Psoriasis.
Patients with psoriasis can find the psychological impact of the disease as debilitating as the physical symptoms. Helen Cloote describes the different types of psoriasis and the treatment methods available and emphasises the important role of the nurse in helping patients to come to terms with this condition.


Reconstruction of Chronic, Retracted Pectoralis Major Tendon Tear With Achilles Tendon Allograft.
Rupture of pectoralis major tendon (PMT) is an uncommon injury, but its incidence has been increasing in the past 2 decades. Although open repair of the torn tendon is the preferred choice of treatment in acute and chronic cases, this often is not possible for chronic retracted tendon injuries. While several techniques have been described for PMT reconstruction, these allografts and autografts are often smaller and less thick than the native PMT. In this study, we describe the use of the Achilles tendon allograft with unicortical suture buttons for the reconstruction of a chronic and retracted PMT. Furthermore, the advantages and disadvantages of this technique are discussed.


Smooth pursuit eye movement, prepulse inhibition, and auditory paired stimuli processing endophenotypes across the schizophrenia-bipolar disorder psychosis dimension.
This study examined smooth pursuit eye movement (SPEM), prepulse inhibition (PPI), and auditory event-related potentials (ERP) to paired stimuli as putative endophenotypes of psychosis across the schizophrenia-bipolar disorder dimension. Sixty-four schizophrenia probands (SZP), 40 psychotic bipolar I disorder probands (BDP), 31 relatives of SZP (SZR), 26 relatives of BDP (BDR), and 53 healthy controls (HC) were tested. Standard clinical characterization, SPEM, PPI, and ERP measures were administered. There were no differences between either SZP and BDP or SZR and BDR on any of the SPEM, PPI, or ERP measure. Compared with HC, SZP and BDP had lower SPEM maintenance and predictive pursuit gain and ERP theta/alpha and beta magnitudes to the initial stimulus. PPI did not differ between the psychosis probands and HC. Compared with HC, SZR and BDR had lower predictive pursuit gain and ERP theta/alpha and beta magnitudes to the first stimulus with differences ranging from a significant to a trend level. Neither active symptoms severity nor concomitant medications were associated with neurophysiological outcomes. SPEM, PPI, and ERP scores had low intercorrelations. These findings support SPEM predictive pursuit and lower frequency auditory ERP activity in a paired stimuli paradigm as putative endophenotypes of psychosis common to SZ and BD probands and relatives. PPI did not differ between the psychosis probands and HC. Future studies in larger scale psychosis family samples targeting putative psychosis endophenotypes and underlying molecular and genetic mediators may aid in the development of biology-based diagnostic definitions.


Effect of inoculum size on the induction of endophthalmitis in aphakic rabbit eyes.
A reproducible animal model is necessary to examine the use of antimicrobial agents for prophylaxis and treatment of bacterial endophthalmitis. We determined the minimum inoculum size of S. aureus and P. aeruginosa that consistently produced endophthalmitis when injected into aphakic rabbit eyes immediately following surgery. Both anterior chamber and intravitreal injections were examined. For S. aureus, an intravitreal inoculum of 19.3 +/- 7.5 CFU and an anterior chamber inoculum of 50.5 +/- 4.0 CFU were required. For P. aeruginosa, an intravitreal inoculum of 5.5 +/- 2.6 CFU and an anterior chamber inoculum of 97.5 +/- 10.7 CFU consistently produced a fulminant infection. Lower inocula of both bacteria produced endophthalmitis in both locations, but the effect was inconsistent.


Should We Screen This Patient for Carotid Artery Stenosis?: Grand Rounds Discussion From Beth Israel Deaconess Medical Center.
In July 2014, the U.S. Preventive Services Task Force (USPSTF) published a clinical guideline on screening for asymptomatic carotid artery stenosis. The guideline recommended against screening in asymptomatic adults, based primarily on the results of 3 large randomized trials (grade D recommendation). The principal screening test was carotid ultrasonography, and the intervention in the 3 trials was carotid endarterectomy for patients with stenosis exceeding 50% to 60%. In a meta-analysis, carotid endarterectomy reduced rates of 1) perioperative stroke, death, or subsequent ipsilateral stroke and 2) perioperative stroke, death, or any subsequent stroke. The corresponding absolute risk differences were -2.0% (95% CI, -3.3% to -0.7%) and -3.5% (CI, -5.1% to -1.8%), respectively. However, perioperative stroke and death were substantially less common among the 3 randomized trials than in contemporaneous cohort studies (1.9% vs. 3.3%). In addition to stroke or death in patients receiving carotid endarterectomy, a harm of screening included the risk for angiography prompted by abnormal results on carotid ultrasonography. In this article, 2 discussants address the risks and benefits of screening for carotid artery disease as well as how to apply the guideline to an individual patient who is deciding whether to be screened.


Internet-based health promotion and disease control in the 8 cities: successes, barriers, and future plans.
The objective of this paper is to provide a detailed description of Internet-based sexually transmitted disease/human immunodeficiency virus prevention in the 8 US cities most affected by syphilis in men who have sex with men. By reviewing the efforts under way in these 8 cities, we will understand the barriers and facilitators associated with Internet-based prevention efforts. This is a review of Internet activities taking place in 8 major US cities. Efforts in the 8 cities vary, with some cities reporting little or no Internet-based prevention activities. Other cities have attempted banner advertising, online outreach, online partner notification, online laboratory slips for syphilis testing, and auditorium-style chat sessions. Though a number of policy-related barriers prevent some cities from engaging in Internet-based prevention, these activities are clearly important to the overall prevention effort. In order to surmount local policy barriers, it is essential to obtain evaluation data from the programs initiated.


Duodenal stump fistula after gastrectomy for gastric cancer: risk factors, prevention, and management.
A duodenal stump fistula is one of the most severe complications after gastrectomy for gastric cancer. We aimed to analyze the risk factors for this problem, and to identify the methods used for its prevention and management. We retrospectively reviewed the clinical data of 716 consecutive patients who underwent curative gastrectomy with a duodenal stump for gastric cancer between 2008 and 2013. A duodenal stump fistula occurred in 16 patients (2.2%) and there were 2 deaths in this group. Univariate analysis revealed age >60 years (odds ratio [OR], 3.09; 95% confidence interval [CI], 0.99-9.66), multiple comorbidities (OR, 4.23; 95% CI, 1.50-11.92), clinical T stage (OR, 2.91; 95% CI, 1.045-8.10), and gastric outlet obstruction (OR, 8.64; 95% CI, 2.61-28.61) to be significant factors for developing a duodenal stump fistula. Multivariate analysis identified multiple comorbidities (OR, 3.92; 95% CI, 1.30-11.80) and gastric outlet obstruction (OR, 5.62; 95% CI, 1.45-21.71) as predictors of this complication. Multiple comorbidities and gastric outlet obstruction were the main risk factors for a duodenal stump fistula. Therefore, preventive methods and aggressive management should be applied for patients at high risk.


7,8-Dihydroxyflavone inhibits adipocyte differentiation via antioxidant activity and induces apoptosis in 3T3-L1 preadipocyte cells.
Anti-obesity effects of a natural plant flavonoid 7,8-dihydroxyflavone (7,8-DHF) were evaluated using 3T3-L1 preadipocyte cells. The cell viability was determined using MTT assay. Effects of 7,8-DHF on intracellular lipid droplets and intracellular reactive oxygen species (ROS) were measured using a 2,7-dichlorofluorescein diacetate (DCF-DA) assay and Oil Red O staining method, respectively. Apoptotic cell death was monitored by annexin V-FITC/PI double staining and by a TUNEL assay. Antioxidant enzyme mRNA levels and protein expression of adipogenic transcription factors were determined by real-time PCR and Western blotting, respectively. Whereas the cell viability of 3T3-L1 preadipocytes was not affected by lower concentrations of 7,8-DHF (<20 μM), higher concentrations of 7,8-DHF (>20 μM) induced apoptotic cell death. 7,8-DHF (<20 μM) significantly reduced the intracellular lipid droplets and the expression of major adipogenic transcription factors, such as CCAAT/enhancer-binding protein-α (C/EBP-α), C/EBP-β, and peroxisome proliferator activated receptor-γ (PPAR-γ). 7,8-DHF treatment also dose-dependently reduced the intracellular ROS level, attenuated MAPK pathway activation, and increased the expression of antioxidant enzymes, such as Mn-superoxide dismutase (Mn-SOD), catalase (CAT), and heme oxygenase-1 (HO-1). The results of this study indicated that 7,8-DHF inhibits the adipogenesis of 3T3-L1 preadipocyte cells by down-regulating the expression of adipogenic transcription factors, reduces lipid accumulation, and attenuates ROS accumulation by inducing antioxidant enzymes in differentiated 3T3-L1 cells, suggesting for the first time that 7,8-DHF has an anti-obesity effect in vitro via its anti-oxidant activity.


Rapid Generation of Ventral Spinal Cord-like Astrocytes from Human iPSCs for Modeling Non-Cell Autonomous Mechanisms of Lower Motor Neuron Disease.
Astrocytes play important roles in the function and survival of neuronal cells. Dysfunctions of astrocytes are associated with numerous disorders and diseases of the nervous system, including motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Human-induced pluripotent stem cell (iPSC)-based approaches are becoming increasingly important for the study of the mechanisms underlying the involvement of astrocytes in non-cell autonomous processes of motor neuron degeneration in ALS. These studies must account for the molecular and functional diversity among astrocytes in different regions of the brain and spinal cord. It is essential that the most pathologically relevant astrocyte preparations are used when investigating non-cell autonomous mechanisms of either upper or lower motor neuron degeneration in ALS. Here, we describe the efficient and streamlined generation of human iPSC-derived astrocytes with molecular and biological properties similar to physiological astrocytes in the ventral spinal cord. These induced astrocytes exhibit spontaneous and ATP-induced calcium transients, and lack signs of overt activation. Human iPSC-derived astrocytes with ventral spinal cord features offer advantages over more generic astrocyte preparations for the study of both ventral spinal cord astrocyte biology and the involvement of astrocytes in mechanisms of lower motor neuron degeneration in ALS.


