Formalized prediction of clinically significant prostate cancer: is it possible?
Greater understanding of the biology and epidemiology of prostate cancer in the last several decades have led to significant advances in its management. Prostate cancer is now detected in greater numbers at lower stages of disease and is amenable to multiple forms of efficacious treatment. However, there is a lack of conclusive data demonstrating a definitive mortality benefit from this earlier diagnosis and treatment of prostate cancer. It is likely due to the treatment of a large proportion of indolent cancers that would have had little adverse impact on health or lifespan if left alone. Due to this overtreatment phenomenon, active surveillance with delayed intervention is gaining traction as a viable management approach in contemporary practice. The ability to distinguish clinically insignificant cancers from those with a high risk of progression and/or lethality is critical to the appropriate selection of patients for surveillance protocols versus immediate intervention. This chapter will review the ability of various prediction models, including risk groupings and nomograms, to predict indolent disease and determine their role in the contemporary management of clinically localized prostate cancer.


Detection of rare mRNA species in a complex RNA population by blot hybridization techniques: a comparative survey.
The detection of very rare mRNA species in a complex RNA preparation by current RNA blotting techniques is not straightforward. To be able to determine the size of mRNA molecules representing 10(-6) to 10(-7) of the total mass of an RNA preparation, a quantitative comparison of the level of detection of denatured mRNA species electrophoretically separated on agarose gels, followed by transfer to either nitrocellulose or diazobenzyloxymethyl (DBM) paper and hybridization to specific cDNA probes was carried out. Different transfer procedures were analyzed. Optimal conditions have been found which allowed the detection of RNA bands containing as little as 5 pg of a specific sequence within a few days of autoradiography following hybridization with highly labeled [32P]cDNA probes. Using this procedure it was shown that the low amounts of alpha-fetoprotein (AFP) mRNA sequences present in adult rat liver are mature AFP mRNA molecules.


Effects of mobile learning for nursing students in clinical education: A meta-analysis.
The objective of this meta-analysis was to assess the effects of mobile learning for nursing students in clinical nursing education. Five electronic databases including PubMed, CINAHL, EMBASE, the Cochrane library and Web of Science were searched for English language articles published on or before February 10, 2020. Two reviewers retrieved articles, evaluated quality and extracted data independently. Review Manager (RevMan) version 5.3 software was used to perform meta-analysis. A total of 9 studies including 580 nursing students receiving clinical nursing education met the inclusion criteria. The mobile learning intervention led to significant improvements in nursing students' skills (SMD = 1.22, 95% CI [0.29, 2.14], P = 0.009), knowledge (SMD = 0.43, 95% CI [0.11, 0.76], P = 0.009), satisfaction (SMD = 0.31, 95% CI [0.05, 0.56], P = 0.020), and confidence (SMD = 0.4, 95% CI [0.16, 0.63], P < 0.001) compared with the control group. Due to differences in experimental design among studies and limited data availability, we cautiously conclude that mobile learning has a beneficial effect on clinical nursing education for nursing students compared with conventional methods.


Weight loss, reproductive output, and the cost of reproduction in the common frog, Rana temporaria.
The consequences of reproduction for body weight, growth and survival were studied in a Swiss population of the explosive breeder, Rana temporaria. Males and females continuously loss weight in the range of 0.5% of total body weight per day from the breeding migration throughout May. Females also lost about 33% (1983) and 29% (1984) due to spawning. In addition to this significant year-to-year variation, there was also considerable individual variation in reproductive output. Skeletochronological techniques indicated that breeding male or female frogs experienced a growth reduction of several millimeters relative to non-breeding frogs of the same body size. There was no relationship between an individual female's reproductive output in consecutive years or with her subsequent growth or survival. It was concluded that weight loss is caused by a seasonally elevated metabolism in combination with a lack of feeding and represents a basic energetic cost of reproduction, resulting in lowered growth. Individual variation in relative reproductive output is mostly environmentally induced and is not an expression of different reproductive strategies. This may explain the lack of trade-offs that are predicted by the cost-of-reproduction-hypothesis.


The anabolic effects of parathyroid hormone therapy.
PTH represents an important new advance in the therapy of osteoporosis. As an anabolic agent, its potential might be substantially greater than that of antiresorptive agents. Clear evidence in human trials now documents the ability of PTH to stimulate cancellous bone formation and to reduce fractures. Because antiresorptive agents and PTH work by distinct mechanisms of action, it is possible that the combination of these agents could be significantly more potent than either agent alone. There are other unanswered questions about PTH. More studies are needed to document an anabolic effect on cortical bone. In addition, more large-scale studies are needed to further determine the reduction in nonvertebral fractures with PTH, especially at the hip. More information is also required to determine the possible need for antiresorptive therapy after PTH. Protocols to consider PTH as an intermittent recycling therapy would be of interest. In the future, PTH is likely to be modified for easier and more targeted delivery. Oral or transdermal delivery systems may become available. Recently, Gowen et al [78] have described an oral calcilytic molecule that antagonizes the parathyroid cell calcium receptor, thus stimulating the endogenous release of PTH. This approach could represent a novel endogenous delivery system for intermittent PTH administration. Ultimately, when the anabolic and catabolic mechanisms of PTH can be clearly distinguished, both mechanistically and in molecular terms, it may be possible to develop PTH analogs that are more purely anabolic.


Sulforaphane Reverses the Amyloid-β Oligomers Induced Depressive-Like Behavior.
Depression is one of the most common behavioral and psychological symptoms in people with Alzheimer's disease (AD). To date, however, the molecular mechanisms underlying the clinical association between depression and AD remained elusive. Here, we study the relationship between memory impairment and depressive-like behavior in AD animal model, and investigate the potential mechanisms. Male SD rats were administered amyloid-β oligomers (AβOs) by intracerebroventricular injection, and then the depressive-like behavior, neuroinflammation, oxidative stress, and the serotonergic system were measured in the brain. Sulforaphane (SF), a compound with dual capacities of anti-inflammation and anti-oxidative stress, was injected intraperitoneally to evaluate the therapeutic effect. The results showed that AβOs induced both memory impairment and depressive-like behavior in rats, through the mechanisms of inducing neuroinflammation and oxidative stress, and impairing the serotonergic axis. SF could reduce both inflammatory factors and oxidative stress parameters to protect the serotonergic system and alleviate memory impairment and depressive-like behavior in rats. These results provided insights into the biological mechanisms underlying the clinical link between depressive disorder and AD, and offered new drug options for the treatment of depressive symptoms in dementia.


A case of carcinoid heart metastases.
Carcinoid tumor is an uncommon tumor that has often already developed metastases at the time of diagnosis. The primary site of tumors are the gastrointestinal tract, breast, and bronchus. The first manifestation of "carcinoid syndrome" occurs as a result of hormone production and cardiac involvement can be recognized in approximately half of the patients. The tricuspid or pulmonary valves are often affected, while, more rarely, the myocardial wall is of interest. A 51-year-old female patient affected by a primary pancreatic carcinoid showed interventricular septum carcinoid disease diagnosed by 2D echocardiography.


Accurate fixation of plates and screws for the treatment of acetabular fractures using 3D-printed guiding templates: An experimental study.
To investigate the feasibility of the use of 3D-printed guiding templates for accurate placement of plates and screws for internal fixation of acetabular fractures. 3D models of the pelvises of 14 adult cadavers were reconstructed using computed tomography (CT). Twenty-eight acetabular fractures were simulated and placement positions for plates and screw trajectories were designed. Bending module was obtained by 3D cutting; guiding template was manufactured using 3D printing, and the plate was pre-bent according to the bending module. Plates and screws were placed in cadaveric pelvises using the guiding template, and 3D model was reconstructed using CT. The designed and real trajectories were matched using 3D registration including the coordinates (entry and exit points) of designed trajectory. The number of qualified points with different accuracy levels was compared using Chi-squared test. Sixty-four plates and 339 screws were placed with no cortical breach. The absolute difference of the X, Y, and Z coordinates between the designed and real entry points were 0.52±0.45, 0.43±0.36, and 0.53±0.44mm, respectively. The corresponding values for the exit points were 0.83±0.67, 1.22±0.87, and 1.26±0.83mm, respectively. With an accuracy degree ≥1.9mm for the entry points and ≥3.8mm for the exit points, there was no significant difference between the designed and the real trajectories. The 3D-printed guiding template helped achieve accurate placement of plates and screws in the pelvis of adult cadavers.


Daily and seasonal heat usage patterns analysis in heat networks.
Heat usage patterns, which are greatly affected by the users' behaviors, network performances, and control logic, are a crucial indicator of the effective and efficient management of district heating networks. The variations in the heat load can be daily or seasonal. The daily variations are primarily influenced by the customers' social behaviors, whereas the seasonal variations are mainly caused by the large temperature differences between the seasons over the year. Irregular heat load patterns can significantly raise costs due to pricey peak fuels and increased peak heat load capacities. The in-depth analyses of heat load profiles are regrettably quite rare and small-scale up until now. Therefore, this study offers a comprehensive investigation of a district heating network operation in order to exploit the major features of the heat usage patterns and discover the big factors that affect the heat load patterns. In addition, this study also provides detailed explanations of the features that can be considered the main drivers of the users' heat load demand. Finally, two primary daily heat usage patterns are extracted, which are exploited to efficiently train the prediction model.


Increased lipid peroxide levels and myeloperoxidase activity in the vitreous of patients suffering from proliferative diabetic retinopathy.
Lipid peroxide (LPO) levels, as determined by high-performance liquid chromatography (HPLC) and by the thiobarbituric acid (TBA) method, and myeloperoxidase (MPO) activity in vitreous of patients vitrectomized because of proliferative diabetic retinopathy were compared with LPO levels and MPO activity in vitreous of patients with no vitreoretinal proliferation. Both LPO levels and MPO activity were significantly elevated in the vitreous of patients with fibrovascular vitreoretinal proliferations secondary to diabetes. The TBA method produced higher values for LPO levels than did the HPLC method. The correlation between the two methods was 0.94. Our results suggest that both oxygen-free radicals and inflammation-related reactions can participate in the pathogenesis of diabetic retinopathy.


