Prognostic significance of lymphocyte-to-monocyte ratio and CRP in patients with nonmetastatic clear cell renal cell carcinoma: a retrospective multicenter analysis.
Inflammation has been reported to be involved in carcinogenesis and cancer progression. This study was designed to explore the prognostic significance of lymphocyte-to-monocyte ratio (LMR) and serum C-reactive protein (CRP) in nonmetastatic clear cell renal cell carcinoma (ccRCC) patients after treatment. The retrospective study consisted of 985 patients with ccRCC who had undergone nephrectomy from 2005 to 2010 at multiple centers. The patients were divided into four groups using a quartile of LMR or CRP, and their associations with clinical characteristics and outcome were systematically estimated. Both low LMR and high CRP significantly diminished overall survival (OS) and metastasis-free survival (MFS) in patients with ccRCC. Further investigation indicated that LMR and CRP were independent prognostic factors of both OS and MFS. Integration of LMR and CRP into a predictive model, including significant variables in multivariate analysis, established a nomogram to predict accurately the 3- and 5-year survival for nonmetastatic patients with ccRCC. LMR and CRP represent independent prognostic factors of OS and MFS for patients with ccRCC. Incorporation of LMR and CRP into the traditional TNM staging system may improve their predictive performance.


Using creative, sensory and embodied research methods when working with people with dementia: a method story.
: People with dementia are often excluded from research due to ethical concerns and a reliance upon conventional research methods which focus on recall and verbal expression. Creative, sensory and embodied research methods typically involve techniques that conceptually bring individuals "into" the research, thus affording an expressive capacity that traditional methods do not. This paper details a "method story", presenting three interlinked cycles of study used to explore the significance of clothing to people with dementia living in a care home. The studies drew upon arts-based and design led practices. This paper details the methods used and the opportunities that they presented when exploring the lived experience of dementia. Creative, sensory and embodied approaches enabled people with dementia to engage with research, supporting imaginative, spontaneous and flexible participation. This supports the use of novel methods when undertaking research with people who have dementia.


Critical role of mitochondria-mediated apoptosis for JNJ-26481585-induced antitumor activity in rhabdomyosarcoma.
JNJ-26481585 is a second-generation histone deacetylase inhibitor with broad-range efficacy and improved pharmacodynamic properties. In the present study, we investigated the therapeutic potential of JNJ-26481585 and its molecular mechanisms of action in rhabdomyosarcoma (RMS). Here, we report that JNJ- 26481585's anticancer activity critically depends on an intact mitochondrial pathway of apoptosis. JNJ-26481585 induces apoptosis and also inhibits long-term clonogenic survival of several RMS cell lines at nanomolar concentrations that cause histone acetylation. Importantly, JNJ-26481585 significantly suppresses tumor growth in vivo in two preclinical RMS models, that is, the chorioallantoic membrane model and a xenograft mouse model. Mechanistically, we identify activation of the mitochondrial pathway of apoptosis as a key event that is critically required for JNJ-26481585-mediated cell death. JNJ-26481585 upregulates expression levels of several BH3-only proteins including Bim, Puma and Noxa, which all contribute to JNJ-26481585-mediated apoptosis, as knockdown of Bim, Puma or Noxa significantly inhibits cell death. This shift toward proapoptotic Bcl-2 proteins promotes activation of Bax and Bak as a critical event, as genetic silencing of Bax or Bak protects against JNJ-26481585-induced apoptosis. Intriguingly, rescue experiments reveal that JNJ-26481585 triggers Bax/Bak activation independently of caspase activation and activates caspase-9 as the initiator caspase in the cascade, as Bcl-2 overexpression, but not the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) blocks JNJ-26481585-induced Bax/Bak activation and caspase-9 cleavage. In conclusion, JNJ-26481585 exerts potent antitumor activity against RMS in vitro and in vivo by engaging mitochondrial apoptosis before caspase activation and represents a promising therapeutic for further investigation in RMS.