CXCL12 and CXCR4 expression by human gingival fibroblasts in periodontal disease.
CXCL12 is a CXC chemokine that is related to lymphocyte infiltration and angiogenesis in inflammatory sites such as arthritis. However, the expression and roles of CXCL12 in periodontal disease are uncertain. The aim of this study was to assess the expression of CXCL12 and its receptor, CXCR4, in periodontal tissue and to investigate the properties of CXCL12 and CXCR4 expression by human gingival fibroblasts (HGF). RT-PCR analysis revealed that CXCL12 and CXCR4 mRNA were expressed in both normal gingival tissues and periodontal diseased tissues. Immunohistochemistry disclosed that CXCL12 was expressed and CXCR4 positive cells were found in both normal and periodontal diseased gingival tissues. Our in vitro experiments elucidated that HGF constitutively produced CXCL12, and the levels were enhanced by stimulation with tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), transforming growth factor-beta (TGF-beta), regulated upon activation normal T cell expressed and secreted (RANTES) and macrophage inflammatory protein 3(alpha) (MIP-3(alpha)). On the other hand, heat killed Porphyromonas gingivalis (P. gingivalis) and P. gingivalis LPS reduced the CXCL12 production by HGF. Flow cytometry analysis clarified that CXCR4 was highly expressed on HGF, and CXCR4 expression was abrogated by TNF-alpha, IFN-gamma and P. gingivalis LPS. Moreover, CXCL12 induced vascular endothelial growth factor (VEGF) production by HGF. Our results demonstrated that CXCL12 might be related to CXCR4+ cells infiltration and angiogenesis both in normal periodontal tissues and periodontal diseased tissue. P. gingivalis, a known periodontal pathogen, inhibits the production of CXCL12 and the expression of CXCR4 by HGF. This fact means that P. gingivalis may inhibit CXCR4+ cells infiltration and neovascularization in periodontal tissue and escape from the immune response.


The mitochondrial DNA constitution shaping T-cell immunity in patients with rectal cancer at high risk of metastatic progression.
A significant percentage of colorectal cancer patients proceeds to metastatic disease. We hypothesised that mitochondrial DNA (mtDNA) polymorphisms, generated by the high mtDNA mutation rate of energy-demanding clonal immune cell expansions and assessable in peripheral blood, reflect how efficiently systemic immunity impedes metastasis. We studied 44 rectal cancer patients from a population-based prospective biomarker study, given curative-intent neoadjuvant radiation and radical surgery for high-risk tumour stage and followed for metastatic failure. Blood specimens were sampled at the time of diagnosis and analysed for the full-length mtDNA sequence, composition of immune cell subpopulations and damaged serum mtDNA. Whole blood total mtDNA variant number above the median value for the study cohort, coexisting with an mtDNA non-H haplogroup, was representative for the mtDNA of circulating immune cells and associated with low risk of a metastatic event. Abundant mtDNA variants correlated with proliferating helper T cells and cytotoxic effector T cells in the circulation. Patients without metastatic progression had high relative levels of circulating tumour-targeting effector T cells and, of note, the naïve (LAG-3+) helper T-cell population, with the proportion of LAG-3+ cells inversely correlating with cell-free damaged mtDNA in serum known to cause antagonising inflammation. Numerous mtDNA polymorphisms in peripheral blood reflected clonal expansion of circulating helper and cytotoxic T-cell populations in patients without metastatic failure. The statistical associations suggested that patient's constitutional mtDNA manifests the helper T-cell capacity to mount immunity that controls metastatic susceptibility. ClinicalTrials.gov NCT01816607; registration date: 22 March 2013.


Protective effect of verapamil on ischaemic renal injury in dogs.
Three groups of female mongrel dogs were used. In each dog right nephrectomy was performed. In the first group, 60-min complete occlusion of the left renal artery was followed by 50.4% reduction in RBF (P less than 0.05), 53.4% reduction in GFR (P less than 0.01) and 46.7% reduction in urine flow rate (UV) (P less than 0.05). These haemodynamic changes were accompanied by a significant (P less than 0.01) increase in urinary enzyme activity. In the second group, following Verapamil 0.5 mg/kg i.v. bolus, there was diuresis and natriuresis, urine flow rate (UV) increased by 39% and UNaV by 60% (P greater than 0.05); there were no changes in RBF or GFR. In the third group, pretreatment with Verapamil prior to the arterial occlusion modified the deleterious effects of the 60-min renal ischaemia. RBF decreased by 9.4%, GFR by 28.5% and UV by 11.1% (P greater than 0.05); there was no change in the urinary enzyme activity. It is concluded that Verapamil can protect against ischaemic renal damage.


Role of prostaglandins in acute phase proteins in inflammation.
Prostaglandin E1, a mediator of inflammation, was investigated for its effects on serum acute phase proteins, alpha 2 macroglobulin (alpha 2M). Induction of carrageenin inflammation in rats caused an elevation of alpha 2M to a maximum level (100%) at 1 day. Similarly, administration of PGE1 (1 mg/kg) was found to increase serum alpha 2M levels in normal rats. On the other hand, sc injection of PGE1 into inflamed rats significantly reduced the alpha 2M in serum as well as edema. In vitro studies with liver slices showed increasing rates of incorporation of [14C]leucine into alpha 2M with the addition of PGE1 to the medium. It was followed by the secretion of alpha 2M-bound radioactivity into media. But addition of higher doses (greater than 100 ng/ml) of PGE1 resulted in the suppression of incorporation and secretion of alpha 2M-bound radioactivity. Incubation of inflamed liver slices with PGE1, however, showed only decreased incorporation and secretion of alpha 2M-bound radioactivity. These results indicate that (a) primary prostaglandins, like PGE1, generated during inflammation may be responsible for the increase of alpha 2M in serum, and (b) PGE1 enhanced the synthesis of alpha 2M in liver and its secretion into the medium, so the anti-inflammatory drugs which decrease levels of PGs are likely to alter alpha 2M levels.


Pembrolizumab in advanced recurrent endometrial cancer: A cost-effectiveness analysis.
To determine the cost-effectiveness of pembrolizumab in patients with recurrent endometrial cancer that have failed first-line chemotherapy. We created a model to evaluate the cost-effectiveness of pembrolizumab compared to pegylated liposomal doxorubicin (PLD) or bevacizumab for the treatment of women with recurrent endometrial cancer who have failed carboplatin and paclitaxel. Microsatellite instability-high (MSI-H) and non-microsatellite instability-high (non-MSI-H) tumors were evaluated. We included 4400 patients in the model; 800 patients were assumed to have MSI-H tumors. Drug costs were calculated using 2016-2017 wholesale acquisition costs, and cost of Grade III-IV toxicities was estimated from clinical experience. Effectiveness was calculated as 2-year overall survival (OS). We calculated incremental cost-effectiveness ratios (ICERs) to determine the cost per 2-year survivor. Univariate sensitivity analyses were performed. The willingness to pay threshold was $100,000 per year of OS. The cost of therapy with PLD and bevacizumab were $33.2 million (M) and $167.9 M, respectively. The cost of pembrolizumab therapy was $318.3 M for non-MSI-H patients compared to $57.9 M for MSI-H patients. For non-MSI-H patients, bevacizumab was cost-effective relative to PLD with an ICER of $153,028, while pembrolizumab was not cost-effective relative to bevacizumab with an ICER of $341,830. For MSI-H patients, pembrolizumab was cost-effective compared to PLD with an ICER of $147,249, while bevacizumab was subjected to extended dominance. Sensitivity analysis revealed that for non-MSI-H patients, one cycle of pembrolizumab would need to cost $7253 or less to be cost-effective. For patients with MSI-H recurrent endometrial cancers who have failed first-line chemotherapy, pembrolizumab is cost-effective relative to other single agent drugs. To be cost-effective in non-MSI-H patients, the cost of pembrolizumab should decrease substantially.


Influence of immunosuppressants on the establishment of Paragonimus miyazakii in albino rats.
The present investigation has shown that combined treatment with dexamethasone and prednisolone of with hydrocortisone and dexamethasone enhances the susceptibility of albino rats to Paragonimus miyazakii, presumably by suppressing the host's immune responses. In the rats given these combined treatments, the size and egg production of worms were markedly increased. Use of dexamethasone or prednisolone alone had relatively little influence on the growth and maturity of P. miyazakii. In serological analysis and agar double diffusion, considerable differences were recognized between the gamma-globulin fractions and antigen-antibody systems (precipitin bands) of the treated groups and the untreated group. The mechanism of action of these immunosuppressants in this system remains obscure.


Aluminum in foci of pelvic calcification in neoplastic and nonneoplastic conditions.
Both aluminum and calcium are present in many pelvic concretions that have traditionally been attributed to calcium and phosphorus alone. There is considerable variation in both the amount and the distribution of aluminum when it is present.


Elbasvir/Grazoprevir: First Global Approval.
A fixed-dose combination tablet of the hepatitis C virus (HCV) NS5A inhibitor elbasvir and the HCV NS3/4A protease inhibitor grazoprevir (elbasvir/grazoprevir; Zepatier™) is under development by Merck. Oral elbasvir/grazoprevir 50/100 mg once daily has been approved in the USA for the treatment of adults with chronic HCV genotype 1 or 4 infection. This article summarizes the milestones in the development of elbasvir/grazoprevir leading to this first global approval for chronic HCV genotype 1 or 4 infection.


Surgery for perforated small bowel malignancy: a single institution's experience over 4 years.
Surgery for perforated small bowel malignancy is associated with dismal morbidity and mortality rates. The aim of the paper was to highlight our institution's surgical experience in the management of patients with malignant small bowel perforation. A retrospective review of all patients who underwent operative intervention for malignant small bowel perforation from 2004 to 2007 was performed. The diagnosis was confirmed upon histological evaluation. Emergency surgery was performed in seven patients with perforated small bowel malignancy during the study period. All were above 55 years old, with the majority (6/7) having an ASA score of 3 and above. Pneumoperitoneum on chest radiograph was seen in only one patient while computed tomographic scans demonstrating the pathology were performed in the rest. All patients underwent exploratory laparotomy with resection of the diseased segments within 24 h of admission. Jejunum and the ileum were the sites of perforation in six and one patients, respectively. Three patients had synchronous small bowel tumours. Two patients had stoma created due to extensive peritoneal soilage and haemodynamic instability. Lymphoma was the aetiology in four patients. The other pathologies included leiomyosarcoma (n = 1) and metastatic lung tumours (n = 2). The 30-day peri-operative mortality rate was 42.9% (n = 3). One was discharged to a hospice while another two received chemotherapy upon discharge. These three patients passed away within a year from the surgery. The last patient defaulted follow up. In our small series, patients who were admitted for perforated small bowel malignancy have a high peri-operative mortality rates. For those who survived the initially operation, the long term outlook is still dismal.