Differential effects of low-magnitude high-frequency vibration on reloading hind-limb soleus and gastrocnemius medialis muscles in 28-day tail-suspended rats.
Low-magnitude high-frequency vibration (LMHFV) was reported beneficial to muscle contractile functions in clinical and preclinical studies. This study aims to investigate the effects of LMHFV on myofibers, myogenic cells and functional properties of disused soleus (Sol) and gastrocnemius medialis (GM) during reloading. Sprague Dawley rats were hind-limb unloaded for 28 days and assigned to reloading control (Ctrl) or LMHFV group (Vib). Sol and GM of both groups were harvested for fiber typing, proliferating myogenic cell counting and in vitro functional assessment. Myogenic cells proliferation was promoted by LMHFV in both Sol and GM (p<0.001 and p<0.05 respectively). Force generating capacity was not much affected (Vib=Ctrl, p>0.05) but fast-fiber favorable changes in fiber type switching (more type IIA but lower type I in Vib; p<0.05 and 0.01 respectively) and fiber hypertrophy (type I, Vib<Ctrl; p<0.01) were observed mainly in GM. LMHFV was not detrimental to reloading muscles but the outcomes were muscle dependent. The unique fiber type composition and anatomical differences between Sol and GM might render the differential muscle responses to LMHFV. Further investigations on myofibers type specific responses to different LMHFV regimes and myogenic cell interaction with associated myofiber were proposed.


Therapeutic strategies for diffuse midline glioma from high-throughput combination drug screening.
Diffuse midline gliomas (DMGs) are universally lethal malignancies occurring chiefly during childhood and involving midline structures of the central nervous system, including thalamus, pons, and spinal cord. These molecularly related cancers are characterized by high prevalence of the histone H3K27M mutation. In search of effective therapeutic options, we examined multiple DMG cultures in sequential quantitative high-throughput screens (HTS) of 2706 approved and investigational drugs. This effort generated 19,936 single-agent dose responses that inspired a series of HTS-enabled drug combination assessments encompassing 9195 drug-drug examinations. Top combinations were validated across patient-derived cell cultures representing the major DMG genotypes. In vivo testing in patient-derived xenograft models validated the combination of the multi-histone deacetylase (HDAC) inhibitor panobinostat and the proteasome inhibitor marizomib as a promising therapeutic approach. Transcriptional and metabolomic surveys revealed substantial alterations to key metabolic processes and the cellular unfolded protein response after treatment with panobinostat and marizomib. Mitigation of drug-induced cytotoxicity and basal mitochondrial respiration with exogenous application of nicotinamide mononucleotide (NMN) or exacerbation of these phenotypes when blocking nicotinamide adenine dinucleotide (NAD+) production via nicotinamide phosphoribosyltransferase (NAMPT) inhibition demonstrated that metabolic catastrophe drives the combination-induced cytotoxicity. This study provides a comprehensive single-agent and combinatorial drug screen for DMG and identifies concomitant HDAC and proteasome inhibition as a promising therapeutic strategy that underscores underrecognized metabolic vulnerabilities in DMG.


U2 snRNP binds intronless histone pre-mRNAs to facilitate U7-snRNP-dependent 3' end formation.
In metazoa, pre-mRNA 3' end formation occurs via two pathways: cleavage/polyadenylation for the majority of RNA polymerase II transcripts and U7-snRNP-dependent cleavage for replication-dependent histone pre-mRNAs. An RNA element derived from a replication-dependent histone gene affects multiple steps of pre-mRNA processing. Here, we demonstrate that a portion of this RNA element, present in the majority of histone mRNAs, stimulates U7-snRNP-dependent cleavage. Surprisingly, this element binds U2 snRNP, although it is derived from an intronless mRNA. Specifically, SF3b, a U2 and U12-snRNP component, contacts the RNA element both in vitro and in vivo in conjunction with hPrp43, a DEAH-box helicase. Tethering either U2 or U12 snRNP to histone pre-mRNA substrates stimulates U7-snRNP-dependent cleavage in vitro and in vivo. Finally, we show that U2 snRNP associates with histone pre-mRNAs in vivo. We conclude that U2 snRNP plays a nonsplicing role in histone mRNA maturation.


Public attitudes towards automated external defibrillators: results of a survey in the Australian general population.
Swift defibrillation by lay responders using automated external defibrillators (AEDs) increases survival in out-of-hospital cardiac arrest (OHCA). This study evaluated newly designed yellow-red vs. commonly used green-white signage for AEDs and cabinets and assessed public attitudes to using AEDs during OHCA. New yellow-red signage was designed to enable easy identification of AEDs and cabinets. A prospective, cross-sectional study of the Australian public was conducted using an electronic, anonymised questionnaire between November 2021 and June 2022. The validated net promoter score investigated public engagement with the signage. Likert scales and binary comparisons evaluated preference, comfort and likelihood of using AEDs for OHCA. The yellow-red signage for AED and cabinet was preferred by 73.0% and 88%, respectively, over the green-white counterparts. Only 32% were uncomfortable with using AEDs, and only 19% indicated a low likelihood of using AEDs in OHCA. The majority of the Australian public surveyed preferred yellow-red over green-white signage for AED and cabinet and indicated comfort and likelihood of using AEDs in OHCA. Steps are necessary to standardise yellow-red signage of AED and cabinet and enable widespread availability of AEDs for public access defibrillation.


Differential cytotoxicity of cis-platinum and blenoxane against human carcinoma KBE cells in multicellular spheroids of different ages: response at different temperatures.
Human KBE epidermoid carcinoma cells were reproducibly grown in suspension as multicellular spheroids (MCS). Initial aggregation at 48 hours is followed by a rapid diameter increase until day 10. The size increase then continues with daily refeedings, under the growth conditions used, but at a slower rate. When cells are treated in MCS with either blenoxane (bleomycin) or cis-diamminedichloroplatinum (II) (cis-platinum), the survival of cells (by cloning efficiency (CE) essay) varied from that of surface attached (SA) cells. The survival was dependent on the age of the MCS as well as their size; the age response was significantly different for cis-platinum and blenoxane. Hyperthermic incubation of KBE cells in MCS at different ages for 1 hour (40-43 degrees C) resulted in cell killing similar to that observed after hyperthermic incubation of surface attached cells. In combined hyperthermia/chemotherapy experiments, simultaneous treatment with blenoxane resulted in little or no increase in MCS cell toxicity at 40 degrees C; at 42.5 degrees C, there was increased toxicity. The increase in toxicity was similar for MCS of different ages. Upon simultaneous cis-platinum treatment, an increase in toxicity was observed at 40 degrees C, but only in older MCS. At 42.5 degrees C, an increased toxicity (relative to treatment at 37 degrees C) was observed in MCS of all ages. These results are, in general, similar to those described for other in vitro and in vivo systems, but emphasize the differences in the survival response which can result for treatment of human cancer cells in MCS of different ages over even a small size range (up to 1 mm diameter). This is much smaller than clinically detectable tumors. This reproducible human cancer cell multicellular spheroid model has great potential for representing the variability likely to be present in micrometastases of different sizes, and in small regions of solid tumors, and therefore for assisting in preliminary evaluation of combined modality protocols.


Observation of Rayleigh-Lamb waves generated by the 2022 Hunga-Tonga volcanic eruption with the POLA detectors at Ny-Ålesund.
The eruption of the Hunga-Tonga volcano in the South Pacific Ocean on January 15, 2022, at about 4:15 UTC, generated a violent explosion, which created atmospheric pressure disturbances in the form of Rayleigh-Lamb waves detected all over the globe. Here we discuss the observation of the Hunga-Tonga shock-wave performed at the Ny-Ålesund Research Station on the Spitsbergen island, by the detectors of the PolarquEEEst experiment and their ancillary sensors. Online pressure data as well as the results of dedicated offline analysis are presented and discussed in details. Results include wave arrival times, wave amplitude measurements and wave velocity calculation. We observed five passages of the shock wave with a significance larger than 3 [Formula: see text] and an amplitude up to 1 hPa. The average propagation velocity resulted to be (308 ± 0.6) m/s. Possible effects of the atmospheric pressure variation associated with the shock-wave multiple passages on the cosmic-ray rate at ground level are also investigated. We did not find any significant evidence of this effect.


Assessment of monitoring methods for early detection of three species of storage mite in bulk oilseed rape.
Two types of trap, the BT Trap and PC(TM) pitfall cone trap, were evaluated against the most widely used method of sampling and sieving for their ability to detect low numbers of storage mites (Acarus siro, Tyrophagus longior and Lepidoglyphus destructor) in bulk oilseed rape, under UK maritime conditions. In addition, a synthetic lure (2-nonanone) was incorporated into the two types of trap to assess whether its presence improved trapping performance. The BT traps and PC traps were significantly more effective in detecting low numbers of mites of all species compared with sampling and sieving. The PC trap with synthetic lure was the most effective method. As the PC trap is already widely used for monitoring insects in cereal bulks in the UK, extending its application to include oilseed rape, and to detect mites, would be a logical and cost effective extension of its use.


Waon therapy mobilizes CD34+ cells and improves peripheral arterial disease.
We previously reported that Waon therapy upregulates endothelial nitric oxide synthase protein, and augments ischemia-induced angiogenesis in mice with hindlimb ischemia, and it improves limb ischemia in patients with peripheral arterial disease (PAD). The aim of this study was to investigate the underlying mechanism of Waon therapy for the treatment of patients with PAD, and to determine whether Waon therapy can mobilize blood-derived progenitor cells. 21 consecutive PAD patients received standard medications, and were randomly divided into control (n=10) and Waon therapy groups (n=11). The Waon therapy group received Waon therapy daily for 6 weeks. The control group continued conventional therapy for 6 weeks. Leg pain was scored using a visual analogue scale. The ankle-brachial pressure index (ABPI) and the 6-min walking distance were measured at baseline and 6 weeks after therapy. Frequency of circulating CD34+ progenitor cell numbers was measured by quantitative real-time polymerase chain reaction, and the serum nitrate and nitrite levels were also measured at baseline and 6 weeks after therapy. The leg pain score, ABPI and the 6-min walking distance improved significantly after 6 weeks in the Waon therapy group, but not in the control group. Frequency of circulating CD34+ cells increased after 6 weeks of Waon therapy [2.0 ± 1.2 (×10(-4)) at baseline to 3.9 ± 1.9 (×10(-4)), p=0.015], while it remained unchanged in the control group [1.8 ± 1.8 (×10(-4)) at baseline to 1.2 ± 0.9 (×10(-4))]. Serum nitrate and nitrite levels increased significantly after Waon therapy (29.6 ± 17.6 to 36.0 ± 17.7 μmol/ml, p<0.05), but not in the control group (34.4 ± 9.4 to 38.3 ± 8.8 μmol/ml). Waon therapy mobilized circulating endothelial progenitor cells and improved limb ischemia in patients with PAD. Waon therapy is a highly promising therapy for patients with PAD.