A case of single lymph node metastasis near the common hepatic artery following a curative endoscopic resection for gastric mucosal cancer.
Although the absolute indication for endoscopic resection (ER) in gastric cancer is widely accepted, expanded indication for endoscopic submucosal dissection (ESD) is still regarded as investigational because of the risk of concomitant lymph node (LN) metastasis or recurrence following ESD. However, LN metastasis in early gastric cancer confined to absolute indication for ER cannot be negligible. Herein we report a 72-year-old man who underwent laparoscopic distal gastrectomy for LN metastasis around the common hepatic artery following curative ESD to the lesion that had met as an absolute indication for ER 1 year ago. There was only one metastatic LN near the common hepatic artery (LN 8), without malignancy at the ESD site or other harvested LNs.


Behavioral effects of aluminum ingestion on animal and human subjects.
Abnormally high brain aluminum concentrations have been detected in hemodialysis patients who died of an unexplained encephalopathy. As a result, this study was undertaken to examine whether the ingestion of aluminum produces behavioral aberrations in non-dialysed human subjects and rats with ostensibly normal renal function. Rats were fed AlCl3 by intubation in varying doses, and tests measuring learning ability, visual temporal acuity, motor coordination and activity were administered. It was found that orally ingested aluminum is absorbed by rats and deposited in the brain. High brain aluminum levels are associated with rapid general activity, decreased ability to maintain roto-rod activity, and increased sensitivity to flicker. Behavioral tests were also given to elderly human subjects and performance correlated with serum aluminum level. High serum levels of aluminum in elderly humans are associated with impaired visuo-motor coordination, poor long-term memory, and increased sensitivity to flicker.


Significant elevation of plasma matrix metalloproteinase-9 level and its ratio to matrix metalloproteinase-2 in patients with pelvic inflammatory disease.
To detect the expression of plasma matrix metalloproteinase-2 (MMP-2) and MMP-9, and MMP-9:MMP-2 ratio in patients with pelvic inflammatory disease (PID). A consecutive study with approximate 1:2 case-to-control ratio. University hospital. Forty-seven patients with PID and 80 healthy women. Collected blood specimens of patients with PID before and after treatment. ELISA and gelatin zymography were used to measure the expression of plasma MMP-2 and MMP-9. The level of plasma MMP-9 or MMP-9:MMP-2 ratio was elevated in patients with PID compared with healthy controls and decreased significantly after treatment. The activity of MMP-9, but not MMP-2, tended to be higher in 47 patients with PID before the treatment compared with that after the treatment. Pretreatment plasma MMP-9 or MMP-9:MMP-2 ratio was significantly correlated with white blood cell (WBC) and neutrophil counts. As prediction markers for PID, the sensitivities of MMP-9 and MMP-9:MMP-2 ratio were 76.6% and 76.6%, whereas the negative predictive values were 82.5% and 83.3%. Level of plasma MMP-9 and MMP-9:MMP-2 ratio may act as prediction markers for PID. In patients with PID, 80% have a plasma MMP-9 level higher than 115 ng/mL or a MMP-9:MMP-2 ratio higher than 2.15.


Patterns of paediatric massive blood transfusion protocol use in trauma and non-trauma patients.
Massive blood transfusion is infrequently required by children but can be a lifesaving intervention for haemorrhage or coagulopathy. Product volumes and ratios administered during the initiation of paediatric massive blood transfusion protocol (MBTP) are highly variable and the optimal component ratio is unknown. We performed a single-centre retrospective chart review of patients (<20 years) who received MBTP activation from August 2012 through January 2018. Logistic regression was used to determine the association between MBTP use characteristics (including blood product type and volume transfused, extracorporeal membrane oxygenation [ECMO] support, and cardiac arrest occurrence) and 24-h mortality. "Low" product ratio was defined as a ratio of plasma or platelets to red blood cells (RBCs) of <1:2 and "high" as ≥1:2. Ninety-eight MBTPs were activated for 89 patients (range 1-4 per patient). The most common underlying diagnoses were congenital heart disease (CHD, n = 28, 31.5%), followed by cardiopulmonary disease, and trauma. CHD patients required the greatest volume of RBCs (226.3 ml/kg, 95%CI [160.0, 292.7], p = 0.002) and platelets (46.7 ml/kg, 95%CI [33.2, 60.2], p < 0.001). A "low" product ratio was more common for the MBTP, with its incidence similar among the underlying diagnoses. An MBTP developed for trauma patients can be applied to non-trauma patients but standard MBTP components may not be optimal for all children. These findings show that underlying patient diagnoses may be a factor when designing an MBTP for a heterogeneous paediatric population.