Some metabolic effects of maximal exercise in the horse and adaptations with training.
The effects of intermittent maximal exercise (galloping) before and after a 10 week training programme were studied in 6 horses. Determinations were carried out on venous blood for packed cell volume, total plasma protein, glucose, glycerol, free fatty acids, lactate, 11-hydroxycorticosteroids, blood gases and pH. There were marked changes associated with galloping and some of these could be modified with training. The major findings included (i) an elevated blood glucose, (ii) a large increase in glycerol, which was greatest at 30 min post-exercise and was higher following training, (iii) smaller increases in free fatty acids following training, (iv) higher levels of lactate after training, (v) a marked fall in pH which was less after training, (vi) an increase in 11-hydroxycorticosteroids with possibly a more rapid return to resting levels following training. It was concluded that with maximal exercise in the horse both glycogen and free fatty acids served as important substrates for working muscle, and following training greater utilisation of both these substrates occurred.


A swarm-optimizer-assisted simulation and prediction model for emerging infectious diseases based on SEIR.
Mechanism-driven models based on transmission dynamics and statistic models driven by public health data are two main methods for simulating and predicting emerging infectious diseases. In this paper, we intend to combine these two methods to develop a more comprehensive model for the simulation and prediction of emerging infectious diseases. First, we combine a standard epidemic dynamic, the susceptible-exposed-infected-recovered (SEIR) model with population migration. This model can provide a biological spread process for emerging infectious diseases. Second, to determine suitable parameters for the model, we propose a data-driven approach, in which the public health data and population migration data are assembled. Moreover, an objective function is defined to minimize the error based on these data. Third, based on the proposed model, we further develop a swarm-optimizer-assisted simulation and prediction method, which contains two modules. In the first module, we use a level-based learning swarm optimizer to optimize the parameters required in the epidemic mechanism. In the second module, the optimized parameters are used to predicate the spread of emerging infectious diseases. Finally, various experiments are conducted to validate the effectiveness of the proposed model and method.


The effects of various indwelling ureteral catheter materials on the normal canine ureter.
In an attempt to objectively evaluate the biocompatibility of materials commonly used for ureteral stenting, stent-catheters made of four different materials were placed randomly in 31 ureters of 19 mongrel dogs. Animals underwent urography at four weeks and were sacrificed at six weeks. Mild hydronephrosis was noted in eight instances, essentially unrelated to specific material. Silicone, C-flex and polyurethane stents caused a similar, mild degree of ureteral edema, but ureters stented with Silitek demonstrated fairly marked edema. Epithelial ulceration and erosion, often severe, occurred with all polyurethane stents, and rarely with the three other materials. All materials differed statistically from controls, and C-flex caused less reaction overall than polyurethane, indicating differences in biocompatibility of the various materials which may be relevant to their use in patients undergoing long-term ureteral stenting. In practical terms, these suggest that certain materials, notably silicone and C-flex, are more suitable for ureteral stenting than others.


Beneficial effects of atorvastatin on sd LDL and LDL phenotype B in statin-naive patients and patients previously treated with simvastatin or pravastatin.
The presence of increased levels of small dense (sd) LDL (phenotype B) is associated with a substantial increase of cardiovascular disease risk. Since lowering of plasma low-density lipoprotein-cholesterol (LDL-C) by statins involves an up-regulation of the LDL receptor, we questioned whether LDL lowering by atorvastatin affects different LDL subfractions equally. Fifty-four hypercholesterolemic patients, requiring treatment for prevention of coronary heart disease received atorvastatin (10, 20 or 40 mg/day), either as initial therapy (n=33), or as replacement therapy (n=21) for pravastatin or simvastatin (both at 40 mg/day). In addition to plasma lipid measurements, cholesterol LDL subfractions were separated and analysed before and after 3 months of treatment. In addition to the expected LDL-C decrease (-34%; p<0.0001), a major reduction in sd LDL occurred after atorvastatin therapy (-38.2%; p<0.0001). Interestingly, sd LDL decreased as much in patients previously treated with other statins (-36%; p<0.002). A close correlation (r=0.89, p<0.001) was found between reduction of sd LDL and that of LDL-C, in patients with phenotype B. Although high-density lipoprotein-cholesterol (HDL-C) was not affected by atorvastatin treatment, plasma triglycerides decreased by 27.4% (p<0.0001). Only a weak correlation (r=0.35, p<0.01) was found between the reduction of plasma triglycerides and the decrease of sd LDL after atorvastatin treatment. These results show that the reduction of LDL-C by atorvastatin largely reflects a lowering of sd LDL. Our data also suggest that triglyceride lowering plays only a partial role in sd LDL reduction.


Recycling of Chemical Eluent and Soil Improvement After Leaching.
Ethylenediaminetetraacetic acid disodium salt (EDTA) was selected among various eluents due to its highest removal efficiency for lead (Pb) (43.7%) and zinc (Zn) (57.1%) leaching from Pb-Zn contaminated soil by soil column experiment. Compared with newly prepared EDTA eluent, using recycled EDTA eluent can still leaching down 71.1% of Pb and 63.2% of Zn respectively, which showed the reusable benefits of recycled EDTA eluent. After soils were leached by EDTA, soil quality decline, such as reducing of urease, catalase, invertase activities and microorganism numbers. However, adding 5% nutrition soil or earthworm fertilizer can significantly improve the quality of EDTA leached soil, and promote growth of peas and ryegrass compared with EDTA treatments. Overall, the improvement of EDTA leached soil by adding nutrition soil or earthworm fertilizer is important, and recycled EDTA eluent can recycle and re-use for Pb-Zn contaminated soil remediation.


Electrophoretic mobility of high-molecular-weight, double-stranded DNA on agarose gels.
A new theoretical model for the migration of high-molecular-weight, double-stranded DNA on agarose gels is presented. This leads to the prediction that under certain conditions of electrophoresis, a linear relationship will exist between the molecular weight of a DNA molecule, raised to the (-2/3) power, and its electrophoretic mobility. Agarose gel electrophoresis of the fragments of bacteriophage lambda DNA produced by several restriction endonucleases confirms this relationship, and establishes some of the limits on its linearity. For this work, a polyacrylamide slab gel apparatus was modified for use with agarose gels. This apparatus has several advantages over others commercially available for agarose gel electrophoresis, including the abilities to run a larger number of samples at one time, to use lower-concentration gels, and to maintain better temperature stability across the width of the gel. The validation of the relationship developed here between molecular weight and electrophoretic mobility should make this a useful method for determining the molecular weights of DNA fragments.


Placental MRI.
Placental function is of fundamental importance for normal fetal growth and development. The movement of blood within the placenta ensures adequate transfer of nutrients and waste products across the feto-maternal barrier. The placenta is a relatively easy organ to study with magnetic resonance imaging (MRI) as it has a very high blood volume. MRI can be used to assess both the growth and function of the normal placenta and can distinguish differences from normal in placentas from pregnancies compromised by fetal growth restriction and pre-eclampsia.


"GIOSAT": a tool to assess CanMEDS competencies during simulated crises.
Our objective was to develop and evaluate a Generic Integrated Objective Structured Assessment Tool (GIOSAT) to integrate Medical Expert and intrinsic (non-medical expert) CanMEDS competencies with non-technical skills for crisis simulation. An assessment tool was designed and piloted using two pediatric anesthesia scenarios (laryngospasm and hyperkalemia). Following revision of the tool, we used previously recorded videos of anesthesia residents (n = 50) who managed one of two intraoperative advanced cardiac life support (ACLS) scenarios (ventricular tachycardia or ventricular fibrillation). Four independent trained raters, blinded to the residents' level of training, analyzed the video recordings using the GIOSAT scale. Inter-rater reliability was calculated using intraclass correlations (ICCs) for single raters (single measure) and the average of the four raters (average measure), and construct validity was investigated by correlating GIOSAT scores with postgraduate year of residency (PGY). Total GIOSAT scores for the ACLS scenarios had single measure ICCs of 0.62 and average measure ICCs of 0.85. Inter-rater reliability was substantial for both Medical Expert and intrinsic competencies (single measure ICCs 0.69 and 0.62, respectively; average measure ICCs 0.90 and 0.82, respectively). We found significant correlations between PGY level and total GIOSAT score (r = 0.36; P = 0.011) and between PGY level and Medical Expert competencies (r = 0.42; P = 0.003); however, correlations were not found between PGY level and intrinsic CanMEDS competencies (r = 0.24; P = 0.09). Inter-rater reliability of the total GIOSAT scores using four trained raters was substantial. Significant correlation between PGY and (i) total GIOSAT score and (ii) Medical Expert competencies supports construct validity. Evidence of validity was not obtained for intrinsic CanMEDS competencies.


Patterns of Progression After 68Ga-PSMA-Ligand PET/CT-Guided Radiation Therapy for Recurrent Prostate Cancer.
To determine the patterns of progression after 68Ga prostate-specific membrane antigen (PSMA)-ligand positron emission tomography (PET)/computed tomography (CT)-guided radiation therapy (RT) for recurrent oligometastatic prostate cancer (PCa). One hundred and eight patients with increased prostate-specific antigen levels, who received 68Ga-PSMA-ligand PET/CT-guided RT for recurrent oligometastatic disease after primary therapy for PCa were included. The biochemical progression-free survival and distant disease-free survival after PSMA-ligand PET/CT-guided RT were determined. The patterns of progression were determined using renewed 68Ga-PSMA-ligand PET/CT in patients with biochemical progression and compared with the clinical target volume of the 68Ga-PSMA-ligand PET/CT-guided RT. The frequency of infield and outfield relapses was recorded. A total of 97.2% (105 of 108) of patients showed a decrease in prostate-specific antigen levels after RT and were classified as biochemical responders. After the median follow-up of 18 months, 43.5% (47 of 108) of the patients experienced biochemical progression, resulting in an estimated biochemical progression-free survival of 16 months. Renewed 68Ga-PSMA-ligand PET/CT allowed localization of recurrent disease in 91.7% (33 of 36) of patients. Analysis of the patterns of progression resulted in a cumulative infield relapse rate of 12.1% (4 of 33) and a cumulative outfield relapse rate of 87.9% (29 of 33). The resultant median disease-free survival was 11 months. In terms of the pattern of progression, we observed a shift in the pattern of metastases toward skeletal involvement and distant lymph node metastases. Of these patients, 45.5% (15 of 33) were treated with further RT to delay initiation or escalation of systemic therapies. PSMA-ligand PET/CT-guided RT for relapsed PCa with limited tumor burden allowed individualization of treatment approaches, provided effective local control, and resulted in considerably prolonged biochemical progression-free survival. As indicated by the PSMA-ligand PET/CT-based patterns of progression, repeated PET/CT-guided RT may represent a treatment option in well-selected patients with relapse after RT for oligometastatic disease.