Physiological parameters regulating circulating levels of the IGFBP-4/Stanniocalcin-2/PAPP-A axis.
Insulin Growth Factor Binding Protein 4 (IGFBP-4), Stanniocalcin-2 (STC-2) and Pregnancy-Associated Plasma Protein-A (PAPP-A) have a well-documented involvement in several physiological functions in humans but predictors of their circulating levels remain largely unknown. We aimed to identify anthropometric and biochemical parameters associated with circulating levels of IGFBP-4/STC-2/PAPP-A axis (ISPa) cross-sectionally and to study their day-night variation and their regulation in response to mixed meal and exercise. One hundred twenty two healthy individuals were evaluated cross-sectionally. Subgroups were subjected to standardized mixed meal ingestion in increasing quantities of 125mL or 250mL, or aerobic exercise for 30min, or day-night rhythm study. Main outcome measurements were circulating IGFBP-4 (total and intact), STC-2 and PAPP-A levels. In multivariate models, the main predictors of serum total IGFBP-4 were PAPP-A and female gender. Intact IGFBP-4 was positively associated with serum creatinine. Height was inversely and female gender and % of total body fat were positively correlated with STC-2. PAPP-A decreased after ingesting both the 125mL (p=0.03) and 250mL quantities (p=0.001), while total IGFBP-4 was reduced after the 250mL quantity (p=0.001). Exercise increased STC-2 and PAPP-A levels (p<0.001 for both). Intact, and to a lesser extent total, IGFBP-4 displayed a cortisol-like day/night variation. We report for the first time anthropometric and physiological modulators of ISPa serum levels in healthy humans.


[Quantitative Evaluation of Airway Lesions in Chronic Obstructive Pulmonary Disease by Applying Deep Learning Reconstruction to Ultra-high-resolution CT Images: Correlation between Wall Area Percentage and Forced Expiratory Volume in One Second Percentage].
Using ultra-high-resolution images reconstructed with the Advanced intelligent Clear-IQ Engine (AiCE) lung to measure wall area percentage (WA%), we demonstrated that WA% measured in more distal bronchus has a stronger correlation with respiratory function (FEV1%). Furthermore, we also demonstrated that WA% measured from images with the higher spatial resolution has a stronger correlation with FEV1%. The modulation transfer function (MTF) and noise power spectrum (NPS) of the ultra-high-resolution images reconstructed by the AiCE body and the AiCE lung were compared. In addition, WA% from the first- to seventh-generation bronchus was measured for B1 and B10 in the right lung from clinical images obtained with the two reconstruction methods, and the correlation coefficients with FEV1% were evaluated. The MTF was more superior for the AiCE lung than for the AiCE body, and the NPS was lower for the AiCE lung than for the AiCE body in the low-frequency region. The correlation between WA% and FEV1% was slightly stronger in the AiCE lung than in the AiCE body. This study showed that WA% measured from the 7th-generation bronchus using ultra-high-resolution images reconstructed with the AiCE lung strengthens the correlation with FEV1%. Furthermore, the higher the spatial resolution of the measurement images, the stronger the correlation between WA% and FEV1%.


Towards a hybrid anaerobic digester-microbial fuel cell integrated energy recovery system: an overview of the development of an electrogenic biofilm.
An electrogenic biofilm was developed on a macroporous chitosan-carbon nanotube (CHIT-CNT) electrode under constant poised potential (-0.25V versus Ag/AgCl reference electrode) and flow through conditions utilizing the effluent of an anaerobic digester as both the inoculant and substrate for the electrogenic biofilm. After 125 days of inoculation the bioelectrode demonstrated an open circuit potential of -0.62V and a current density of 9.43μAcm(-3) (at -0.25V). Scanning electron microscopy images indicate thorough surface coverage of the biofilm with a high density of bacterial nanowires physically connecting bacteria to bacteria and bacteria to carbon nanotube (electrode surface) suggesting the nanowires are electrically conductive. DGGE was used to identify the major bacterial and archaeal populations.


Baseline and Exercise Predictors of V˙O2peak in Systolic Heart Failure Patients: Results from SMARTEX-HF.
This study aimed to investigate baseline, exercise testing, and exercise training-mediated predictors of change in peak oxygen uptake (V˙O2peak) from baseline to 12-wk follow-up (ΔV˙O2peak) in a post hoc analysis from the SMARTEX Heart Failure trial. We studied 215 patients with heart failure with left ventricular ejection fraction (LVEF) ≤35%, and New York Heart Association (NYHA) classes II-III who were randomized to either supervised high-intensity interval training with exercise target intensity of 90%-95% of peak heart rate (HRpeak) or supervised moderate continuous training (MCT) with target intensity of 60%-70% of HRpeak, or who received a recommendation of regular exercise on their own. Predictors of ΔV˙O2peak were assessed in two models: a logistic regression model comparing highest and lowest tertiles (baseline parameters) and a multivariate linear regression model (test/training/clinical parameters). The change in V˙O2peak in response to the interventions (ΔV˙O2peak) varied substantially, from -8.50 to +11.30 mL·kg·min. Baseline NYHA (class II gave higher odds vs III; odds ratio (OR), 7.1 (2.0-24.9); P = 0.002), LVEF (OR per percent, 1.1 (1.0-1.2); P = 0.005), and age (OR per 10 yr, 0.5 (0.3-0.8); P = 0.003) were associated with ΔV˙O2peak.In the multivariate linear regression, 34% of the variability in ΔV˙O2peak was explained by the increase in exercise training workload, ΔHRpeak between baseline and 12-wk posttesting, age, and ever having smoked. Exercise training response (ΔV˙O2peak) correlated negatively with age, LVEF, and NYHA class. The ability to increase workload during the training period and increased ΔHRpeak between baseline and the 12-wk test were associated with a positive outcome.


Workers' exposures and potential health risks to air toxics in a petrochemical complex assessed by improved methodology.
This study was designed to comprehensively evaluate workers' potential health risks of exposure to 39 air toxics in the Ta-sher Petrochemical Complex. Open-Path Fourier Transform Infrared Spectroscopy (OP-FTIR) was used to measure concentrations of air toxics. We used the measured worksite concentrations between 1997 and 1999 at 11 companies in the petrochemical complex, employing 3,100 on-site workers. The 39 measured air toxics included 10 chemicals with acute reference exposure levels (RELa), 19 chemicals with chronic reference exposure levels (RELc), and 3 chemicals classified as Class 1 or 2A human carcinogens by the International Agency for Research on Cancer (IARC). We then used RELa to calculate the hazard index of acute health effects (HI ( A )) for workers in individual plants. We also calculated the hazard index of chronic health effects (HIc) and cancer risks for all workers in the entire petrochemical complex. Workers in five companies had HI ( A ) greater than 1 because of toluene, benzene, methyl ethyl ketone, chloroform and isopropanol exposures. Workers in this petrochemical complex had HIc greater than 1 because of acrylonitrile, 1,3-butadiene, hydrogen cyanide, and n,n-dimethylformamide exposures. Risk of hematopoietic system cancer because of benzene and ethylene oxide exposure, and respiratory system cancer because of 1,3-butadiene exposure was estimated to be 3.1-6.1 x 10(-4) and 5.2-7.1 x 10(-4), respectively. Our findings indicated that workers in the petrochemical complex might have excess cancer and noncancer risks due to acute or chronic exposures to air toxics from multiple emission sources.


Finding incident cancer cases through outpatient oncology clinic claims data and integration into a state cancer registry.
Cancer data from population-based cancer registries under-report cancer cases, especially for cancers primarily diagnosed and treated in outpatient clinical settings, away from hospital-based cancer registrars. Previously, we developed alternative methods of cancer case capture including a claims-based method, which identified a large proportion of cancer cases missed by traditional population-based cancer registries. In this study, we adapted a claims-based method for statewide implementation of cancer surveillance in Florida. Between 2010 and 2017 the claims-based method identified 143,083 cancer abstracts, of which 42% were new and 58% were previously registered. The claims-based method led to the creation of 53,419 new cancer cases in the state cancer registry, which made up 9.3% of all cancer cases registered between 2010 and 2017. The types of cancers identified by the claims-based method were typical of the kinds primarily diagnosed and treated in outpatient oncology clinic settings, such as hematological malignancies, prostate cancer, melanoma, breast cancer, and bladder cancer. These cases were added to the Florida cancer registry and may produce an artefactual increase in cancer incidence, which is believed to be closer to the actual burden of cancer in the state.


The nutrient intakes of pregnant and lactating mothers of good socio-economic status in Cambridge, UK: some implications for recommended daily allowances of minor nutrients.
1. Forty-two mothers from social classes I, II and III non-manual and twenty-one from social classes III manual M), IV and V were studied longitudinally. The mean daily nutrient intakes in months 4-9 of pregnancy, months 2-4 of lactation and 3 and 6 months post-lactation are presented and are compared with the UK and the US recommended daily allowances (RDA). 2. The quality of the diets (nutrients per 4184 kJ (1000 kcal] was found to be better than that of other adult female populations studied in the UK, except for a group of dietitians. 3. The mean daily intakes of nutrients for which there are UK RDA were almost all greater than 100% of the RDA. The exceptions were iron, which in the manual group (social classes IIIM, IV and V) was 85% of the RDA in pregnancy and 75% post-lactation, and vitamin D. 4. Among the nutrients for which there are US, but not UK RDA, only phosphorus and vitamin B12 intakes were greater than 100% of the RDA in both groups at all stages of the study. Intakes of other nutrients were below the RDA: pantothenate 70-91, vitamin B6, zinc, vitamin E and copper 40-72, folate 21-44, and biotin less than 20% of the RDA. 5. The bases of the RDA for adult women were examined; for most nutrients the information is limited. It was concluded that the RDA for magnesium, vitamin E and pantothenate are probably higher than necessary and that deficiency is unlikely; that zinc, copper, vitamin B6 and folate are probably 'marginal' nutrients for 'at risk' groups; and that information on biotin is insufficient even roughly to assess the dietary requirement.


Report of a rare and aggressive case of oral malignant melanoma.
Oral melanoma is a very rare malignancy with unknown etiology. Its higher incidence is between 41 and 60 years of age. A high localization of oral melanoma was found in the maxilla. Gender distribution was reported as 1:1. Oral melanoma represents 0.2% to 8% of the all the total cases of melanoma of the body. In this article we report an aggressive case of oral melanoma in a 71-year-old male with chief complaint of black swelling of the gingiva, paresthesia, and denture ill fitting. Most oral melanomas are asymptomatic and painless in early stages and unfortunately diagnosis delayed until symptoms occurred. Early detection of suspected melanotic lesions by patient, dentist, and physician is very important.


Ethanol suppresses phagosomal adhesion maturation, Rac activation, and subsequent actin polymerization during FcγR-mediated phagocytosis.
Clinical and laboratory investigations have provided evidence that ethanol suppresses normal lung immunity. Our initial studies revealed that acute ethanol exposure results in transient suppression of phagocytosis of Pseudomonas aeruginosa by macrophages as early as 3 h after initial exposure. Focusing on mechanisms by which ethanol decreases macrophage Fcγ-receptor (FcγR) phagocytosis we targeted the study on the focal adhesion and cytoskeletal elements that are necessary for phagosome progression. Ethanol inhibited macrophage phagocytosis of IgG-coated bead recruitment of actin to the site of the phagosome, dampened the phosphorylation of vinculin, but had no effect on paxillin phosphorylation suggesting a loss in "phagosomal adhesion" maturation. Moreover, our observations revealed that FcγR-phagocytosis induced Rac activation, which was increased by only 50% in ethanol exposed cells, compared to 175% in the absence of ethanol. This work is the first to show evidence of the cellular mechanisms involved in the ethanol-induced suppression of FcγR-mediated phagocytosis.