Expression level of lncRNA PVT1 in serum of patients with coronary atherosclerosis disease and its clinical significance.
The purpose of this study was to detect the expression level of PVT1 in the serum of coronary artery disease (CAD) patients, and to explore the clinical significance of PVT1 in CAD. A total of 200 CAD patients and 200 healthy controls in the same period were included. The serum level of PVT1 in every subject was detected. Then, the correlation between PVT1 level and Gensini score in CAD patients was analyzed by Spearman correlation test. Finally, multivariable Logistic regression test was conducted to assess risk factors influencing coronary atherosclerosis disease. It was found that PVT1 was highly expressed in the serum of CAD patients and its level was correlated with Gensini score (r=0.761, p=0.023). Besides, multivariable Logistic regression test obtained that PVT1 was the risk factor influencing coronary atherosclerosis disease (crude OR = 2.074, 95% CI: 1.642-3.529; adjusted OR = 1.762, 95% CI: 1.382-2.096). Serum level of PVT1 helps to distinguish mild and severe CAD. Meanwhile, PVT1 is an independent risk factor influencing the development of coronary atherosclerosis disease.


Imaging of acute gastric emergencies: a case-based review.
The stomach is one of the most frequently imaged organs in the body with dedicated and incidental inclusion in chest imaging modalities. Gastric emergencies often present clinically with non-specific abdominal, nausea, and vomiting. As such, imaging plays a critical role in early identification and treatment of a myriad of gastric emergencies. The goal of this paper is to showcase gastric emergencies as they appear on multimodality imaging.


Fiber type-related changes in rat skeletal muscle calcium homeostasis during aging and restoration by growth hormone.
The mechanisms by which aging induces muscle impairment are not well understood yet. We studied the impact of aging on Ca2+ homeostasis in the slow-twitch soleus and the fast-twitch extensor digitorum longus (EDL) muscles of aged rats by using the fura-2 fluorescent probe. In both muscles aging increases the resting cytosolic calcium concentration ([Ca2+]i). This effect was independent on calcium influx since a reduced resting permeability of sarcolemma to divalent cations was observed in aged muscles likely due to a reduced activity of leak channels. Importantly the effects of aging on resting [Ca2+]i, fiber diameter, mechanical threshold and sarcolemmal resting conductances were less pronounced in the soleus muscle, suggesting that muscle impairment may be less dependent on [Ca2+]i in the slow-twitch muscle. The treatment of aged rats with growth hormone restored the resting [Ca2+]i toward adult values in both muscles. Thus, an increase of resting [Ca2+]i may contribute to muscle weakness associated with aging and may be considered for developing new therapeutic strategies in the elderly.