Activities of urea-cycle enzymes in chronic liver disease.
The activities of urea-cycle enzymes were measured in liver biopsies of patients suffering from chronic-persistent hepatitis (CPH), chronic-active hepatitis (CAH) and liver cirrhosis. Most of the activities of urea-cycle enzymes did not differ in the case of CPH as compared to controls. Chronic-active hepatitis and liver cirrhosis are associated with a significant (p less than 0.05) decrease of enzyme activity as compared to normal persons. Most of the urea-cycle enzymes are significantly decreased in patients with CAH in comparison with CPH. No significant differences can be demonstrated in the case of CAH as compared to patients with complete cirrhosis. In conclusion, progression of chronic liver disease is associated with increasing alterations of enzyme activities catalyzing a liver specific metabolic pathway. The decrease of the activities of the key enzymes of the urea cycle (Carbamylphosphate-Synthetase and Arginino-succinate-Synthetase) is nearly identical both in CAH and liver cirhosis, although CAH may be a reversible disease. Therefore, marked alterations in the metabolic pathway of ammonia detoxification seem to preceed the histological manifestation of irreversible liver damage.


Experimental and clinical monitoring of glucose by microdialysis.
The aim of this investigation was to assess the use of cerebral extracellular glucose as a parameter for microdialytic monitoring in neurosurgical critical care patients. Samples were collected from four patients with severe head injury and one with subarachnoid haemorrhage for periods of 4.5-67 h. Glucose and lactate were analysed in the dialysates. The ratios of glucose to lactate were calculated to partially allow for changes in microdialytic conditions over time. On-line pH was measured for up to 3 days in three patients. In experiments with spontaneous hypertensive rats we found that extracellular glucose became unmeasurable in the ischemic zone after middle cerebral artery occlusion. Similarly, in 3 patients glucose became undetectable for several hours, and glucose/lactate tended to decrease during measurement. This was accompanied by high ICP in one patient, and by a hypoxic episode in another. In the two other patients glucose/lactate ratios showed a rising trend. Findings indicate that glucose, and the glucose/lactate ratio show some correlations with clinical course and are promising parameters for cerebral monitoring and therapeutic decision making.


Cerebral Regional Tissue Oxygenation as Surrogate for Blood Loss in Nonhuman Primate Models of Shock.
Hemorrhage is the leading cause of preventable death, with a majority of mortalities in the prehospital setting. Current hemorrhage resuscitation guidelines cannot predict the critical point of intervention to activate massive transfusion (MT) and prevent cardiovascular decompensation. We hypothesized that cerebral regional tissue oxygenation (CrSO2) would indicate MT need in nonhuman primate models of hemorrhagic shock. Nineteen anesthetized male rhesus macaques underwent hemorrhage via a volume-targeted (VT) or pressure-targeted (PT) method. VT animals were monitored for 30 min following 30% blood volume hemorrhage. PT animals were hemorrhaged to mean arterial pressure (MAP) of 20 mmHg and maintained for at least 60 min until decompensation. Statistics for MAP, heart rate (HR), end tidal carbon dioxide (EtCO2), and CrSO2 were analyzed via one- or two-way repeated-measures analysis of variance, Pearson's R, and receiver-operator curve. A P < 0.05 is considered significant. Following initial hemorrhage (S0), there were no significant differences between groups. After cessation of hemorrhage in the VT group, MAP and EtCO2 returned to baseline while CrSO2 plateaued. The PT group maintained model-defined low MAP, suppressing EtCO2, and significantly decreased CrSO2 compared to the VT group by S25. Linear regression of CrSO2versus shed blood volume demonstrated R2 = 0.7539. CrSO2 of 47% was able to detect >40% blood loss with an area under the curve of 0.9834 at 92.3% (66.7%-99.6%) sensitivity and 95.5% (84.9%-99.2%) specificity. Regardless of hemorrhage modality and compensatory response, CrSO2 correlated strongly with shed blood volume. Analysis demonstrated that CrSO2 values below 49% indicate Advanced Trauma Life Support class IV shock (blood loss>40%). CrSO2 at the point of care may help indicate MT need earlier and more accurately than traditional markers.


A tale of two lineages: how the strains of the earliest divergent symbiotic Frankia clade spread over the world.
It is currently assumed that around 100 million years ago, the common ancestor to the Fabales, Fagales, Rosales and Cucurbitales in Gondwana, developed a root nodule symbiosis with a nitrogen-fixing bacterium. The symbiotic trait evolved first in Frankia cluster-2; thus, strains belonging to this cluster are the best extant representatives of this original symbiont. Most cluster-2 strains could not be cultured to date, except for Frankia coriariae, and therefore many aspects of the symbiosis are still elusive. Based on phylogenetics of cluster-2 metagenome-assembled genomes (MAGs), it has been shown that the genomes of strains originating in Eurasia are highly conserved. These MAGs are more closely related to Frankia cluster-2 in North America than to the single genome available thus far from the southern hemisphere, i.e., from Papua New Guinea.To unravel more biodiversity within Frankia cluster-2 and predict routes of dispersal from Gondwana, we sequenced and analysed the MAGs of Frankia cluster-2 from Coriaria japonica and Coriaria intermedia growing in Japan, Taiwan and the Philippines. Phylogenetic analyses indicate there is a clear split within Frankia cluster-2, separating a continental from an island lineage. Presumably, these lineages already diverged in Gondwana.Based on fossil data on the host plants, we propose that these two lineages dispersed via at least two routes. While the continental lineage reached Eurasia together with their host plants via the Indian subcontinent, the island lineage spread towards Japan with an unknown host plant.


Alterations in the organisation of cytokeratin filaments in normal and malignant human colonic epithelial cells during mitosis.
An ultrastructural analysis of the organisation of 10 nm intermediate filaments during mitosis, in normal and malignant human colonic epithelial cells present in resected material, was carried out. Similar changes in the integrity of the 10 nm filaments were seen both in normal mitotic cells (which have a highly specialised filamentous network during interphase), and malignant cells (which show a disorganised network during interphase). The 10 nm filaments were seen to shorten and 'fray' in early mitosis. This was associated with the formation of spheroidal aggregates of thin filaments and small granules, both free in the cytoplasm and associated with surface desmosomes. At mid-mitosis cells were essentially devoid of obvious filamentous material, (including the spheroidal aggregates). The filaments reformed in daughter cells after cytokinesis was completed.


Pilot Study to Investigate Enteral Feeding Practices and the Incidence of Underfeeding Among Mechanically Ventilated Critically Ill Patients at a Specialist Tertiary Care Hospital in Saudi Arabia.
Enteral nutrition (EN) is an essential therapeutic intervention. Many studies internationally have reviewed feeding practices in intensive care units (ICUs) and recorded the incidence of underfeeding in these settings, yet none were performed in the Middle East, including Saudi Arabia. The purpose of the study is to assess the adequacy of EN delivery and investigate the enteral feeding practices in the ICU at a specialized tertiary care hospital in Saudi Arabia. In this observational study, we prospectively monitored energy and protein delivery for 6 consecutive days in critically ill patients. Malnutrition was assessed by Nutrition Risk Screening (NRS-2002) scores. Underfeeding was identified by comparing the intake against the calculated requirements. Patients were categorized into early and late EN starters to investigate whether the time of EN initiation impacts the cumulative nutrition intake. This study included 43 patients. About 44% (19 of 43) of the patients were malnourished on admission to ICU, and the prevalence of underfeeding was >90%. The median cumulative intake of energy and protein was 39% and 31% of the estimated requirements, respectively. Patients who started early EN had statistically higher cumulative energy and protein intake (P-value = .00). Patients treated with inotropes received less energy and protein compared with those who did not receive inotropes (P-value = .00). Higher NRS-2002 score was associated with fewer ventilation-free hours (r = -0.369, P-value = .045). Protein underfeeding remains a significant problem in ICU settings. The time of EN initiation plays a major role in determining when the nutrition requirements will be met. Therefore, it is crucial to implement effective feeding protocols to ensure early initiation of EN when permissible.


Theoretical, computer-assisted prediction versus SRK prediction of postoperative refraction after intraocular lens implantation.
The postoperative refraction prediction was evaluated in 99 patients with a 19.0-diopter standard power anterior chamber lens using a theoretical, computer-assisted method based on Gaussian optics and an empirical intraocular lens calculation method based on the SRK formula. Both the theoretical and the empirical predictions accorded with the observed values in the near emmetropia region. In the prediction of ametropia, the SRK method showed a tendency to predict refractions that were lower than the actual values in hyperopic eyes and higher than the actual values in myopic eyes. The bias of the SRK method may be due to the use of an erroneous refraction factor that converts the ametropia to the deviation in implant power from the emmetropia power. By introducing an individual refraction factor, the accuracy of the SRK method approached that of the theoretical method.


Proprioceptive feedback contributes to the adaptation toward an economical gait pattern.
Humans generally prefer gait patterns with a low metabolic cost, but it is unclear how such patterns are chosen. We have previously proposed that humans may use proprioceptive feedback to identify economical movement patterns. The purpose of the present experiments was to investigate the role of plantarflexor proprioception in the adaptation toward an economical gait pattern. To disrupt proprioception in some trials, we applied noisy vibration (randomly varying between 40-120Hz) over the bilateral Achilles tendons while participants stood quietly or walked on a treadmill. For all 10min walking trials, the treadmill surface was initially level before slowly increasing to a 2.5% incline midway through the trial without participant knowledge. During standing posture, noisy vibration increased sway, indicating decreased proprioception accuracy. While walking on a level surface, vibration did not significantly influence stride period or metabolic rate. However, vibration had clear effects for the first 2-3min after the incline increase; vibration caused participants to walk with shorter stride periods, reduced medial gastrocnemius (MG) activity during mid-stance (30-65% stance), and increased MG activity during late-stance (65-100% stance). Over time, these metrics gradually converged toward the gait pattern without vibration. Likely as a result of this delayed adaptation to the new mechanical context, the metabolic rate when walking uphill was significantly higher in the presence of noisy vibration. These results may be explained by the disruption of proprioception preventing rapid identification of muscle activation patterns which allow the muscles to operate under favorable mechanical conditions with low metabolic demand.


Successful Treatment of Keratosis Pilaris Rubra with Pulsed Dye Laser.
Keratosis pilaris rubra is a common but rarely reported condition characterized by follicular-based hyperkeratotic papules on a background of erythema. It can be embarrassing and symptomatic for patients, particularly adolescent boys. We sought to explore the efficacy of pulsed dye laser (PDL) in the treatment of keratosis pilaris rubra. Eight patients were treated with PDL for keratosis pilaris rubra. All patients reported noticeable improvement after one to four treatments. PDL is an effective, easily accessible, and underused therapy in the treatment of keratosis pilaris rubra.