Comparison of facial morphologies between adult Chinese and Houstonian Caucasian populations using three-dimensional imaging.
The objective of this study was to compare the facial morphologies of an adult Chinese population to a Houstonian white population. Three-dimensional (3D) images were acquired via a commercially available stereophotogrammetric camera system, 3dMDface™. Using the system, 100 subjects from a Houstonian population and 71 subjects from a Chinese population were photographed. A complex mathematical algorithm was performed to generate a composite facial average (one for males and one for females) for each subgroup. The computer-generated facial averages were then superimposed based on a previously validated superimposition method. The facial averages were evaluated for differences. Distinct facial differences were evident between the subgroups evaluated. These areas included the nasal tip, the peri-orbital area, the malar process, the labial region, the forehead, and the chin. Overall, the mean facial difference between the Chinese and Houstonian female averages was 2.73±2.20mm, while the difference between the Chinese and Houstonian males was 2.83±2.20mm. The percent similarity for the female population pairings and male population pairings were 10.45% and 12.13%, respectively. The average adult Chinese and Houstonian faces possess distinct differences. Different populations and ethnicities have different facial features and averages that should be considered in the planning of treatment.


Assignment of charge movements to electrogenic reaction steps of Na,K-ATPase by analysis of salt effects on the kinetics of charge movements.
Na,K-ATPase-enriched membrane fragments adsorbed to lipid bilayers were used to study electrogenic Na+ movements induced by enzyme phosphorylation when ATP was photo-released from inactive caged ATP, and simultaneously by externally applied alternating voltages which allowed the measurement of small ATP-induced membrane admittance changes. A detailed analysis of frequency dependence of the capacitance and conductance increments showed that the observed process consists of more than one electrogenic step. The frequency dependence could be described by the sum of two Lorentzian functions and a constant term. The faster process (approximately 2000 s(-1)) was assigned to the release of the first extracellular Na+ ion. The corner frequency of the slower Lorentzian (about 30 s(-1)) coincided with the reciprocal exponential time constant of the falling phase of the transient current, which can be assigned to the conformational transition. Preferentially, the slower process showed a dependence on the ion concentration of choline salts with different anions. The effectiveness of the used chaotropic anions to decelerate the kinetics decreased in agreement with the Hofmeister series, I- > Br- > Cl-. This observation matches their effect on the partition between two phosphoenzyme states of the Na,K-ATPase, as established previously.


Murder and assault arrests of White House cases: clinical and demographic correlates of violence subsequent to civil commitment.
The authors studied arrest records and clinical data on 217 persons formerly hospitalized as "White House Cases" because they were psychotically preoccupied with prominent political figures. Prior arrest for violent crime was the variable most strongly associated with arrest for violent crime after hospital discharge. Male gender and a history of weapons possession were also correlated with future violence. For those with prior violent crime arrests, hospital incidents requiring seclusion were also associated with later violence. For those without prior arrests, subsequent violence was associated with threats, living outside Washington, and command hallucinations. For those previously arrested for nonviolent crimes, only persecutory delusions were associated with later violence.


Acute toxicity of copper and silver to Ceriodaphnia dubia in the presence of food.
Food is added to exposure solutions in cladoceran chronic toxicity tests and sometimes in acute toxicity tests, but its effects on the bioavailability of toxicants have not been studied extensively. We compared the toxicity of waterborne Ag and Cu to Ceriodaphnia dubia in the presence or absence of food (a mixture of a yeast--Cerophyll--trout chow slurry and a green alga) in two series of acute toxicity tests. In the first series, we added food to Ag or Cu exposure solutions 0, 30, 60, or 120 min before transferring C. dubia into the solutions. In the second series, we exposed C. dubia to waterborne Ag or Cu for 30, 60, and 120 min in the absence of food. Adding food before transferring C. dubia into the exposure solutions greatly decreased the toxicity of Ag, but had less effect on the toxicity of Cu. In contrast, adding food after transferring C. dubia into the exposure solutions did not alter the toxicity of Ag considerably and did not alter the toxicity of Cu as much as the reverse sequence. Median effects concentrations (EC50s) for 30-, 60-, and 120-min unfed Ag tests were within the range of EC50s for 48-h unfed Ag tests, suggesting most uptake that contributes to acute Ag toxicity to C. dubia occurs within the first 30 to 60 min. However, uptake that contributes to acute Cu toxicity to C. dubia appears to occur over more than 2 h. Therefore, standard food decreases the toxicity of waterborne Ag and Cu to C. dubia, and the timing of adding food to exposure solutions is especially important in Ag tests.


[Development of an identification method for Streptococcus oligofermentans: a new species of oral streptococci with molecular markers].
To establish a quick and reliable method to identify Streptococcus oligofermentans, a new species of oral streptococci. With two-step PCR, a pair of the 16S rDNA-specific primers of Streptococcus oligofermentans and a pair of primers of lactate oxidase gene (lox) were used to amplify the gene fragments from the genomic DNAs of 11 strains consisting of 9 species of the pure culture of oral streptococci. Pooled plaque samples from 9 caries-free volunteers were cultured on a selective medium of MSA with erythromycin and tentative strains of Streptococcus oligofermentans were isolated. The isolates were further identified by the two-step PCR and finally confirmed by 16S rDNA sequence analysis. With the two-step PCR, the two gene fragments were only amplified from the three identified strains of Streptococcus oligofermentans, but not the rest of 8 strains of oral streptococci. Isolates from the dental plaque of caries-free volunteers were identified as Streptococcus oligofermentans by PCR and then further confirmed by 16S rDNA sequence homology analysis. Streptococcus oligofermentans could be identified by the two-step PCR approach with the specific 16S rDNA primers and lactate oxidase gene primers.


Ablation of sphingosine kinase 2 suppresses fatty liver-associated hepatocellular carcinoma via downregulation of ceramide transfer protein.
Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancer, the third leading cause of cancer-associated death worldwide. With the increasing prevalence of metabolic conditions, non-alcoholic fatty liver disease (NAFLD) is emerging as the fastest-growing HCC risk factor, and it imposes an additional layer of difficulty in HCC management. Dysregulated hepatic lipids are generally believed to constitute a deleterious environment cultivating the development of NAFLD-associated HCC. However, exactly which lipids or lipid regulators drive this process remains elusive. We report herein that sphingosine kinase 2 (SphK2), a key sphingolipid metabolic enzyme, plays a critical role in NAFLD-associated HCC. Ablation of Sphk2 suppressed HCC development in NAFLD livers via inhibition of hepatocyte proliferation both in vivo and in vitro. Mechanistically, SphK2 deficiency led to downregulation of ceramide transfer protein (CERT) that, in turn, decreased the ratio of pro-cancer sphingomyelin (SM) to anti-cancer ceramide. Overexpression of CERT restored hepatocyte proliferation, colony growth and cell cycle progression. In conclusion, the current study demonstrates that SphK2 is an essential lipid regulator in NAFLD-associated HCC, providing experimental evidence to support clinical trials of SphK2 inhibitors as systemic therapies against HCC.


Characterization of the interactions of the pneumolysoid, Δ6 PLY, with human neutrophils in vitro.
The pneumolysin toxoid, Δ6 PLY, is a prototype pneumococcal protein vaccine candidate. However, its potentially detrimental residual pro-inflammatory interactions with human neutrophils are unknown. In the current study the effects of the toxoid (8-1000 ng/ml) have been compared with those of wild-type pneumolysin (WT/PLY, 8 ng/ml) on neutrophil cytosolic Ca(2+) fluxes, generation of leukotriene B(4) (LTB(4)), and release of matrix metalloproteinase-9 (MMP-9), using spectrofluorimetric, and ELISA procedures (LTB(4) and MMP-9) respectively. Exposure of neutrophils to WT/PLY resulted in influx of Ca(2+) and significant (P<0.05) release of MMP-9 and generation of LTB(4). However, treatment of the cells with Δ6 PLY at concentrations of up to 1000 ng/ml had only trivial effects on Ca(2+) influx and no effects on either release of MMP-9 or LTB(4) production. The observed absence of pro-inflammatory interactions of Δ6 PLY with neutrophils is clearly an important property of this pneumococcal protein vaccine candidate.


Physical Activity, Medical Home, and Health Behavior Counseling Among Adolescents with Special Health Care Needs: NSCH 2016-2017.
Aim 1 was to establish updated prevalence estimates for meeting national physical activity (PA) guidelines among adolescents with and without special healthcare needs (SHCN), 12-17 years old. To identify at-risk subgroups, our sub-aim was to compare the distribution of prevalence estimates across PA levels by SHCN subtypes, and in reference to peers without SHCN. Aim 2 was to examine the association between meeting PA guidelines, having a medical home, and receiving positive health behavior counseling in this population. Weighted prevalence estimates for meeting the 2018 National PA Guidelines (inactive, insufficiently active, sufficiently active: guidelines met) were calculated from a secondary analysis of the National Survey of Children's Health 2016-2017 ( n = 16,171, 27% SHCN). Adjusted odds ratios and 95% CIs were estimated from logistic regression models to measure the association between PA, medical home, and postive health behavior counseling. Of adolescents with SHCN, 15% were reported to be meeting PA guidelines compared to 19% of peers without SHCN peers. Among adolescents with a medical home, regardless of SHCN status, those receiving positive health behavior counseling had 1.70 times the adjusted odds of meeting PA guidelines compared to peers without counseling. Adolescents with and without SHCN were more likely to meet PA guidelines if they had a medical home and received positive health behavior counseling, highlighting the value of comprehensive healthcare practices for PA promotion.


Axial pertubations on the electronic and magnetic properties of ferric porphyrins. II. Solvent effects on the proton NMR spectra of low-spin cyano complexes.
The proton NMR spectra of a series of low-spin bis-cyano ferric complexes of tetraarylporphyrins and octaethylporphyrin in a variety of solvents have been recorded and analyzed. The hyperfine shifts are shown to be very sensitive to the solvent, experiencing an overall downfield bias as the solvent hydrogen-bonding donor strength increased. The characteristic pattern of the contact and dipolar shifts for the meso-aryl group in tetraarylporphyrin complexes are shown to permit a quantitative separation of the dipolar and contact contributions to the hyperfine shift. The separated components indicate that increased solvent hydrogen bonding strength significantly decreases the magnetic anisotropy of the iron and diminishes porphyrin replaced by iron pi bonding. The changes in anisotropy with solvent are shown to be consistent with the coordinated cyanide acting as a proton acceptor. Although similar solvent effects are found to be absent in bis-imidazole complexes, a downfield bias of half the magnitude of the bis-cyano complexes is observed in mixed cyano/imidazole complexes. Hence, the heme hyperfine shifts in cyano-metmyoglobins and -hemoglobins may serve as probes for the protonation of the distal histidyl imidazole.