A novel combined intelligent algorithm prediction model for the tunnel surface settlement.
To ensure the safety and stability of the shield tunnel construction process, the ground settlement induced by the shield construction needs to be effectively predicted. In this paper, a prediction method combining empirical mode decomposition (EMD), chaotic adaptive sparrow search algorithm (CASSA), and extreme learning machine (ELM) is proposed. First, the EMD is used to decompose the settlement sequence into trend vectors and fluctuation vectors to fully extract the effective information of the sequence; Second, the sparrow search algorithm is improved by introducing Cubic chaotic mapping to initialize the population and adaptive factor to optimize the searcher's position formula, and the chaotic adaptive sparrow search algorithm is proposed; Finally, the CASSA-ELM prediction model is constructed by using CASSA to find the optimal values of weights and thresholds in the extreme learning machine. The fluctuation components and trend components decomposed by EMD are predicted one by one, and the prediction results are superimposed and reconstructed to obtain the predicted final settlement. Taking a shield interval in Jiangsu, China as an example, the meta-heuristic algorithm-optimized ELM model improves the prediction accuracy by 10.70% compared with the traditional ELM model. The combined EMD-CASSA-ELM prediction model can greatly improve the accuracy and speed of surface settlement prediction, and provide a new means for safety monitoring in shield tunnel construction. Intelligent prediction methods can predict surface subsidence more automatically and quickly, becoming a new development trend.


Studies on flow-mediated vasodilation and intima-media thickness of the brachial artery in patients with primary hyperparathyroidism.
The endothelium is a newly recognized target organ of parathyroid hormone (PTH) and may contribute to its effects on vascular tone and blood pressure regulation. Flow-mediated vasodilation (FMD), brachial and carotid intima-media thickness (IMT) were studied in patients with primary hyperparathyroidism (pHPT) and controls to evaluate endothelial function and structural arterial vessel wall alterations. Sixteen patients with pHPT (mean +/- SEM, age 44 +/- 5 years; PTH 229 +/- 72 ng/L; serum calcium 3.0 +/- 0.06 mmol/L; serum phosphate 2.0 +/- 0.2 mg/L) and 16 normocalcemic control subjects matched for age, sex, and blood pressure were included. Diabetes, hypertension, and vascular disease were excluded in both groups. End-diastolic diameter, flow-mediated (FMD) and nitroglycerin-mediated (NMD) dilation of the brachial artery were measured by a multigate pulsed Doppler system (echo-tracking). IMT was determined using automatic analysis of the M-line signal. Endothelium-dependent FMD was impaired in patients compared to controls (4.6 +/- 1.6% v 19.2 +/- 3.9%, P < .001). NMD (23.8 +/- 3.1% v. 22.4 +/- 2.8%, P = NS), carotid and brachial IMT (0.60 +/- 0.04 mm v 0.64 +/- 0.06 mm, P = NS, and 0.46 +/- 0.04 mm v 0.47 +/- 0.08 mm, P = NS, respectively) and artery diameters were not different. Endothelium-dependent vasodilation is impaired in patients with primary hyperparathyroidism despite normal IMT. Endothelial dysfunction may contribute to increased cardiovascular morbidity and mortality in pHPT.


Predictors of durable electrical isolation in the setting of second-generation cryoballoon ablation: A comparison between left superior, left inferior, right superior, and right inferior pulmonary veins.
The aim of this study is to assess specific per-vein procedural predictors of pulmonary vein (PV) late reconnection in cryoballoon ablation (CbA) METHODS AND RESULTS: We enrolled 148 consecutive patients undergoing a redo procedure after a previous index CbA in our center. A reconnection in at least one PV was found in 80 patients (54.1%) and the most frequently reconnected PV was the right inferior pulmonary vein (RIPV). Overall, pulmonary vein reconnection (PVr) was associated with longer time to -40°C (Tt-40°C) (54.4 ± 21.7 vs 67.6 ± 27.6 seconds; P < .001), warmer nadir temperature (NT) (-49.7°C ± 5.4°C vs -46.5°C ± 5.8°C; P < .001) and temperature at 60 seconds (-41.8°C ± 4.5°C vs -39.8°C ± 4.2°C; P < .001). The performance of these predictors differed between the veins. In particular, a comparable behavior was observed for left superior pulmonary vein (LSPV) and right superior pulmonary vein (RSPV), where NT ≤ -48°C showed a sensibility and a specificity, respectively, of 62% and 65% and 71% and 72% in predicting durable PV isolation. For RIPV, NT ≤ -48°C showed a sensitivity of 74% but low specificity (53%). Tt -40°C less than 60 seconds showed good negative predictive values, respectively, 83.9% for LSPV, 94.9% for left inferior pulmonary vein (LIPV), 90.2% for RSPV, and 82.7% for RIPV. Previous predictors cannot be used for LIPV. Freezing behavior and reconnection rates differ significantly among the four PVs. Freezing temperature parameters strongly predict late PVr in superior PVs and are slightly different in RIPV but can be applied as well. LIPV freezing behavior is the most different. Its reconnection is uncommon even in the subset of worse freezing temperatures and specific CB predictors cannot be identified.