Mice expressing a human K(ATP) channel mutation have altered channel ATP sensitivity but no cardiac abnormalities.
Patients with severe gain-of-function mutations in the Kir6.2 subunit of the ATP-sensitive potassium (K(ATP)) channel, have neonatal diabetes, muscle hypotonia and mental and motor developmental delay-a condition known as iDEND syndrome. However, despite the fact that Kir6.2 forms the pore of the cardiac K(ATP) channel, patients show no obvious cardiac symptoms. The aim of this project was to use a mouse model of iDEND syndrome to determine whether iDEND mutations affect cardiac function and cardiac K(ATP) channel ATP sensitivity. We performed patch-clamp and in vivo cine-MRI studies on mice in which the most common iDEND mutation (Kir6.2-V59M) was targeted to cardiac muscle using Cre-lox technology (m-V59M mice). Patch-clamp studies of isolated cardiac myocytes revealed a markedly reduced K(ATP) channel sensitivity to MgATP inhibition in m-V59M mice (IC(50) 62 μmol/l compared with 13 μmol/l for littermate controls). In vivo cine-MRI revealed there were no gross morphological differences and no differences in heart rate, end diastolic volume, end systolic volume, stroke volume, ejection fraction, cardiac output or wall thickening between m-V59M and control hearts, either under resting conditions or under dobutamine stress. The common iDEND mutation Kir6.2-V59M decreases ATP block of cardiac K(ATP) channels but was without obvious effect on heart function, suggesting that metabolic changes fail to open the mutated channel to an extent that affects function (at least in the absence of ischaemia). This may have implications for the choice of sulfonylurea used to treat neonatal diabetes.


Conservative and divergent base sequence regions in the maxicircle kinetoplast DNA of several trypanosomatid flagellates.
The structure of kinetoplast maxicircle DNA from trypanosomatids Crithidia oncopelti, C. luciliae, Leptomonas pessoai and Leishmania gymnodactyli was compared by the blot hybridization method. The sizes of these molecules are 24.5, 34, 31 and 38 kilobase pairs (kbp), respectively. Labelled maxicircle fragments from C. oncopelti were used as probes. A general model of the structural organization of maxicircles is proposed according to which this molecule is composed of a 17kbp conservative region and a divergent one occupying the rest of the molecule. The conservative region contains the sequences homologous to those in all trypanosomatids. The sequence of the divergent region exhibits no cross homology detectable by high stringency hybridization. The main size differences between the maxicircle molecules from different trypanosomatid species are explained by the length variability of their divergent regions.


Identification and analysis of divergent immune gene families within the Tasmanian devil genome.
The Tasmanian devil (Sarcophilus harrisii) is being threatened with extinction in the wild by a disease known as devil facial tumour disease (DFTD). In order to prevent the spread of this disease a thorough understanding of the Tasmanian devil immune system and its response to the disease is required. In 2011 and 2012 two genome sequencing projects of the Tasmania devil were released. This has provided us with the raw data required to begin to investigate the Tasmanian devil immunome in depth. In this study we characterise immune gene families of the Tasmanian devil. We focus on immunoglobulins, T cell receptors and cytokine families. We identify and describe 119 cytokines including 40 interleukins, 39 chemokines, 8 interferons, 18 tumour necrosis family cytokines and 14 additional cytokines. Constant regions for immunoglobulins and T cell receptors were also identified. The repertoire of genes in these families was similar to the opossum, however devil specific duplications were seen and orthologs to eutherian genes not previously identified in any marsupial were also identified. By using multiple data sources as well as targeted search methods, highly divergent genes across the Tasmanian devil immune system were identified and characterised. This understanding will allow for the development of devil specific assays and reagents and allow for future studies into the immune response of the Tasmanian devil immune system to DFTD.


The importance of serum LMAN2 level in septic shock and prognosis prediction in sepsis patients.
To study the importance of LMAN2 in septic shock and prognosis prediction in sepsis patients. Serum LMAN2 was measured by ELISA in 109 sepsis patients within 24 h after their admission to ICU. We also collected clinical and laboratory variables. Compared with sepsis group (1.21 (1.05) ng/ml), serum LMAN2 level was significantly higher in patients with septic shock (1.75 (2.04) ng/ml) on the day of admission to the ICU (P < 0.001), and serum LMAN2 level were significantly higher in the sepsis non-survival group (1.91 (1.66) ng/ml) than in the survival group (1.15 (1.17) ng/ml). COX regression analysis showed that high serum LMAN2 level (>1.28 ng/ml) was a predictor of 28-day mortality in sepsis patients. This study shows that high serum LMAN2 level may indicate septic shock and is associated with an unfavorable prognosis for sepsis patients.


Aphasia and right hemiplegia after cervical myelography with metrizamide. A case report.
We report a case of aphasia and right hemiplegia, developing after myelography with metrizamide and lasting for an unusually long time. The neurological disorders, manifested 1 h after the examination was completed, were due to accidental passage of contrast medium into the basal cisterns. In the light of analogous case reports in the literature, as well as experimental data concerning the biochemical activity of metrizamide, possible aetiopathogenetic mechanisms responsible for such disturbances are indicated. The authors underline the lack of effective therapeutic measures after the onset of the disorders, and thus the importance of preventing such complications that behave functionally as true ictuses although with no anatomic substratum.


Recurrence of disease after liver transplantation.
Over the past decade, we have seen an increased number of patients living more than 20 years with their liver grafts. In turn, we are gaining more experience with recurrence of the original disease. Disease recurrence can be divided into 4 main groups: (1) malignant disease, (2) viral disease, (3) autoimmune diseases like primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSO), and finally (4) researched lifestyle that caused the original disease, eg, obesity causing nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or alcoholic liver disease (ALD). This overview reports follow up, diagnosis, and treatment of recurrences.


In situ demonstration of the activity of 3 beta-hydroxysteroid dehydrogenase on steroid hormone secreting cells within the paraaortic lymph nodes of golden hamster.
The in situ activity of 3 beta-hydroxysteroid dehydrogenase was detected in clustered cells which showed steroid-producing morphology, within the capsule of the paraaortic lymph node. In light and electron microscopic studies, the positive reaction products were detected on intracapsular cell clusters. This result indicates that these unique cells may have a steroid secreting function within the lymph nodes.


Biochemical and biophysical characterization of the smallest pyruvate kinase from Entamoeba histolytica.
Entamoeba histolytica infection is highly prevalent in developing countries across the globe. The ATP synthesis in this pathogen is solely dependent on the glycolysis pathway where pyruvate kinase (Pyk) catalyzes the final reaction. Here, we have cloned, overexpressed and purified the pyruvate kinase (EhPyk) from E. histolytica. EhPyk is the shortest currently known Pyk till date as it contains only two of the three characterized domains when compared to the other homologues and our phylogenetic analysis places it on a distinct branch from the known type I/II Pyks. Our purification results suggested that it exists as a homodimer in solution. The kinetic characterization showed that EhPyk has maximum activity at pH 7.5 where it exhibited Michaelis-Menten's kinetics for phosphoenolpyruvate with a Km of 0.23 mM, and it lost its activity at both the acidic pH 4.0 and basic pH 10.0. We also determined the key secondary structural elements of EhPyk at different pH values. MD simulation of EhPyk structure at different pH values suggested that it is most stable at pH 7.0, while least stable at pH 10.0 followed by pH 4.0. Together, our computational simulations correlate well with the experimental studies. In summary, this study expands the current understanding of the EhPyk identified earlier in the amoebic genome and provides the first characterization of this bacterially expressed protein.


Doxorubicin-liposome combined with clodronate-liposome inhibits hepatocellular carcinoma through the depletion of macrophages and tumor cells.
Macrophages in the liver have capacities of capturing and phagocytosing nanocarriers. Macrophages also play an important role in the inflammatory microenvironment and in the tumorigenesis, development and progression of hepatocellular carcinoma (HCC). Several studies have shown that depletion of macrophages is a viable strategy for drug delivery and tumor microenvironment regulation. We prepared liposomes containing doxorubicin and clodronate using an ammonium sulfate gradient and thin film hydration method. The repressive therapeutic effects of liposomes were compared by intrasplenic injection at different stages of a primary HCC model induced by diethylnitrosamine (DEN) in rats. Doxorubicin-liposome (DOX-LIP) and clodronate-liposome (CL-LIP) about 180-200 nm were successfully prepared and characterized. We found that DOX-LIP combined with CL-LIP could effectively inhibit the occurrence and development of liver cancer without major organ damage and side effects. The combination of doxorubicin and clodronate liposomes notably decreased hepatic CD68 + macrophages, enriched DOX in plasma and accumulated it for a long time in the liver and spleen, thus improving the tumor microenvironment, inhibiting the activation of hepatic progenitor cells (HPCs) and promoting the apoptosis of tumor cells, and finally producing the inhibitory and therapeutic effects of HCC in rats. Results of this study were expected to provide a new prospect for the chemotherapy of HCC.


Low pangolin consumption in Hong Kong pre- and post- the COVID-19 outbreak: Conservation and health concerns both contribute to people's attitudes.
Pangolins have recently received significant media attention globally as the trade for their scales and meat is driving many species closer to extinction. As a result of this, there have been increased legal regulations placed on pangolin trade in recent years. The suggestion that pangolins may have been involved in the transmission of COVID-19 further brought the issues of pangolin consumption to the fore in 2020. However, we have little understanding of the attitudes of the general public towards pangolin consumption pre- or post the outbreak of COVID-19. We conducted surveys in Hong Kong, a critical transit hub in the trafficking routes for pangolins, in 2015 (n = 1037) and 2020 (n = 1028) to determine general attitudes towards pangolin consumption in the city, and whether these attitudes changed since the onset of COVID-19. We found low reported rates of pangolin consumption (< 1% of respondents) in both surveys, and most of the respondents who professed to eating pangolins were aged above 50. Perceptions of how trends in pangolin consumption are changing were consistent between 2015 and 2020, with 55% of the public in 2015 and 57% in 2020 believing that consumption has declined over time. In 2020, respondents cited conservation (endangered status of pangolins) and health concerns (risk of disease transmission) as the two primary reasons (> 50%) for declining attitudes toward consumption. Overall, COVID-19 does not, specifically, appear to be associated with changed perceptions of pangolin consumption in Hong Kong: > 75% of respondents stated that there is no relationship between pangolins and COVID-19, or were unsure about any such connection. Only 1% mentioned an awareness of the illegality of pangolin consumption as a reason for not consuming them. As such, our results challenge simple narratives regarding the impact of COVID-19 on pangolin consumption. We suggest that future demand reduction efforts could emphasize the conservation impact and health risks of consuming pangolins, and specifically focus on the older generations. As pangolins continue to be trafficked and threatened with extinction, further research into the perceptions and attitudes of consumers of these products is needed to inform targeted and effective interventions.