Quality inspection and result analysis of the spirometer calibration cylinder.
To understand the accuracy of volume calibration syringes used in China and compare the difference between new and old volume calibration syringes, technical testing was performed on volume calibration syringes in clinical lung function instruments. A standard validator device (Model 1180, Hans Rudolph, USA) was used to perform leak testing and volume accuracy testing for calibration syringes. Sixteen volume calibration syringes from 8 brands (CareFusion in Germany, Vyaire in Germany, Yaeger in Germany, Vitalograph in the United Kingdom, MGC Diagnostics in the United States, U-Breath in Zhejiang, China, Wendi in Ningbo, Zhejiang, and Boya in Ningbo, China) were tested. A total of 75% (12/16) of the volume calibration syringes passed the pressure decay leak test, 69% (11/16) of the volume calibration syringes passed the volume accuracy and repeatability test, and 56% (9/16) passed both tests; there was no significant difference in the total passing of the new and old volume calibration syringe quality tests (P > 0.05). A standard validator device should be used for both leakage tests and volume accuracy and repeatability tests to ensure the reliability of volume calibration syringes. It is suggested that the quality verification of volume calibration syringes should be regularly conducted to ensure the accuracy of the pulmonary function tests.


Biophysics of zebrafish (Danio rerio) sperm.
In the past two decades, laboratories around the world have produced thousands of mutant, transgenic, and wild-type zebrafish lines for biomedical research. Although slow-freezing cryopreservation of zebrafish sperm has been available for 30 years, current protocols lack standardization and yield inconsistent post-thaw fertilization rates. Cell cryopreservation cannot be improved without basic physiological knowledge, which was lacking for zebrafish sperm. The first goal was to define basic cryobiological values for wild-type zebrafish sperm and to evaluate how modern physiological methods could aid in developing improved cryopreservation protocols. Coulter counting methods measured an osmotically inactive water fraction (Vb) of 0.37+/-0.02 (SEM), an isosmotic cell volume (V(o)) of 12.1+/-0.2 microm(3) (SEM), a water permeability (L(p)) in 10% dimethyl sulfoxide of 0.021+/-0.001(SEM)microm/min/atm, and a cryoprotectant permeability (P(s)) of 0.10+/-0.01 (SEM)x10(-3)cm/min. Fourier transform infrared spectroscopy indicated that sperm membranes frozen without cryoprotectant showed damage and lipid reorganization, while those exposed to 10% glycerol demonstrated decreased lipid phase transition temperatures, which would stabilize the cells during cooling. The second goal was to determine the practicality and viability of shipping cooled zebrafish sperm overnight through the mail. Flow cytometry demonstrated that chilled fresh sperm can be maintained at 92% viability for 24h at 0 degrees C, suggesting that it can be shipped and exchanged between laboratories. Additional methods will be necessary to analyze and improve cryopreservation techniques and post-thaw fertility of zebrafish sperm. The present study is a first step to explore such techniques.


What makes an orthopaedic paper highly citable? A bibliometric analysis of top orthopeadic journals with 10-year follow up.
To examine a series of papers from top ranked orthopaedic journals with respect to the number of citations over a 10-year observation period to identify factors that lead to high citation rates. The Web of Science database was consulted to identify all published papers from the first-year term of 2010 (January-May) from four top orthopaedic journals: AJSM, Arthroscopy, JBJS Am and KSSTA. The database was used to analyze and compare the papers with respect to their characteristics and citations up to 2019. Basic information for each paper was collected including the author, country, study type and average citations per year (ACY). The most (Top20%) and least (Bottom20%) frequently cited papers were identified and differences were extracted. Five hundred sixteen papers were included with a total of 19,261 citations. Most of the published papers were from the United States (n = 245). On average, a paper received 37.3 citations over the 10-year observation period. The most cited paper was cited 322 times. The most cited study type was randomized controlled trial (RCT) (Ø80.8). The Top20% papers were cited 37 times more often than the Bottom20%. Among the Top20%, the largest group was cohort study (n = 20) followed by case series (n = 19). Among others, the number of authors, the number of keywords and the number of references significantly correlated with the number of citations (p < 0.001). Factors influencing citation frequency were identified.


Microvesicle induction of prostate specific gene expression in normal human bone marrow cells.
Transfer of genetic material from cancer cells to normal cells occurs via microvesicles. Cell specific phenotypes can be induced in normal cells by the transfer of material in microvesicles, leading to genetic changes. We report the identification and expression of prostate specific genes in normal human marrow cells co-cultured with human prostate cancer cells. We harvested prostate tissue from 11 patients with prostate cancer. In 4 cases prostate tissue was co-cultured across from human marrow for 2 or 7 days but separated from it by a 0.4 μM polystyrene membrane. In 5 cases conditioned medium from patient cancer tissue was collected and ultracentrifuged, and microvesicles were collected for co-culture (3) and vesicle characterization (3). Explanted human marrow was harvested from cultures and RNA extracted. Real-time reverse transcriptase-polymerase chain reaction was done for select prostate specific genes. Marrow exposed to human prostate tumor or isolated microvesicles in culture in 4 and 3 cases, respectively, showed at least 2-fold or greater prostate gene expression than control marrow. In 1 case in which normal prostate was co-cultured there were no prostate gene increases in normal marrow. Prostate cancer tumor cells co-cultured with human bone marrow cells induce prostate specific gene expression. The proposed mechanism of transfer of genetic material is via microvesicles. This represents an opportunity for novel therapeutic agents, such as antibodies, to block microvesicle release from cancer cells or for agents that may block cells from accepting microvesicles.


Multicellular contractility contributes to the emergence of mesothelioma nodules.
Malignant pleural mesothelioma (MPM) has an overall poor prognosis and unsatisfactory treatment options. MPM nodules, protruding into the pleural cavity may have growth and spreading dynamics distinct that of other solid tumors. We demonstrate that multicellular aggregates can develop spontaneously in the majority of tested MPM cell lines when cultured at high cell density. Surprisingly, the nodule-like aggregates do not arise by excessive local cell proliferation, but by myosin II-driven cell contractility. Prominent actin cables, spanning several cells, are abundant both in cultured aggregates and in MPM surgical specimens. We propose a computational model for in vitro MPM nodule development. Such a self-tensioned Maxwell fluid exhibits a pattern-forming instability that was studied by analytical tools and computer simulations. Altogether, our findings may underline a rational for targeting the actomyosin system in MPM.


An automatic MEG low-frequency source imaging approach for detecting injuries in mild and moderate TBI patients with blast and non-blast causes.
Traumatic brain injury (TBI) is a leading cause of sustained impairment in military and civilian populations. However, mild (and some moderate) TBI can be difficult to diagnose because the injuries are often not detectable on conventional MRI or CT. Injured brain tissues in TBI patients generate abnormal low-frequency magnetic activity (ALFMA, peaked at 1-4 Hz) that can be measured and localized by magnetoencephalography (MEG). We developed a new automated MEG low-frequency source imaging method and applied this method in 45 mild TBI (23 from combat-related blasts, and 22 from non-blast causes) and 10 moderate TBI patients (non-blast causes). Seventeen of the patients with mild TBI from blasts had tertiary injuries resulting from the blast. The results show our method detected abnormalities at the rates of 87% for the mild TBI group (blast-induced plus non-blast causes) and 100% for the moderate group. Among the mild TBI patients, the rates of abnormalities were 96% and 77% for the blast and non-blast TBI groups, respectively. The spatial characteristics of abnormal slow-wave generation measured by Z scores in the mild blast TBI group significantly correlated with those in non-blast mild TBI group. Among 96 cortical regions, the likelihood of abnormal slow-wave generation was less in the mild TBI patients with blast than in the mild non-blast TBI patients, suggesting possible protective effects due to the military helmet and armor. Finally, the number of cortical regions that generated abnormal slow-waves correlated significantly with the total post-concussive symptom scores in TBI patients. This study provides a foundation for using MEG low-frequency source imaging to support the clinical diagnosis of TBI.


[Diagnostic usefulness of magnetic resonance cholangiopancreatography (MRCP) in comparison with retrograde cholangiopancreatography (ERCP) for cholelithiasis].
To elucidate MRCP diagnostic usefulness compared to ERCP. 29 MRCP performed patients diagnosed by ERCP were studied. MRCP showed 92%, 67% sensitivity and 73%, 100% specificity in choledocholithiasis (CBD) and cholecystolithiasis (GB), respectively. MRCP revealed 4.0 false positive and 1.5 false negative in CBD and GB, respectively. MRCP could detect 22 stones out of 33 in CBD and 13 out of 42 in GB. As for the maximal diameter, MRCP depicted 31% for less than 5 mm and 100% for over 6 mm in CBD. In GB, 7% for less than 5 mm, 83% for 6-10 mm and 100% for over 11 mm. Although the depection of tiny stone is limited, MRCP is a useful diagnostic tool for cholelithiasis, especially choledocholithiasis.


[Tuberculosis].
Tuberculosis is still one of the most important infectious disease worldwide. In Germany the tuberculosis incidence has been declining for decades to currently about 4500 new cases per year. A new challenge poses the rising number tuberculosis cases with drug resistant strains of Mycobacterium tuberculosis. Substantiell progress has been achieved in the diagnosis of tuberculosis with new molecular techniques that can lead to a much faster and more reliable identification of cases with acid-fast bacilli smear-negative tuberculosis and in the identification of drug-resistant strains of M. tuberculosis. Tuberculosis caused by drug resistant strains of M. tuberculosis is difficult to treat with the currently available medications and is related to very high costs of care. New therapeutic approaches and drugs are urgently needed. Interferon-γ tests have made the diagnosis of latent infection with M. tuberculosis more specific, but hardly contribute to the diagnosis of active tuberculosis.This article presents a brief summary of current knowledge concerning the epidemiology, risk factors, diagnosis and treatment of active tuberculosis and latent infection with M. tuberculosis. Moreover, current treatment approaches and economic aspects of care are discussed.