Amifostine reduces side effects and improves complete response rate during radiotherapy: results of a meta-analysis.
To evaluate the efficacy of amifostine in diminishing radiotherapy side effects and whether or not it protects the tumor. We performed a systematic review and meta-analysis of 14 included randomized controlled trials, comprising 1451 patients, comparing the use of radiotherapy vs. radiotherapy plus amifostine for cancer treatment. The use of amifostine significantly reduced the risk of developing mucositis (odds ratio [OR], 0.37; 95% confidence interval [CI], 0.29-0.48; p < 0.00001), esophagitis (OR, 0.38; CI, 0.26-0.54; p < 0.00001), acute xerostomia (OR, 0.24; CI, 0.15-0.36; p < 0.00001), late xerostomia (OR, 0.33; CI, 0.21-0.51; p < 0.00001), dysphagia (OR, 0.26; CI, 0.07-0.92; p = 0.04), acute pneumonitis (OR, 0.15; CI, 0.07-0.31; p < 0.00001) and cystitis (OR, 0.17; CI, 0.09-0.32; p < 0.00001). There was no difference in overall response rate between the groups. However, complete response rate was superior for patients using amifostine (OR, 1.81; CI, 1.10-2.96; p = 0.02). This systematic review shows that amifostine significantly reduces the side effects of radiation therapy. The efficacy of radiotherapy was not itself affected by the use of this drug and patients receiving amifostine were able to achieve higher rates of complete response.


Cytophilic antibodies to Plasmodium falciparum glutamate rich protein are associated with malaria protection in an area of holoendemic transmission.
Several studies conducted in areas of medium or low malaria transmission intensity have found associations between malaria immunity and plasma antibody levels to glutamate rich protein (GLURP). This study was conducted to analyse if a similar relationship could be documented in an area of intense malaria transmission. A six month longitudinal study was conducted in an area of holoendemic malaria transmission in north-eastern Tanzania, where the incidence of febrile malaria decreased sharply by the age of three years, and anaemia constituted a significant part of the malaria disease burden. Plasma antibodies to glutamate rich protein (GLURP) were analysed and related with protection against malaria morbidity in models correcting for the effect of age. The risk of febrile malaria episodes was reduced significantly in children with measurable anti-GLURP IgG1 antibodies at enrollment [adjusted odds ratio: 0.39 (95% CI: 0.15, 0.99); P = 0.047]. Interestingly, there was an inverse relationship between the plasma anti-GLURP IgG1 and IgG3 levels and the levels of parasitaemia at enrollment. However, anti-GLURP IgG2 and IgG4 levels were not associated with reduction in parasite density. Similarly, antibody levels were not associated with haemoglobin levels or anaemia risk. Cytophilic IgG1 and IgG3 antibodies against R0-GLURP may contribute to the control of parasite multiplication and reduction in febrile malaria incidence in children living in an area of intense malaria transmission.