Diagnostic yield of inpatient video-electroencephalographic monitoring: experience from a Chinese comprehensive epilepsy center.
Video-electroencephalographic monitoring (VEEG) is useful in the diagnosis of seizure disorders; however, its diagnostic yield in developing countries is not well known. The current study retrospectively reviewed the charts of 484 consecutive patients who were admitted to our center between July 2012 and September 2013. Of these patients, 298 (61.6%) were admitted for diagnostic clarification and underwent VEEG for a mean duration of 1.3days (range=1-9days). The patients were divided into two groups: those whose diagnosis was changed and those whose diagnosis was not changed as a result of VEEG. A patient with a preadmission diagnosis of epilepsy who was discharged with a diagnosis of nonepileptic events (NEEs) or who was further classified as focal/generalized epilepsy on discharge was included in the "change in diagnosis" group. A patient admitted with an uncertain diagnosis and discharged with a diagnosis of NEEs or epilepsy (including focal epilepsy and generalized epilepsy) was also included in the "change in diagnosis" group. Video-electroencephalographic monitoring recorded typical ictal events (epileptic events or nonepileptic events) in 147 (49.3%) of the patients admitted for diagnostic clarification. In total, 181 (60.7%) patients had a change in diagnosis after VEEG. Among them, 103 (56.9%) patients had a preadmission diagnosis of epilepsy, which was further classified as focal epilepsy (88 patients) or generalized epilepsy (15 patients); the diagnosis of NEEs and epilepsy was clarified in 78 (43.1%) patients. The number of patients diagnosed with NEEs increased from 31 (10.4%) on admission to 88 (29.5%) on discharge. Among all the patients admitted for diagnostic clarification, therapeutic plans were changed for 104 (57.5%) patients. In 117 (39.3%) patients with no diagnostic change, VEEG evaluation provided confirmative diagnostic information in 47 (15.8%) patients and no additional diagnostic information in 70 (23.5%) patients. The study indicates that VEEG is useful in terms of clarifying seizure diagnoses and evaluating seizure frequency. In our cohort study, VEEG of a relatively short mean duration produced a comparable diagnostic yield as that reported in other studies.


The Role of Cytokines, Chemokines, and Growth Factors in the Pathogenesis of Pityriasis Rosea.
Pityriasis rosea (PR) is an exanthematous disease related to human herpesvirus- (HHV-) 6/7 reactivation. The network of mediators involved in recruiting the infiltrating inflammatory cells has never been studied. Object. To investigate the levels of serum cytokines, growth factors, and chemokines in PR and healthy controls in order to elucidate the PR pathogenesis. Interleukin- (IL-) 1, IL-6, IL-17, interferon- (IFN-) γ, tumor necrosis factor- (TNF-) α, vascular endothelial growth factor (VEGF), granulocyte colony stimulating factor (G-CSF), and chemokines, CXCL8 (IL-8) and CXCL10 (IP-10), were measured simultaneously by a multiplex assay in early acute PR patients' sera and healthy controls. Subsequently, sera from PR patients were analysed at 3 different times (0, 15, and 30 days). Serum levels of IL-17, IFN-γ, VEGF, and IP-10 resulted to be upregulated in PR patients compared to controls. IL-17 has a key role in host defense against pathogens stimulating the release of proinflammatory cytokines/chemokines. IFN-γ has a direct antiviral activity promoting NK cells and virus specific T cells cytotoxicity. VEGF stimulates vasculogenesis and angiogenesis. IP-10 can induce chemotaxis, apoptosis, cell growth, and angiogenesis. Our findings suggest that these inflammatory mediators may modulate PR pathogenesis in synergistic manner.


Spatiotemporal patterns and determinants of dengue at county level in China from 2005-2017.
To identify the high risk spatiotemporal clusters of dengue cases and explore the associated risk factors. Monthly indigenous dengue cases in 2005-2017 were aggregated at county level. Spatiotemporal cluster analysis was used to explore dengue distribution features using SaTScan9.4.4 and Arcgis10.3.0. In addition, the influential factors and potential high risk areas of dengue outbreaks were analyzed using ecological niche models in Maxent 3.3.1 software. We found a heterogeneous spatial and temporal distribution pattern of dengue cases. The identified high risk region in the primary cluster covered 13 counties in Guangdong Province and in the secondary clusters included 14 counties in Yunnan Province. Additionally, there was a nonlinear association between meteorological and environmental factors and dengue outbreaks, with 8.5%-57.1%, 6.7%-38.3% and 3.2%-40.4% contribution from annual average minimum temperature, land cover and annual average precipitation, respectively. The high risk areas of dengue outbreaks mainly are located in Guangdong and Yunnan Provinces, which are significantly shaped by environmental and meteorological factors, such as temperature, precipitation and land cover.


Longitudinal Effects of a sit-stand desk intervention - persistence, Fade-Out, and psychological momentum: a Randomized Controlled Trial.
This study examined whether the effects of a sit-stand desk (SSD) intervention on employees' musculoskeletal complaints (i.e., intensity and prevalence) and activation (i.e., vigilance and vitality) persist or fade out and whether velocity and acceleration of health improvements can predict medium-term (six-month) and long-term (24-month) improvements. Drawing from dynamic models of self-regulation, as well as the psychological momentum theory, we hypothesized that velocity and acceleration of health improvements in the early stages of the intervention would predict medium-term health improvements, which sustain long-term. We used data from a six-month seven-wave randomized controlled trial with employees in mostly sedentary occupations and supplemented this by follow-up data from the same participants 18 months later, resulting in eight waves. Bayesian structural equational modeling revealed no significant intervention effect after 24 months implying a fade-out. But more importantly, velocity and, partially, acceleration of health improvements at earlier stages predicted medium-term improvements in musculoskeletal complaints and long-term improvements in vigilance. The findings of this study suggest that positive intervention effects fade out over time and health effects benefit from prompt progresses at the beginning of the intervention, warranting exploration in prolonged longitudinal studies.


Psychiatric diagnosis and intervention in older and younger patients in a primary care clinic: effect of a screening and diagnostic instrument.
To determine whether patient age is associated with psychiatric diagnosis or provider intervention in a busy primary care clinic, and, if so, whether a screening and diagnostic tool, the PRIME-MD, modifies age-related differences. PRIME-MD use, psychiatric diagnosis, and provider interventions for psychiatric conditions were recorded for eligible patients attending a Veterans Affairs Medical Center primary care clinic. Data from 952 younger (<65 years) and 1135 older patients (> or =65 years) were analyzed to determine whether there were age-related differences in diagnosis/intervention and if use of the PRIME-MD modified these differences. Implementation of the PRIME-MD, a two-step instrument consisting of a self-administered patient questionnaire and a provider-administered structured diagnostic interview. Outcome measures were rates of (1) PRIME-MD use, (2) overall psychiatric diagnosis, (3) new psychiatric diagnosis, and (4) provider intervention for psychiatric conditions. There was no association between patient age and PRIME-MD use. Older patients were less likely to receive a psychiatric diagnosis in analyses that adjusted for "highly positive" screening questionnaires (OR = .45; P<.001). Older patients were also less likely to receive an intervention for a psychiatric condition in analyses that adjusted for whether a psychiatric diagnosis (OR = .62, P = .015) or a new psychiatric diagnosis (OR = .36, P<.001) was made during the study visit. The PRIME-MD increased rates of diagnosis and intervention but did not alter age-related disparities. Decreased rates of psychiatric diagnosis and intervention in older primary care patients are of concern. Implementing the PRIME-MD will likely increase rates of diagnosis and intervention but will need to be accompanied by additional measures to eliminate age-related disparities.


Enhancing Prefrontal Neuron Activity Enables Associative Learning of Temporally Disparate Events.
The ability to link events that are separated in time is important for extracting meaning from experiences and guiding behavior in the future. This ability likely requires the brain to continue representing events even after they have passed, a process that may involve the prefrontal cortex and takes the form of sustained, event-specific neuron activity. Here, we show that experimentally increasing the activity of excitatory neurons in the medial prefrontal cortex (mPFC) enables rats to associate two stimuli separated by a 750-ms long temporal gap. Learning is accompanied by ramping increases in prefrontal theta and beta rhythms during the interval between stimuli. This ramping activity predicts memory-related behavioral responses on a trial-by-trial basis but is not correlated with the same muscular activity during non-memory conditions. Thus, the enhancement of prefrontal neuron excitability extends the time course of evoked prefrontal network activation and facilitates the formation of associations of temporally disparate, but correlated, events.


Foot and ankle fractures in dancers.
Fractures in the dance population are common. Radiography, CT, MRI, and bone scan should be used as necessary to arrive at the correct diagnosis after meticulous physical examination. Treatment should address the fracture itself and any surrounding problems such as nutritional/hormonal issues and training/performance techniques and regimens. Compliance issues in this population are a concern, so treatment strategies should be tailored accordingly. Stress fractures in particular can present difficulties to the treating physician and may require prolonged treatment periods. This article addresses stress fractures of the fibula, calcaneus, navicular, and second metatarsal; fractures of the fifth metatarsal, sesamoids, and phalanges; and dislocation of toes.


Distribution of TRPC1 and TRPC5 in medial temporal lobe structures of mice.
The transient receptor potential (TRP) superfamily comprises a group of non-selective cation channels that have been implicated in both receptor and store-operated channel functions. The family of the classical TRPs (TRPCs) consists of seven members (TRPC1-7). The presence of TRPC1 and TRPC5 mRNA in the brain has previously been demonstrated by real-time polymerase chain reaction. However, the distribution of these receptors within different brain areas of mice has not been investigated in detail. We have used antibodies directed against TRPC1 and TRPC5 to study the distribution and localization of these channels in murine medial temporal lobe structures. Both TRPC1 and TRPC5 channels are present in the various nuclei of the amygdala, in the hippocampus, and in the subiculum and the entorhinal cortex. We have found that TRPC1 channels are primarily expressed on cell somata and on dendrites, whereas TRPC5 channels are exclusively located on cell bodies. Moreover, TRPC1 channels are selectively expressed by neurons, whereas TRPC5 channels are mainly expressed by neurons, but also by non-neuronal cells. The expression of TRPC1 and TRPC5 channels in mammalian temporal lobe structures suggests their involvement in neuronal plasticity, learning and memory.