Histological and CBCT evaluation of a pulpotomised primary molar using calcium enriched mixture cement.
Pulpotomy is one of the most commonly used treatments for retaining pulpally involved primary molar teeth in order to prevent tooth extraction and maintain space within the jaws. A recent randomised clinical trial found that calcium enriched mixture (CEM) cement demonstrated favourable 2-year treatment outcomes for pulpotomy of carious primary molars comparable with mineral trioxide aggregate (MTA). The use of cone beam computer tomography (CBCT) has not previously been used to evaluate pulpotomy and histological outcomes. A coronal pulpotomy was performed on a carious maxillary first primary molar in a 7-year-old child with non-contributory medical history. Following haemostasis, the radicular pulp was covered with 2-3 mm of CEM and the tooth restored. At the 2-year follow-up appointment, clinical/radiographic examinations of the pulpotomised tooth revealed that vital pulp therapy was successful in maintaining the tooth asymptomatic; however, the first maxillary molars had to be extracted for orthodontic reasons. CBCT and histological examinations showed thick/complete calcific bridges with tubular dentine at the amputation sites. The underlying dental pulp had normal structure and was un-inflamed. Based on these findings, it seems that CEM cement can induce a favourable biological response in dental pulps of primary teeth and CBCT may be useful to evaluate pulpotomy outcomes.


Expression of nestin, desmin and vimentin in intact and regenerating muscle spindles of rat hind limb skeletal muscles.
We describe the expression and distribution patterns of nestin, desmin and vimentin in intact and regenerating muscle spindles of the rat hind limb skeletal muscles. Regeneration was induced by intramuscular isotransplantation of extensor digitorum longus (EDL) or soleus muscles from 15-day-old rats into the EDL muscle of adult female inbred Lewis rats. The host muscles with grafts were excised after 7-, 16-, 21- and 29-day survival and immunohistochemically stained. Nestin expression in intact spindles in host muscles was restricted to Schwann cells of sensory and motor nerves. In transplanted muscles, however, nestin expression was also found in regenerating "spindle fibers", 7 and 16 days after grafting. From the 21st day onwards, the regenerated spindle fibers were devoid of nestin immunoreactivity. Desmin was detected in spindle fibers at all developmental stages in regenerating as well as in intact spindles. Vimentin was expressed in cells of the outer and inner capsules of all muscle spindles and in newly formed myoblasts and myotubes of regenerating spindles 7 days after grafting. Our results show that the expression pattern of these intermediate filaments in regenerating spindle fibers corresponds to that found in regenerating extrafusal fibers, which supports our earlier suggestion that they resemble small-diameter extrafusal fibers.


Abciximab/Heparin Therapy for Left Ventricular Assist Device Implantation in Patients With Heparin-Induced Thrombocytopenia.
Optimal anticoagulation strategy remains uncertain in patients with heparin-induced thrombocytopenia (HIT) and undergoing left ventricular assist device (LVAD) implantation. We describe our protocol of abciximab and heparin in these patients. Our protocol is to administer abciximab, 0.25 mg/kg loading dose, followed by continuous infusion of 0.125 μg · kg-1 · min-1 throughout cardiopulmonary bypass. Full-dose heparin is then given with subsequent additional doses to maintain an activated clotting time of 400 seconds or longer. The abciximab infusion is stopped 15 minutes after heparin reversal with protamine, and platelets are transfused. Six patients underwent LVAD implantation with this protocol in our program. HIT was confirmed in 4 patients was suspected in 2, which was negative after the operation. One patient received a HeartMate XVE (Thoratec Corp, Pleasanton, CA) and the others received HeartMate II (Thoratec Corp). There were no thromboembolic complications. One patient required chest reexploration for bleeding and temporary right VAD support. Postoperative anticoagulation with argatroban was restarted on median postoperative day 3 (range, days 1 to 6) and warfarin was started on day 5 (range, days 3 to 12). Median postoperative intensive care unit stay was 9 days (range, 5 to 76 days), and hospital stay was 22 days (range, 18 to 132 days). After the initial LVAD implantation, 1 patient required HeartMate XVE LVAD exchange to HeartMate II and subsequent heart transplant, both of which were performed with the abciximab/heparin protocol. A HeartMate II device was explanted in another patient after myocardial recovery. The remaining 4 patients are alive on device support. This is the first report of a novel abciximab/heparin protocol for LVAD implantation in patients with HIT. The preliminary results suggest the feasibility and safety of this protocol.


Atrial cardiopathy predicts detection of atrial fibrillation in embolic stroke of undetermined source: real-life data.
Atrial cardiopathy (AC) is more frequent in patients with embolic stroke of undetermined source (ESUS) than in patients with non-cardioembolic stroke. The aim of this work was to describe AC in patients with ESUS and to study its impact on detection of atrial fibrillation (AF) during follow-up. This is an observational study of 123 consecutive ESUS patients and 55 ESUS patients from a previous cohort. AC was defined according to the presence of one or more of the following criteria: severe left atrial enlargement, p-wave terminal force in lead V1 > 5000 μVxms, and excessive premature atrial complexes. Unadjusted and adjusted survival analyses for the occurrence of AF and stroke or transient ischemic attack (TIA) were performed. Diagnostic performance of AC for the detection of AF was analyzed. Among 178 patients with ESUS, those with AC (42.7%) were older (p < 0.001), and more frequently had hypertension (p = 0.001) and lower total cholesterol levels (p = 0.001) than patients without AC. The detection of AF during follow-up (median 34 months, interquartile range = 12.8-64) was higher in patients with AC (hazard ratio = 7.00, 95% confidence interval = 2.01-24.39, p = 0.002). This association persisted after adjusting for age, arterial hypertension, and other vascular risk factors. The c-statistic for detection of AF during follow-up for AC was 0.719. There were no differences in stroke or TIA recurrence between groups with and without AC. ESUS patients with AC have different baseline clinical characteristics than patients without AC and have a higher detection of AF during follow-up.


Relation of binaural interaction and spectro-temporal characteristics in the auditory midbrain of the grassfrog.
The relation between binaural interaction type and spectro-temporal characteristics was studied for single units in the auditory midbrain of the grassfrog. Tonal and continuous wideband noise ensembles have been used as stimuli. Spectro-temporal sensitivities were determined for ipsi-, contra- and bilateral stimulus presentation by a closed sound system. Binaural interaction was classified in monaural EO (one ear excitatory), binaural EE (both ears excitatory) and EI (one ear excitatory, the other inhibitory) and purely inhibitory categories. Binaural interaction appeared to be rather invariant to alterations in stimulus intensity and type. A very clear correlation was observed between best frequency and binaural interaction type: EE units are predominantly of high best frequency, whereas EI units are predominantly of low best frequency. The correlation with latency was less significant: EE units tended to have somewhat shorter latencies that EI units. EO units take an intermediate position. Comparisons of ipsi-, contra- and bilateral spectro-temporal sensitivities, revealed differences in best frequency, latency and temporal discharge pattern. In some units a complex interplay of excitatory and inhibitory monaural influences was demonstrated. A number of units was recorded, which were characterized by multiple activation or suppression areas. The majority of these units exhibited frequency-dependent binaural interaction types. In some units it was noticed that binaural interaction type can be dependent on state of adaptation. A comparison of binaural interaction types of neighbouring units provided only weak evidence for a binaural organization in the anuran auditory midbrain, since simultaneously recorded pairs shared the same binaural interaction type only slightly more than expected by mere chance (chi 2-test, P less than 0.10).


Fast fluoride ion conduction of NH4(Mg1-xLix)F3-x and (NH4)2(Mg1-xLix)F4-x assisted by molecular cations.
Aiming development of the fast anion conductors, we proposed a new material design using flexible molecular cation as a host cation, and demonstrated it with fluoride ion conduction in NH4MgF3 and (NH4)2MgF4 based materials. Dominant fluoride ion conduction with relatively high conductivities of 4.8 × 10-5 S cm-1 and 8.4 × 10-6 S cm-1 were achieved at 323 K in (NH4)2(Mg0.85Li0.15)F3.85 and NH4(Mg0.9Li0.1)F2.9, respectively. It is implied that the molecular cation in the host lattice can assist the anion conduction. Our findings suggest molecular cation-containing compounds can be attractive material groups for fast anion conductors.


Communicating climate change findings from IPCC reports: insights from outreach events in India.
In recent years, the Intergovernmental Panel on Climate Change (IPCC) has been collaborating with Indian institutions to organise outreach events. This essay draws on the perspective of participants, speakers and organisers of 17 in-person outreach events conducted across India in 2018 and 2020, to share insights and recommendations for future IPCC events in India and other developing country contexts. The formats analysed in this essay range from panel events with very large public audiences to more focused workshops, meetings and seminars. Target audiences covered both academic and non-academic audiences and included researchers, teachers, students, industry and NGOs. The events, while achieving their main objective of communicating the findings of IPCC reports, also provided a platform for open discussion of localised climate impacts and good practices in adaptation and mitigation. There are, however, notable challenges to public outreach in India, specifically in terms of attracting an adequate number of participants, experts' availability, communicating to a diverse audience and translation into local languages. The biggest challenge faced by speakers was a lack of knowledge about the number of attendees and the composition of the audience prior to an event. It is our recommendation that future outreach events in India are designed to be interactive, tailored to the regional context and complemented by simplified communication materials. Speakers should be provided with audience information and background prior to the event, and greater reach into rural areas, including school children, could be achieved with material in local languages. Additionally, event organisers often require logistical and operational support to host outreach events.


Elucidating the neurological mechanism of the FLASH effect in juvenile mice exposed to hypofractionated radiotherapy.
Ultrahigh dose-rate radiotherapy (FLASH-RT) affords improvements in the therapeutic index by minimizing normal tissue toxicities without compromising antitumor efficacy compared to conventional dose-rate radiotherapy (CONV-RT). To investigate the translational potential of FLASH-RT to a human pediatric medulloblastoma brain tumor, we used a radiosensitive juvenile mouse model to assess adverse long-term neurological outcomes. Cohorts of 3-week-old male and female C57Bl/6 mice exposed to hypofractionated (2 × 10 Gy, FLASH-RT or CONV-RT) whole brain irradiation and unirradiated controls underwent behavioral testing to ascertain cognitive status four months posttreatment. Animals were sacrificed 6 months post-irradiation and tissues were analyzed for neurological and cerebrovascular decrements. The neurological impact of FLASH-RT was analyzed over a 6-month follow-up. FLASH-RT ameliorated neurocognitive decrements induced by CONV-RT and preserved synaptic plasticity and integrity at the electrophysiological (long-term potentiation), molecular (synaptophysin), and structural (Bassoon/Homer-1 bouton) levels in multiple brain regions. The benefits of FLASH-RT were also linked to reduced neuroinflammation (activated microglia) and the preservation of the cerebrovascular structure, by maintaining aquaporin-4 levels and minimizing microglia colocalized to vessels. Hypofractionated FLASH-RT affords significant and long-term normal tissue protection in the radiosensitive juvenile mouse brain when compared to CONV-RT. The capability of FLASH-RT to preserve critical cognitive outcomes and electrophysiological properties over 6-months is noteworthy and highlights its potential for resolving long-standing complications faced by pediatric brain tumor survivors. While care must be exercised before clinical translation is realized, present findings document the marked benefits of FLASH-RT that extend from synapse to cognition and the microvasculature.