Role of the surface characteristics of hyper-crosslinked polymers on the transformation of adsorbed trichlorophenol: Implications for understanding the surface reactivity of biochar derived from waste biomass.
The surface reactivity of biochar derived from waste biomass has not been well understood due to its complex composition and heterogeneity. Therefore, this study synthesized a series of biochar-like hyper-crosslinked polymers (HCPs) with different amounts of phenolic hydroxyl groups on the surface as an indicative tool to investigate the roles of key surface properties of biochar on transforming pollutants being adsorbed. Characterization of HCPs suggested that electron donating capacity (EDC) of different HCPs was positively correlated with increasing amounts of phenol hydroxyl groups, whereas specific surface area, degree of aromatization and graphitization were negatively correlated. It was found that greater amounts of hydroxyl radicals were produced with increasing amounts of hydroxyl groups on the synthesized HCPs. Batch degradation experiments with trichlorophenols (TCPs) suggested that all HCPs could decompose TCP molecules upon contact. The degree of TCP degradation (~45 %) was highest for HCP made from benzene monomer with the lowest amounts of hydroxyl groups, which was likely driven by its greater specific surface area and reactive sites for TCP degradation. Conversely, the degree of TCP degradation (~25 %) by HCPs with the highest hydroxyl group abundance was the lowest, probably because the lower surface area of HCPs had limited TCP adsorption, which led to lower interaction between HCP surface and TCP molecules. The results concluded from the contact of HCPs and TCP suggested both EDC and adsorption capacity of biochar played critical roles in transforming organic pollutants.


Development and validation of the Consumer Quality index instrument to measure the experience and priority of chronic dialysis patients.
Patient experience is an established indicator of quality of care. Validated tools that measure both experiences and priorities are lacking for chronic dialysis care, hampering identification of negative experiences that patients actually rate important. We developed two Consumer Quality (CQ) index questionnaires, one for in-centre haemodialysis (CHD) and the other for peritoneal dialysis and home haemodialysis (PHHD) care. The instruments were validated using exploratory factor analyses, reliability analysis of identified scales and assessing the association between reliable scales and global ratings. We investigated opportunities for improvement by combining suboptimal experience with patient priority. Sixteen dialysis centres participated in our study. The pilot CQ index for CHD care consisted of 71 questions. Based on data of 592 respondents, we identified 42 core experience items in 10 scales with Cronbach's α ranging from 0.38 to 0.88; five were reliable (α ≥ 0.70). The instrument identified information on centres' fire procedures as the aspect of care exhibiting the biggest opportunity for improvement. The pilot CQ index PHHD comprised 56 questions. The response of 248 patients yielded 31 core experience items in nine scales with Cronbach's α ranging between 0.53 and 0.85; six were reliable. Information on kidney transplantation during pre-dialysis showed most room for improvement. However, for both types of care, opportunities for improvement were mostly limited. The CQ index reliably and validly captures dialysis patient experience. Overall, most care aspects showed limited room for improvement, mainly because patients participating in our study rated their experience to be optimal. To evaluate items with high priority, but with which relatively few patients have experience, more qualitative instruments should be considered.


Hematocrit as an index of changes in plasma volume in conscious dogs.
Hematocrit (HCT) measurements were made in intact and splenectomized conscious dogs to determine if observed decreases in HCT were produced by plasma volume expansion or splenic sequestration of erythrocytes. We found that in conscious dogs HCT is a poor indicator of changes in plasma volume.


Characterization and classification of wines according to geographical origin, vintage and specific variety based on elemental content: a new chemometric approach.
A highly informative chemometric approach using elemental data to distinguish and classify wine samples according to different criteria was successfully developed. The robust chemometric methods, such fuzzy principal component analysis (FPCA), FPCA combined with linear discriminant analysis (LDA), namely FPCA-LDA and mainly fuzzy divisive hierarchical associative-clustering (FDHAC), including also classical methods (HCA, PCA and PCA-LDA) were efficaciously applied for characterization and classification of white wines according to the geographical origin, vintage or specific variety. The correct rate of classification applying LDA was 100% in all cases, but more compact groups have been obtained for FPCA scores. A similar separation of samples resulted also when the FDHAC was employed. In addition, FDHAC offers an excellent possibility to associate each fuzzy partition of wine samples to a fuzzy set of specific characteristics, finding in this way very specific elemental contents and fuzzy markers according to the degrees of membership (DOMs).