Purine and phosphoribosylpyrophosphate metabolism of lymphocytes and erythrocytes of an adenosine deaminase deficient immunocompetent child.
Purine metabolism and phosphoribosylpyrophosphate content of lymphocytes and erythrocytes were studied in an immunocompetent black male child with a total deficiency of erythrocyte and partial deficiency of lymphocyte adenosine deaminase. The partial genetic deficiency of adenosine deaminase was demonstrated in intact lymphocytes, and was approximately one third of the deaminating activity of control lymphocytes. Intact lymphocytes of the patient did not incorporate adenosine at a faster rate than those of control lymphocytes. The patient's erythrocytes deaminating activity was low and adenine ribonucleotide synthesis from adenosine was increased several fold, while adenine incorporation into purine ribonucleotides was comparable to that of control erythrocytes. Transfusion with packed erythrocytes temporarily improved the deaminating capacity of circulating erythrocytes, but did not reduce the elevated incorporation of adenosine into purine ribonucleotides. Phosphoribosylpyrophosphate content of the patient's lymphocytes and erythrocytes was not diminished. Incubation of erythrocytes with adenosine lowered phosphoribosylpyrophosphate content while incubation with phosphate increased phosphoribosylpyrophosphate content to the same extent in mutant and control erythrocytes.


Complete zona pellucida removal from vitrified-warmed human blastocysts facilitates earlier in-vitro attachment and outgrowth.
Partial removal of the zona pellucida (ZP) has been performed using a laser system to promote hatching of vitrified-warmed blastocysts. However, low-viability blastocysts cannot hatch even after partial ZP removal. This study examined whether complete removal of the ZP improves embryonic adhesion and outgrowth of vitrified-warmed blastocysts compared with partial removal, using a blastocyst outgrowth model. In all, 217 vitrified human blastocysts, which were discarded and donated for research by consenting couples, were warmed and subjected to assisted hatching to remove the ZP partially or completely, or did not undergo assisted hatching (zona intact controls). Blastocysts were cultured using time-lapse microscopy to monitor hatching, adhesion and outgrowth. Despite partial ZP removal, 36% of blastocysts failed to hatch. Blastocyst outgrowth assays showed improved adhesion rate, shorter time for adhesion and larger outgrowth area in the blastocysts with completely removed ZP compared with those with partially-removed ZP. mRNA expression of integrin α5 and β1 was upregulated in blastocysts with completely removed ZP compared with those with partially-removed ZP. Study findings reveal the advantages of complete ZP removal for assisted hatching. In conclusion, complete ZP removal increases the chance of blastocyst adhesion and subsequent outgrowth in vitro after the vitrification-warming procedure.


Prevalence of amyotrophic lateral sclerosis in Latium region, Italy.
Prevalence estimate of amyotrophic lateral sclerosis (ALS) ranged between 1.1/100,000 and 11.2/100,000 inhabitants with different design of the study (prospective or retrospective) and sample size. The aim of this study is to conduct for the first time an estimate of the ALS prevalence in the Latium region. The study was performed in Latium, a region located in the center of Italy, with a population, as of January 1, 2016, of 5888.472 inhabitants. In this region, a network of 15 clinical centers (of which 4 referral ALS centers are located in Rome) and 10 local health authorities involved in the diagnosis and treatment of ALS patients has been identified. Each patient was classified according to the El Escorial revised criteria. The prevalence study in 2016 identified 353 ALS cases (200 males). By considering population aged >=20 years, the total crude prevalence rate resulted 7.33 (CI95% 6.59-8.14) × 100,000 and 8.75 and 6.05 in males and females, respectively. Age-specific prevalence rates did not differ among males and females in the population aged less than 49 years. The difference emerged in population aged > 50 years. This type of diagnosis was recorded for 343 patients (11 missing). 68% of these patients have a definite diagnosis, 14% likely, 11% possible, and 12% defined as suspect. The estimate of prevalence rates observed in this study is probably in line with the values reported in the literature for prospective prevalence studies.


Epigenetic regulation of mesenchymal stem cell aging through histone modifications.
Stem cell senescence and exhaustion, a hallmark of aging, lead to declines in tissue repair and regeneration in aged individuals. Emerging evidence has revealed that epigenetic regulation plays critical roles in the self-renew, lineage-commitment, survival, and function of stem cells. Moreover, epigenetic alterations are considered important drivers of stem cell dysfunction during aging. In this review, we focused on current knowledge of the histone modifications in the aging of mesenchymal stem cells (MSCs). The aberrant epigenetic modifications on histones, including methylation and acetylation, have been found in aging MSCs. By disturbing the expression of specific genes, these epigenetic modifications affect the self-renew, survival, and differentiation of MSCs. A set of epigenetic enzymes that write or erase these modifications are critical in regulating the aging of MSCs. Furthermore, we discussed the rejuvenation strategies based on epigenetics to prevent stem cell aging and/or rejuvenate senescent MSCs.


Sarcoidosis in Patients Treated with Vemurafenib for Metastatic Melanoma: A Paradoxical Autoimmune Activation.
Vemurafenib, a BRAF inhibitor, is a first-line treatment for inoperable melanoma. Sarcoidosis has never been reported in patients on vemurafenib. We describe 5 cases of sarcoidosis in patients treated with vemurafenib. Seventy patients receiving vemurafenib for a BRAF-mutated inoperable stage III or IV melanoma were treated in our centre. Five patients (7.1%) developed sarcoidosis or a sarcoid-like reaction on vemurafenib; 4 patients had cutaneous signs and 3 had extracutaneous disorders (bilateral hilar lymph nodes, uveitis). Histological analysis of skin lesions revealed epithelioid granulomas without necrosis, consistent with sarcoidosis. Angiotensin-converting enzyme levels were high in 2 patients. Cutaneous and ophthalmological lesions rapidly disappeared on topical corticosteroid treatment without the cessation of vemurafenib treatment. Complete remission of melanoma was observed in 3 patients and partial remission was observed in another. BRAF inhibitors probably have immune system-enhancing effects and should therefore be recognized as potential inducers of sarcoidosis.


Identifying physical and psychological risk factors for musculoskeletal pain in student musicians to tailor the curriculum: a cross-sectional study protocol.
Insufficient identification and understanding of risk factors make musicians engaging in professional practice particularly vulnerable to musculoskeletal pain. To support positive music learning and good mental, physical, and social health, student musicians need health support tailored to their needs and their instrumental practice. However, these preventive actions must be based on sound scientific approaches that reliably identify the most relevant risk factors. MuSa is a cross-sectional study examining contextual and internal risk variables associated with playing-related musculoskeletal disorders in student musicians. The design is a monocentric cross-sectional study involving student musicians in Bachelor's 1, 2, 3 and Master's 1, 2. Free-form questions will identify students' lifestyle characteristics and work habits, and validated questionnaires will evaluate the interaction between pain due to music practice and psychological and physical risk factors. All data will first be analysed descriptively. Psychological network analysis will be used to explore the overall correlational structure of the dataset. A subgroup comparative analysis will be then applied according to the instrumental subcategories and work postures, including singers. The full protocol was approved by the Swiss Ethics Committee 'Commission Cantonale d'Ethique de la Recherche sur l'être humain de Genève' (CCER, no. 2022-02206) on 13 February 2023. Outcomes will be disseminated through publication in peer-reviewed journals and presentations at conferences.


Repeated applications of fipronil, propyzamide and flutriafol affect soil microbial functions and community composition: A laboratory-to-field assessment.
Pesticides play an important role in conventional agriculture by controlling pests, weeds, and plant diseases. However, repeated applications of pesticides may have long lasting effects on non-target microorganisms. Most studies have investigated the short-term effects of pesticides on soil microbial communities at the laboratory scale. Here, we assessed the ecotoxicological impact of fipronil (insecticide), propyzamide (herbicide) and flutriafol (fungicide) on (i) soil microbial enzymatic activities, (ii) potential nitrification, (iii) abundance of the fungal and bacterial community and key functional genes (nifH, amoA, chiA, cbhl and phosphatase) and (iii) diversity of bacteria, fungi, ammonia oxidizing bacteria (AOB) and archaea (AOA) after repeated pesticide applications in laboratory and field experiments. Our results showed that repeated applications of propyzamide and flutriafol affected the soil microbial community structure in the field and had significant inhibitory effects on enzymatic activities. The abundances of soil microbiota affected by pesticides recovered to levels similar to the control following a second application, suggesting that they might be able to recover from the pesticide effects. However, the persistent pesticide inhibitory effects on soil enzymatic activities suggests that the ability of the microbial community to cope with the repeated application was not accompanied by functional recovery. Overall, our results suggest that repeated pesticide applications may influence soil health and microbial functionalities and that more information should be collected to inform risk-based policy development.


Psychological predictors for return to work after a myocardial infarction.
The relationships between a return to work (RTW) 6 months after a myocardial infarction and selected personality traits, emotional reactions, health knowledge and beliefs, expectations and global health perceptions have been examined in a prospective study of 249 patients below 67 yr of age. Patients' in-hospital expectations of their future work capacity proved to be a strong predictor for RTW. In addition, level of anxiety and depression during hospitalization and level of cardiac lifestyle knowledge were independently associated with RTW. These effects could not be explained by demographic, work-related, or medical factors. It is concluded that patients' early illness perceptions and affective reactions influence later work resumption. Outcome-specific expectancy measures may be the most effective methods for early identification of patients needing rehabilitation efforts after an acute somatic disease.


Prevention of post-operative infection in appendicectomy by single dose intravenous metronidazole. An open prospective randomised study.
In an open prospective randomized study of appendicectomy, single-dose (1 g) intravenous metronidazole prophylaxis (and continued metronidazole plus nalidixic acid in perforated appendices) resulted in a lower overall post-operative infection rate (1.4%) than no prophylaxis and doxycycline therapy in the case of perforation (16%, p less than 0.025). In patients with an unperforated appendix no infections occurred after single-dose metronidazole prophylaxis as opposed to 8.2% infections in untreated controls (p less than 0.025).