Shoot-to-root mobile polypeptides involved in systemic regulation of nitrogen acquisition.
Plants uptake nitrogen (N) from the soil mainly in the form of nitrate. However, nitrate is often distributed heterogeneously in natural soil. Plants, therefore, have a systemic long-distance signalling mechanism by which N starvation on one side of the root leads to a compensatory N uptake on the other N-rich side1,2. This systemic N acquisition response is triggered by a root-to-shoot mobile peptide hormone, C-TERMINALLY ENCODED PEPTIDE (CEP), originating from the N-starved roots3,4, but the molecular nature of the descending shoot-to-root signal remains elusive. Here, we show that phloem-specific polypeptides that are induced in leaves upon perception of root-derived CEP act as descending long-distance mobile signals translocated to each root. These shoot-derived polypeptides, which we named CEP DOWNSTREAM 1 (CEPD1) and CEPD2, upregulate the expression of the nitrate transporter gene NRT2.1 in roots specifically when nitrate is present in the rhizosphere. Arabidopsis plants deficient in this pathway show impaired systemic N acquisition response accompanied with N-deficiency symptoms. These fundamental mechanistic insights should provide a conceptual framework for understanding systemic nutrient acquisition responses in plants.


Self-esteem and depression revisited: implicit positive self-esteem in depressed patients?
The cognitive behavioural model of depression holds that negative cognitions related to the self have etiological importance for the maintenance and relapse of depression. This has been confirmed by research using questionnaires. Recent research using the Implicit Association Test, however, showed positive implicit self-esteem in formerly depressed participants, even after negative mood induction [Gemar, Segal, Sagrati, & Kennedy (2001). Mood-induced changes on the implicit association test in recovered depressed patients. Journal of Abnormal Psychology, 110, 282-289]. These results are not in line with cognitive theory of depression. Since this could be an artifact of the specific procedure that was used, we investigated implicit self-esteem of currently depressed participants and healthy controls using three different paradigms: The Implicit Association Test, the Name Letter Preference Task, and the Extrinsic Affective Simon Task. The results of the three experiments are unequivocally indicative of positive implicit self-esteem in currently depressed patients. However, it remains an intriguing question what exactly these indirect measures assess.


Ectopic adrenals in a sirenomelic fetus.
A sirenomelic malformation was diagnosed in a fetus from the first pregnancy of a 25-year-old woman, and it was aborted at the 24th week of gestation. The fetus represented a sympus monopus. The head, organs of the neck, the thorax, and the upper part of abdominal cavity were normally formed. The kidneys, the ureters, the urinary bladder and the urethra were not developed. Adrenals of discoid shape and normal size were present in the normal position. The large bowel ended blindly in the sigmoid colon. Both testes were found in their normal position in the pelvis. Two symmetrical structures, resembling ovaries in shape and colour, were found near the testes. Histological examination established that these two organs were accessory (aberrant) adrenals.


Histology and transcriptomic analyses of barnacles with different base materials and habitats shed lights on the duplication and chemical diversification of barnacle cement proteins.
Barnacles are sessile crustaceans that attach to underwater surfaces using barnacle cement proteins. Barnacles have a calcareous or chitinous membranous base, and their substratum varies from biotic (e.g. corals/sponges) to abiotic surfaces. In this study, we tested the hypothesis that the cement protein (CP) composition and chemical properties of different species vary according to the attachment substrate and/or the basal structure. We examined the histological structure of cement glands and explored the variations in cement protein homologs of 12 barnacle species with different attachment habitats and base materials. Cement gland cells in the rocky shore barnacles Tetraclita japonica formosana and Amphibalanus amphitrite are eosinophilic, while others are basophilic. Transcriptome analyses recovered CP homologs from all species except the scleractinian coral barnacle Galkinia sp. A phylogenomic analysis based on sequences of CP homologs did not reflect a clear phylogenetic pattern in attachment substrates. In some species, certain CPs have a remarkable number of paralogous sequences, suggesting that major duplication events occurred in CP genes. The examined CPs across taxa show consistent bias toward particular sets of amino acid. However, the predicted isoelectric point (pI) and hydropathy are highly divergent. In some species, conserved regions are highly repetitive. Instead of developing specific cement proteins for different attachment substrata, barnacles attached to different substrata rely on a highly duplicated cementation genetic toolkit to generate paralogous CP sequences with diverse chemical and biochemical properties. This general CP cocktail might be the key genetic feature enabling barnacles to adapt to a wide variety of substrata.


Orthograde and retrograde axonal transport of calmodulin in a cat noradrenergic neurone.
Subcellular distribution studies of calmodulin in cat sympathetic ganglia demonstrated that about 90% of the protein remained in the 27,000 g supernatant, suggesting that it is a cytosolic protein. Only 4.5% was recovered in the microsomal fraction pellet. The inferior mesenteric ganglia contained 93.3 +/- 3 ng calmodulin per ganglion, and segments of unligated cat hypogastric nerves had 6.53 +/- 0.32 ng per 5 mm segment. When the nerve was ligated in the middle and left in the cat for 1-6 days, substantial amounts of calmodulin accumulated in segments of nerve immediately proximal (P1) and distal (D1) to the ligature. The amounts found in P1 amounted to 15.3, 20, 30.4 and 39.4 ng calmodulin per 5 mm segment 1, 2, 3 and 6 days after ligation, respectively. The average rate of transport was 5.5 mm per day, which corresponds to a slow component b of axonal transport (SCb). The accumulation of calmodulin in D1 was also increased with the time of ligation. After 1, 2, 3 and 6 days, the amounts of the protein found in D1 were 14.4, 17.7, 19 and 21 ng per 5 mm segment, respectively. The calculated mean rate for the retrograde transport was 3.9 mm per day. Decentralization of the inferior mesenteric ganglia did not affect the rate of accumulation of calmodulin or the basal amounts found in ganglia and nerves. Local injection inhibited the orthograde, but not the retrograde axonal transport of the protein. It is concluded that calmodulin undergoes a process of slow orthograde axonal transport probably incorporated into the axoplasmic matrix of a network of actin microfilaments. The protein is also transported in a retrograde manner.


Survival and growth of hatchling Crocodylus porosus in saltwater without access to fresh drinking water.
It has been suggested that C. porosus select nest sites which provide a source of freshwater for hatchlings during the dry season. From a mark-recapture study, we conclude that hatchling C. porosus can survive and grow in hyperosmotic saltwater without drinking freshwater. Hence, the siting of nests is unlikely to be the consequence of a requirement by hatchlings for freshwater. Considered along with other information, our observations imply that hatchling C. porosus have functional salt glands.


An epigenetically altered tumor cell vaccine.
Functional inactivation of genes critical to immunity may occur by mutation and/or by repression, the latter being potentially reversible with agents that modify chromatin. This study was constructed to determine whether reversal of gene silencing, by altering the acetylation status of chromatin, might lead to an effective tumor vaccine. We show that the expression of selected genes important to tumor immunity, including MHC class II, CD40, and B7-1/2 are altered by treating tumor cells in vitro with a histone deacetylase inhibitor, trichostatin A (TSA). Tumor cells treated in vitro with TSA showed delayed onset and rate of tumor growth in 70% of the J558 plasmacytoma and 100% of the B16 melanoma injected animals. Long-term tumor specific immunity was elicited to rechallenge with wild-type cells in approximately 30% in both tumor models. Splenic T cells from immune mice lysed untreated tumor cells, and SCID mice did not manifest immunity, suggesting that T cells may be involved in immunity. We hypothesize that repression of immune genes is involved in the evasion of immunity by tumors and suggest that epigenetically altered cancer cells should be further explored as a strategy for the induction of tumor immunity.


Effect of coronary bypass surgery and valve replacement on left ventricular function: assessment by intraoperative two-dimensional echocardiography.
Intraoperative two-dimensional echocardiography (2DE) was performed in 15 patients during coronary artery bypass grafting (CABG) and in 14 patients during aortic (AVR) or mitral valve replacement (MVR) before and immediately after cardiopulmonary bypass by means of a 3.5 MHz transducer. Left ventricular ejection fraction (LVEF), end-diastolic (LVEDV) and end-systolic (LVESV) volumes were measured by a light pen system and biplane Simpson's rule from short-axis and apical two-chamber views. In seven patients with CABG and new abnormal Q waves or greater than 5% MB to total CPK ratio postoperatively, the mean LVEF decreased significantly (from 52 +/- 10 to 43 +/- 12%, p = 0.005). Patients undergoing MVR for mitral regurgitation showed, a significant decrease in LVEF (from 63 +/- 10 to 42 +/- 23%, p less than 0.025) and LVEDV (from 166 +/- 34 to 147 +/- 44 ml, p less than 0.05). Mean LVEF also decreased after AVR for aortic regurgitation (from 46 +/- 16 to 26 +/- 15%, p less than 0.05). Six patients with valve replacement and postoperative hypotension had the greatest decrease in intraoperative LVEF (from 50 +/- 12 to 24 +/- 10%, p less than 0.005). It is concluded that: Intraoperative 2DE can be used to assess immediate changes in left ventricular function after CABG or valve replacement. LVEF decreases significantly immediately after AVR for aortic regurgitation and MVR for mitral regurgitation. Intraoperative 2DE may identify those patients who can benefit from inotropic support in the immediate postoperative period after valve replacement.