1H detection and dynamic nuclear polarization-enhanced NMR of Aβ1-42 fibrils.
Several publications describing high-resolution structures of amyloid-β (Aβ) and other fibrils have demonstrated that magic-angle spinning (MAS) NMR spectroscopy is an ideal tool for studying amyloids at atomic resolution. Nonetheless, MAS NMR suffers from low sensitivity, requiring relatively large amounts of samples and extensive signal acquisition periods, which in turn limits the questions that can be addressed by atomic-level spectroscopic studies. Here, we show that these drawbacks are removed by utilizing two relatively recent additions to the repertoire of MAS NMR experiments-namely, 1H detection and dynamic nuclear polarization (DNP). We show resolved and sensitive two-dimensional (2D) and three-dimensional (3D) correlations obtained on 13C,15N-enriched, and fully protonated samples of M0Aβ1-42 fibrils by high-field 1H-detected NMR at 23.4 T and 18.8 T, and 13C-detected DNP MAS NMR at 18.8 T. These spectra enable nearly complete resonance assignment of the core of M0Aβ1-42 (K16-A42) using submilligram sample quantities, as well as the detection of numerous unambiguous internuclear proximities defining both the structure of the core and the arrangement of the different monomers. An estimate of the sensitivity of the two approaches indicates that the DNP experiments are currently ∼6.5 times more sensitive than 1H detection. These results suggest that 1H detection and DNP may be the spectroscopic approaches of choice for future studies of Aβ and other amyloid systems.


The PINNACLE Study: A Double-blind, Randomized, Sham-controlled Study Evaluating the Optilume BPH Catheter System for the Treatment of Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia.
The Optilume BPH Catheter System is a novel drug/device combination minimally invasive surgical therapy for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. The PINNACLE study is a prospective, randomized, double-blind, sham-controlled clinical trial evaluating the safety and efficacy of Optilume BPH against a sham surgical procedure. Eligible patients were men 50 years or older with symptomatic benign prostatic hyperplasia and a prostate size between 20 and 80 g. Subjects were randomized 2:1 to receive treatment with Optilume BPH or a sham surgical procedure. Blinding was maintained for subjects in both arms and evaluating personnel through 1 year postprocedure. Follow-up assessments included the International Prostate Symptom Score, uroflowmetry, and other quality-of-life and sexual function assessments. A total of 148 men were randomized (100 active, 48 sham) at 18 centers in the U.S. and Canada. Subjects randomized to receive Optilume BPH saw a reduction in International Prostate Symptom Score of 11.5±7.8 points at 1 year posttreatment, as compared to a reduction of 8.0±8.3 points at 3 months in the sham arm. Flow rate was dramatically improved after treatment with Optilume BPH, with an improvement of +10.3 mL/s from baseline to 1 year (+125%). Treatment with Optilume BPH provides immediate and sustained improvements in obstructive symptoms and flow rate while preserving erectile and ejaculatory function. Treatment is well tolerated and can be done in an office or ambulatory setting.


Manganese potentiates LPS-induced heme-oxygenase 1 in microglia but not dopaminergic cells: role in controlling microglial hydrogen peroxide and inflammatory cytokine output.
Excessive manganese (Mn) exposure increases output of glial-derived inflammatory products, which may indirectly contribute to the neurotoxic effects of this essential metal. In microglia, Mn increases hydrogen peroxide (H(2)O(2)) release and potentiates lipopolysaccharide (LPS)-induced cytokines (TNF-α, IL-6) and nitric oxide (NO). Inducible heme-oxygenase (HO-1) plays a role in the regulation of inflammation and its expression is upregulated in response to oxidative stressors, including metals and LPS. Because Mn can oxidatively affect neurons both directly and indirectly, we investigated the effect of Mn exposure on the induction of HO-1 in resting and LPS-activated microglia (N9) and dopaminergic neurons (N27). In microglia, 24h exposure to Mn (up to 250 μM) had minimal effects on its own, but it markedly potentiated LPS (100 ng/ml)-induced HO-1 protein and mRNA. Inhibition of microglial HO-1 activity with two different inhibitors indicated that HO-1 is a positive regulator of the Mn-potentiated cytokine output and a negative regulator of the Mn-induced H(2)O(2) output. Mn enhancement of LPS-induced HO-1 does not appear to be dependent on H(2)O(2) or NO, as Mn+LPS-induced H(2)O(2) release was not greater than the increase induced by Mn alone and inhibition of iNOS did not change Mn potentiation of HO-1. However, because Mn exposure potentiated the LPS-induced nuclear expression of small Maf proteins, this may be one mechanism Mn uses to affect the expression of HO-1 in activated microglia. Finally, the potentiating effects of Mn on HO-1 appear to be glia-specific for Mn, LPS, or Mn+LPS did not induce HO-1 in N27 neuronal cells.