Phenotype specific treatment of asthma in childhood.
The term "asthma syndrome" encompasses a range of disorders, all characterised clinically by combinations of cough, wheeze and breathlessness. In older children, evidence of variable airway obstruction is manifest by change in peak flow over time or with treatment, reduction in peak flow on exercise, and a positive methacholine challenge. The underlying pathology includes combinations of bronchial hyperreactivity (BHR), airway inflammation and alterations in underlying baseline airway calibre or compliance. This is not merely of academic importance, but is fundamental to organizing appropriate treatment. In children with symptoms with viral colds and also between colds, and in particular if they are atopic, the underlying abnormality is likely to be T-cell driven, eosinophil-mediated airway inflammation. There is compelling evidence that early treatment with inhaled corticosteroids is essential if airway remodelling is to be avoided and optimum long-term lung function is to be achieved. The pathophysiology of wheezing with viral colds in the non-atopic infant is completely different; such infants have evidence of abnormal lung function soon after birth and before their first episode of viral wheeze, and no evidence of either bronchial hyperreactivity or airflow inflammation. Response to inhaled steroids is very poor. For most infants with wheeze, it is currently not possible to predict whether they will go on to the picture of established asthma. Post-bronchiolitic asthma syndrome also does not respond to inhaled steroids, because prolonged symptoms are likely due to abnormal pre-morbid airway function, albeit worsened by atopy. Phenotype-specific treatment is also important in older children who have severer asthma and do not respond to high dose inhaled steroids. We have delineated a group with marked BHR but no evidence of inflammation who respond to subcutaneous terbutaline, and a second group with steroid resistant inflammation who may do better with cyclosporin. A phenotype-specific treatment approach may also help to delineate which add on therapy (long-acting beta agonist, leukotriene receptor antagonist, theophylline) is best for children with moderate asthma not controlled by moderate dose (400 mcg/day) inhaled corticosteroids. Asthma is not one disease but many, and attention to delineating clinical phenotypes, rather than being obsessed with guidelines based on large heterogeneous groups, may allow rational individual treatment.


Evaluation of cellular and humoral immune response in chickens immunized with flagellin-adjuvanted inactivated newcastle disease virus.
The aim of the present study was to evaluate the potential effect of flagellin as adjuvant in Newcastle disease virus (NDV) vaccine on the cellular and humoral immunity in chickens. Fifty-six specific pathogen-free chickens were assigned to seven groups of eight chickens and immunized twice with a two-week interval, intramuscularly. Group 1, received phosphate buffered saline as control (C), groups 2, 3, 4, 5, 6 and 7 were immunized with inactivated NDV [Ag], Ag + full FliC protein [AgF], Ag + truncated Flic protein [AgT], Ag + native Flic protein [AgN], commercial NDV vaccine [Vac] and Vac + N [VacN], respectively. After 45 days, spleen and bursa of Fabricius samples were collected and analyzed by flow cytometry and responses in control/vaccinated chickens were studied by immunophenotyping. Humoral response was also, evaluated by ELISA during the experiment. Results showed that immunized chickens with Ag + flagellin proteins had significantly higher frequency of circulating CD3+, CD4+ and CD8+ T cells in bursa of Fabricius in AgF, AgT and AgN, respectively, compared with other groups. Similar results were observed for spleen; however, the highest frequency of circulating CD3+, CD4+ and CD8+ T cells belonged to AgT and AgF, respectively. ELISA results showed that all flagellin-adjuvanted groups had higher antibody titers than other groups with the highest antibody response in VacN. It can be concluded that flagellin may induce both humoral and cellular immune responses against ND and is suggested for use as an efficient adjuvant.


Beyond the Booth: Excimer Laser for Cutaneous Conditions.
The excimer laser has emerged as an efficacious treatment modality for many dermatologic diseases. The excimer laser is an alternative to standard narrowband ultraviolet B (NBUVB) phototherapy treatment in patients with limited disease. In comparison to standard NBUVB, the excimer laser requires fewer treatment sessions, has reduced treatment duration, requires a lower cumulative UVB dose, and limits UVB exposure to lesional skin. This review addresses the mechanism, safety, application, and efficacy of the excimer laser for the treatment of these conditions.


The gene encoding a novel halorhodopsin-like protein of extremely halophilic archaeon Haloarcula japonica strain TR-1.
The gene encoding the halorhodopsin (hR)-like protein was cloned and sequenced from Haloarcula japonica strain TR-1. The structural gene consisted of an open reading frame of 828 nucleotides encoding 276 amino acids. The deduced amino acid sequence of the Ha. japonica hR-like protein showed the highest homology to those of cruxhalorhodopsins. Furthermore, we have demonstrated that the Ha. japonica chR gene is transcriptionally induced by light.


GFP variants for multispectral imaging of living cells.
Unlike enzyme markers, green fluorescent protein can be visualized at high resolution in living cells using confocal microscopy. The images are not prone to fixation or staining artifacts, and can be of exceptional clarity. Moreover, the activities of living cells, such as cytoplasmic streaming, are clearly evident during microscopy. Ordinarily, movement within a sample is a nuisance, placing constraints on the use of sometimes lengthy techniques for noise reduction during confocal microscopy, such as frame averaging. However, it is possible to monitor dynamic events by time-lapse confocal microscopy, and this combination of a vital fluorescent reporter with high-resolution optical techniques shows much promise for use in cell biological and physiological experiments. Genetic systems such as that of Arabidopsis provide a large resource of potentially informative mutants, and there has been much recent improvement in techniques for determining the molecular basis of a particular phenotype. The use of fluorescent proteins will provide further tools for examining the biology of mutant cells. The precision with which particular cellular structures can be decorated with GFP and the ease with which subcellular traffic can be monitored indicate that this approach will be very useful for cell biological and physiological observations, particularly for detailed examination of plant mutant phenotypes.


Monoclonal antibodies to staphylococcal enterotoxins B and C: cross-reactivity and localization of epitopes on tryptic fragments.
Murine monoclonal antibodies reactive with staphylococcal enterotoxins B (SEB) and C1 (SEC1) were isolated by hybridoma techniques. Of the nine antibodies, three reacted only with SEB, two reacted with SEB and SEC1, three reacted with all subtypes of SEC, and one reacted only with SEC2 and SEC3. All of the antibodies reacted with protein blotted onto nitrocellulose from electrophoresis gels which corresponded to the enterotoxin band. Fragments of SEB and SEC1 were generated by limited digestion of the toxin with trypsin. With the immunoblot technique, four of the five antibodies reactive with SEB reacted with the tryptic fragment of molecular weight 17,000, and the five antibodies reactive with SEC1 reacted with the tryptic fragment of molecular weight 14,000.


Evolutionary contributions to solving the "matrilineal puzzle": a test of Holden, Sear, and Mace's model.
Matriliny has long been debated by anthropologists positing either its primitive or its puzzling nature. More recently, evolutionary anthropologists have attempted to recast matriliny as an adaptive solution to modern social and ecological environments, tying together much of what was known to be associated with matriliny. This paper briefly reviews the major anthropological currents in studies of matriliny and discusses the contribution of evolutionary anthropology to this body of literature. It discusses the utility of an evolutionary framework in the context of the first independent test of Holden et al.'s 2003 model of matriliny as daughter-biased investment. It finds that historical daughter-biased transmission of land among the Mosuo is consistent with the model, whereas current income transmission is not. In both cases, resources had equivalent impacts on male and female reproduction, a result which predicts daughter-biased resource transmission given any nonzero level of paternity uncertainty. However, whereas land was transmitted traditionally to daughters, income today is invested in both sexes. Possible reasons for this discrepancy are discussed.


Chebulinic acid is a safe and effective antiangiogenic agent in collagen-induced arthritis in mice.
Although vascular endothelial growth factor-A (VEGF)-induced angiogenesis has been reported to play an important role in the pathogenesis of rheumatoid arthritis (RA), serious side effects, mainly grade 2-3 hypertension, which is commonly observed with currently available anti-VEGF agents, can be detrimental for RA patients due to hypertension and associated cardiovascular complications seen in these patients. Thus, identification of anti-VEGF molecules that do not increase blood pressure could be useful for the treatment of RA. Chebulinic acid (CI), a water-soluble small-molecule tannin, can inhibit the actions of VEGF, and a report suggested that CI might not increase blood pressure due to its compensatory effects on the cardiovascular system. Therefore, the effects of CI on blood pressure in mice and the progression of the disease in a murine collagen-induced arthritis (CIA) model were investigated. CIA was induced in DBA/1J mice with type II collagen. The effects of CI in these animals were then evaluated by determination of clinical, histopathological, and immunohistochemical parameters. The effects of CI on VEGF-induced proangiogenic genes and signaling pathways were examined in vitro and in vivo. Significant CD31 and VEGF expressions were detected in the synovial tissues of mice with CIA, similar to their expressions observed in human RA patients. However, treatment with CI significantly inhibited paw swelling, decreased the mean articular index and joint pathology scores in these animals through inhibition of VEGF-induced proangiogenic gene expressions and signaling pathways that regulate angiogenesis. Unlike currently used antiangiogenic agents, CI at a dose that inhibits VEGF actions did not increase blood pressure in mice. CI can act as a safe and potent anti-VEGF antiangiogenic agent for the treatment of types of inflammatory arthritis, such as RA.


[Sudeck's bone atrophy after leg phlebography - a case study of an unusual complication (author's transl)].
In a 39-year old man, a painful oedema had formed at the back of the foot perimalleolary one day after paravasal contrast medium injection following ascending phlebography. 8 weeks later, the x-ray film showed a maculate Sudeck's bone atrophy in the region of the toes, ankles and the heel. Sudeck's bone atrophy had obviously developed on account of a specific vegetative reactivity, subsequent to the local inflammation.


Determinants of trends in prescription opioid use in British Columbia, Canada, 2005-2013.
To explore the determinants of total opioid consumption in a Canadian province, and to examine patterns of opioid dispensations by sex, age, and income quintile. We used population-based administrative data on prescription drug dispensations in British Columbia (BC; population ~4 million). We apply an index-based approach to examine how changes in population exposure, type of opioids used, and intensity of use contributed to changes in total morphine equivalents dispensed per 1000 population. Between 2005 and 2013 in BC, opioid consumption increased by 31%, driven by longer duration of opioid therapy and by an increase in the use of stronger opioids. Consumption increased for oxycodone, hydromorphone, fentanyl, and tramadol; and declined for morphine, codeine, and other opioids. While we did not find large sex and age differences, the total level of opioid consumption was three times as high among individuals in the lowest income quintile compared to those in the highest income quintile. Our findings on changes in the type of opioids used and changes in intensity of use suggest that modifications to clinical management of patients on opioid therapy may be warranted. Similar drug utilization statistics, derived from drug information systems, can be reproduced in other jurisdictions to enable a better understanding of the opioid crisis. Copyright © 2016 John Wiley & Sons, Ltd.