A sporadic Parkinson's disease model via silencing of the ubiquitin-proteasome/E3 ligase component, SKP1A.
Our and other's laboratory microarray-derived transcriptomic studies in human PD substantia nigra pars compacta (SNpc) samples have opened an avenue to concentrate on potential gene intersections or cross-talks along the dopaminergic (DAergic) neurodegenerative cascade in sporadic PD (SPD). One emerging gene candidate identified was SKP1A (p19, S-phase kinase-associated protein 1A), found significantly decreased in the SNpc as confirmed later at the protein level. SKP1 is part of the Skp1, Cullin 1, F-box protein (SCF) complex, the largest known class of sophisticated ubiquitin-proteasome/E3-ligases and was found to directly interact with FBXO7, a gene defective in PARK15-linked PD. This finding has led us to the hypothesis that a targeted site-specific reduction of Skp1 levels in DAergic neuronal cell culture and animal systems may result in a progressive loss of DAergic neurons and hopefully recreate motor disabilities in animals. The second premise considers the possibility that both intrinsic and extrinsic factors (e.g., manipulation of selected genes and mitochondria impairing toxins), alleged to play central roles in DAergic neurodegeneration in PD, may act in concert as modifiers of Skp1 deficiency-induced phenotype alterations ('dual-hit' hypothesis of neurodegeneration). To examine a possible role of Skp1 in DAergic phenotype, we have initially knocked down the expression of SKP1A gene in an embryonic mouse SN-derived cell line (SN4741) with short hairpin RNA (shRNA) lentiviruses (LVs). The deficiency of SKP1A closely recapitulated cardinal features of the DAergic pathology of human PD, such as decreased expression of DAergic phenotypic markers and cell cycle aberrations. Furthermore, the knocked down cells displayed a lethal phenotype when induced to differentiate exhibiting proteinaceous round inclusion structures, which were almost identical in composition to human Lewy bodies, a hallmark of PD. These findings support a role for Skp1 in neuronal phenotype, survival, and differentiation. The identification of Skp1 as a key player in DAergic neuron function suggested that a targeted site-specific reduction of Skp1 levels in mice SNpc may result in a progressive loss of DAergic neurons and terminal projections in the striatum. The injected LV SKP1shRNA to mouse SN resulted in decreased expression of Skp1 protein levels within DAergic neurons and loss of tyrosine hydroxylase immunoreactivity (TH-IR) in both SNpc and striatum that was accompanied by time-dependent motor disabilities. The reduction of the vertical movements, that is rearing, may be reminiscent of the early occurrence of hypokinesia and axial, postural instability in PD. According to the 'dual-hit' hypothesis of neurodegenerative diseases, it is predicted that gene-gene and/or gene-environmental factors would act in concert or sequentially to propagate the pathological process of PD. Our findings are compatible with this conjecture showing that the genetic vulnerability caused by knock down of SKP1A renders DAergic SN4741 cells especially sensitive to genetic reduction of Aldh1 and exposure to the external stressors MPP+ and DA, which have been implicated in PD pathology. Future consideration should be given in manipulation SKP1A expression as therapeutic window, via its induction genetically or pharmacological, to prevent degeneration of the nigra striatal dopamine neurons, since UPS is defective.


HLA product expression and lymphocyte subpopulations in jejunum biopsies of children with idiopathic protracted diarrhoea and enterocyte autoantibodies.
Mature enterocytes from normal human small intestine express HLA Class II molecules, whereas the immature enterocytes of the crypts are devoid of these products. By the use of the Avidin/Biotin immunofluorescence technique, we examined HLA Class I and II expression on cryostat sections of jejunum biopsies from 10 children with idiopathic protracted diarrhoea (IPD) and circulating enterocyte autoantibodies (Ec-Abs). The results were compared with those obtained on gut specimens from nine children with protracted diarrhoea but no evidence of circulating Ec-Abs and from one child affected by gluten-sensitive enteropathy. HLA Class I expression was similar in control and pathological specimens but jejunum biopsies from children with IPD and high titres of Ec-Abs (greater than or equal to 1:64) showed 'inappropriate' Class II molecule expression in the crypt epithelial cells. This was in contrast with normal or only mildly increased Class II reactivity in the mature villi enterocytes. Conversely, jejunum biopsies from children with IPD but with low levels of Ec-Abs (less than or equal to 1:4) possessed a moderate but distinct decrease of Class II expression in mature enterocytes with a decreased number of CD3 and CD8 intraepithelial lymphocytes. It is speculated that quantitative and qualitative variations of HLA product expression in the gut epithelium of children with IPD could reflect the severity of the autoimmune process underlying the clinical picture and point to heterogeneities within the autoimmune enteropathy syndrome.


Neurological aspects of multiple myeloma and related disorders.
The spectrum of neurologic complications of multiple myeloma (MM) and related conditions is as diverse as the conditions themselves. Complications range from direct compression (radiculopathy, spinal cord compression, base-of-the-skull tumor) to the infiltrative (amyloid, peripheral neuropathies, and numb chin syndrome of myeloma), the metabolic (slowed mentation from hyperviscosity, hypercalcemia, or uremia), and to autoimmune or cytokine-mediated (peripheral neuropathy). The two most common presentations are the compressive radiculopathy one sees in multiple myeloma and the peripheral neuropathies associated with many of the other disorders. The authors will review the neurologic complications of MM, monoclonal gammopathy of undetermined significance (MGUS), Waldenström macroglobulinemia (WM), POEMS syndrome, amyloidosis, and cryoglobulinemia.


Epithelial-mesenchymal transition plays a critical role in drug resistance of hepatocellular carcinoma cells to oxaliplatin.
Drug resistance is one characteristic of hepatocellular carcinoma (HCC) and can affect the prognosis of patients directly. To explore drug resistance well, we established an oxaliplatin (OXA)-resistant cell line Bel-7402/OXA by exposure to gradually increased concentration of OXA. Some biological characters, such as proliferation, migration, and invasion, were studied. Drug sensitivity and the mechanisms of drug resistance were also investigated. We found that the resistant index of Bel-7402/OXA was 8.3. In comparison with Bel-7402, the percentages of cells in S and G2/M phase were increased. The nature apoptosis rate and drug-after apoptosis rate were all decreased in Bel-7402/OXA, as compared to Bel-7402. Bel-7402/OXA acquired increased migration and invasion ability with epithelial-mesenchymal transition (EMT) phenotype. Knockdown of EMT transcription factor Snail could reverse EMT and sensitized Bel-7402/OXA cells to OXA. EMT was one mechanism of drug resistance and may be a novel target of treatment for drug resistance.


Histologic aspects of patch test reactions in allergic contact dermatitis.
Twenty subjects with allergic contact dermatitis were patch tested with the responsible allergen applied to four fixed points on the back. Skin biopsies of the four sites were obtained after 6, 12, 24 and 48 hours, fixed in neutral formalin and stained with hematoxylin-eosin, Giemsa and toluidine blue. Sections were examined and lymphomonocytes, mast cells, eosinophils and basophils counted. In all cases the infiltrate consisted mainly of lymphomonocytes (80-82%); mast cells (5%) and basophils (0.2%) do not present clear variations within the given time. Eosinophils showed a definite numerical increase in six cases out of 20.


Influences of resolvin D1 and D2 on the risk of type 2 diabetes mellitus: a Chinese community-based cohort study.
Although cellular and animal studies have reported that resolvin D1 (RvD1) and resolvin D2 (RvD2) are mechanisms involved in the development of type 2 diabetes mellitus (T2DM), the impact of RvD1 and RvD2 on the risk of T2DM at a population level remains unclear. We included 2755 non-diabetic adults from a community-based cohort in China and followed them for seven years. Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of RvD1 and RvD2 with T2DM probability. Time-dependent receiver operator characteristics (ROC) curve was used to evaluate the predictive performance of RvD1 and RvD2 for the risk of T2DM based on the Chinese CDC T2DM prediction model (CDRS). A total of 172 incident T2DM cases were identified. Multivariate-adjusted HRs (95% CI) for T2DM across quartiles of RvD1 levels (Q1, Q2, Q3 and Q4) were 1.00, 1.64 (1.03-2.63), 1.80 (1.13-2.86) and 1.61 (1.01-2.57), respectively. Additionally, body mass index (BMI) showed a significant effect modification in the association of RvD1 with incident T2DM (P interaction = 0.026). After multivariate adjustment, the HR (95% CI) for T2DM in the fourth compared with the first quartile of RvD2 was 1.94 (95% CI: 1.24-3.03). Time-dependent ROC analysis showed that the area under time-dependent ROC curves of the "CDRS+RvD1+RvD2" model for the 3-, 5- and 7-year risk of T2DM were 0.842, 0.835 and 0.828, respectively. Higher RvD1 and RvD2 levels are associated with a higher risk of T2DM at the population level.


Validating screening instruments for neuroepidemiologic surveys: experience in Sicily. Sicilian Neuro-Epidemiologic Study (SNES) Group.
In a hospital setting in Sicily, we assessed a screening instrument developed for a prevalence survey of parkinsonism, peripheral neuropathies, stroke, and epilepsy. The subjects consisted of (1) hospital patients with any of the above-mentioned diseases, to investigate sensitivity; and (2) hospital visitors free of all these diseases, to investigate specificity. The standard for comparison was a clinical evaluation based on specified criteria. Trained interviewers administered the screening instrument, asking subjects to answer symptom questions and to perform simple physical tasks. For the questions and tasks together, the sensitivity estimates were 100% for parkinsonism (n = 21), 96% for peripheral neuropathies (n = 22), 96% for stroke (n = 22), and 96% for epilepsy (n = 22), while the specificity estimate was 86% (n = 21). Analogous estimates were computed for the set of questions, for the set of tasks, and for each question and task individually. Despite limitations in our approach, we concluded that the screening instrument would be adequate for its intended use.


Percutaneous Transluminal Angioplasty and Stenting for Progressive Intracranial Carotid Artery Stenosis Secondary to Invasive Sphenoid Sinus Aspergillosis: A Case Report.
We report a case of invasive sphenoid sinus aspergillosis with progressive internal carotid artery (ICA) stenosis and contralateral carotid occlusion that was successfully treated with percutaneous transluminal angioplasty and stenting (PTAS). A 70-year-old man presented with right-sided visual disturbance, ptosis, and left hemiparesis. Magnetic resonance imaging of the head revealed a space-occupying lesion within the sphenoid sinus with infiltration of the bilateral cavernous sinuses, right ICA occlusion, and multiple watershed cerebral infarcts involving the right cerebral hemisphere. The patient was diagnosed with invasive sinus aspergillosis based on transnasal biopsy findings. Despite intensive antifungal therapy using voriconazole, rapidly progressive aspergillosis led to a new stenotic lesion in the left ICA, which increased the risk of bilateral cerebral hypoperfusion. We performed successful PTAS to prevent critical ischemic events. Finally, aspergillosis was controlled with voriconazole treatment, and the patient was discharged. He showed a favorable outcome, with a patent left ICA observed at a 3-year follow-up. PTAS may be feasible in patients with ICA stenosis and invasive sinus aspergillosis.


Polymorphic Ala-allele carriers at residue 1170 of HER2 associated with Parkinson's disease.
HER2, a receptor tyrosine kinase, was originally identified based on its role in cancer research. The protein has subsequently received attention for its role in nerve injury and neurodevelopment. We investigated the polymorphic association of HER2 variants at amino acid residues 655 and 1170 with Parkinson's disease (PD), a neurodegenerative disorder. Polymerase chain reaction (PCR) was used to amplify DNA samples from PD patients and control subjects. The resulting PCR fragments, which spanned HER2 residues 655 and 1170, were analyzed by restriction fragment length polymorphism and/or direct nucleotide sequencing. The genetic distribution at residue 655 in PD patients did not differ from that in controls. However, homozygosity for genes encoding Pro at residue 1170 (Pro/Pro) occurred at a significantly lower rate among PD subjects. In other words, Ala-allele carries higher frequency in PD, especially among female PD subjects. Different signals or potency of the kinase activities resulting from the Ala1170Pro allele of HER2 may be associated with vulnerability to stress on dopaminergic neurons in PD.