthetized rats. FMRI of the rat lumbar spinal cord was performed at 9.4 Tesla. Stimuli included injection of 25 microL of capsaicin (128 microg/mL in 7.5% dimethyl sulfoxide [DMSO]) into the right forepaw or 75 microL into the right ankle joint followed by a light touch stimulus, with and without physiotherapy manipulation. Activation of pain areas of the spinal cord (dorsal horn) was found in all animals after injection of capsaicin into the plantar surface of the rat hindpaw and ankle joint. Overlay maps depicting activations and deactivations showed significant reproducibility between experiments. Greater overlay of activations were observed for intrajoint compared to intradermal capsaicin injection. The distribution of activations after stimulation of the hindpaw using a light touch stimulus was somewhat more varied; activation of the dorsal horn was evident, with greater overlap resulting when joint mobilization was not performed. Results suggest a trend toward decreased areas of activation in the spinal cord associated with pain, as a result of hyperalgesia, following physiotherapy joint mobilization.


Incidence trends of prostate cancer in East Anglia, before and during the era of PSA diagnostic testing.
We investigated prostate cancer incidence in East Anglia from 1971 to 2000. Using age-period-cohort modelling, the number of cases expected in 1991-2000, based on pre-PSA trends, 1971-1990, was compared with that observed. Based on pre-1991 trends, 9203 new cases were expected in 1991-2000, but 9788 cases were observed, an excess of 6%.


Influence of groundwater characteristics on the survival of enteric viruses.
This study was undertaken to further understand the processes affecting the persistence of enteric viruses in groundwater. Varying temperature, oxygen and nutrient levels were tested in the presence and absence of groundwater micro-organisms to determine which of the factors tested had dominant influence on the decay of Escherichia coli, the bacteriophage MS2, poliovirus and coxsackievirus. The results indicated that the most influential factor affecting the decay of the viruses and E. coli was the presence of groundwater micro-organisms. The results also implied that temperature, the presence of oxygen and nutrient levels indirectly influence viruses and E. coli decay by influencing the activity of the groundwater micro-organisms. E. coli and the viruses displayed maximum decay under aerobic conditions, at 28 degrees C without the addition of nutrients in the presence of groundwater micro-organisms. The results suggest that if the mode of action of the groundwater micro-organisms could be determined then the decay of viral pathogens in recharged waters may be more easily predicted.


Clinical trial of cisplatinum (NSC 119875) in metastatic renal cell carcinoma.
Thirty-two patients with metastatic renal cell carcinoma were treated with cisplatinum, 100 mg./M2 at twenty-eight-day intervals. The drug was given intravenously after first assuring adequate hydration. Response could be determined in 23 patients. There were no partial or complete responses, although 1 patient had less than a 50 per cent reduction in pulmonary lesions and 7 patients had stabilization of their disease for periods ranging from three to seven months. It is concluded that the therapeutic value of cisplatinum in the treatment of advanced renal carcinoma is negligible when used as a single agent.