Discourse in aphasia: integration deficits in processing reference.
The present study investigated moderately impaired aphasic subjects' ability to integrate information across sentences by having them identify antecedents for ambiguous pronouns in brief narratives. In order to disambiguate the pronouns, the subjects had to consult either textual cues and/or extratextual cues. In addition, the subjects' ability to retrieve factual information was measured by having them identify explicitly stated noun referents. The results show that the aphasic subjects had significant difficulty using textual cues to resolve referents when the referents were not readily accessible through world knowledge. The patients had little difficulty interpreting referents which were recoverable from world knowledge or were stated explicitly. The explanatory power of world knowledge effects, grammatical class effects, memory effects, and linguistic integration effects in accounting for the deficit pattern observed is considered.


A Partly Fermented Infant Formula with Postbiotics Including 3'-GL, Specific Oligosaccharides, 2'-FL, and Milk Fat Supports Adequate Growth, Is Safe and Well-Tolerated in Healthy Term Infants: A Double-Blind, Randomised, Controlled, Multi-Country Trial.
This study investigated growth, safety, and tolerance in healthy infants consuming a partly fermented infant formula (IF) with postbiotics, 2'-linked fucosyllactose (2'-FL), a specific prebiotic mixture of short-chain galacto-oligosaccharides (scGOS) and long-chain fructo-oligosaccharides (lcFOS), and milk fat. This double-blind, controlled trial randomised 215 fully IF-fed infants ≤ 14 days of age to either: Test Group (IF) containing 26% fermented formula with postbiotics derived from Lactofidus fermentation process (including 3'-Galactosyllactose; 3'-GL), 0.8 g/100 mL scGOS/lcFOS (9:1), 0.1 g/100 mL 2'-FL, and milk fat), or Control group (IF with 0.8 g/100 mL scGOS/lcFOS (9:1)) until 17 weeks of age. Fully breastfed infants were included as a reference. Anthropometric measures, gastrointestinal symptoms, and safety were assessed monthly. Equivalence in weight gain (primary outcome) between the Test and Control groups was confirmed (difference in means -0.08 g/day; 90% CI (-1.47;1.31)) with estimated mean weight gain (SE) of 31.00 (0.59) g/day and 31.08 (0.60) g/day, respectively, (PP population, n = 196). Equivalence in length and head circumference gain between the randomised groups was also confirmed. No statistically significant differences were observed in adverse events or gastrointestinal tolerance between randomised IF groups. A partly fermented IF with postbiotics, specific oligosaccharides, 2'-FL, and milk fat supports adequate infant growth and is safe and well-tolerated in healthy term infants.


Classical swine fever virus NS5A protein interacts with 3'-untranslated region and regulates viral RNA synthesis.
To investigate the function of classical swine fever virus (CSFV) NS5A protein, the experiments for viral RNA synthesis and viral replication were performed in the co-presence of NS5A and NS5B. Results showed that small concentrations of NS5A stimulated, large concentrations of NS5A inhibited, viral RNA synthesis and viral replication. Affinity chromatography experiments and UV-crosslinking assays revealed that CSFV NS5A and NS5B bound its cognate 3'UTR and that NS5A had higher affinity than NS5B protein in binding to 3'UTR. 200 ng of NS5A inhibited NS5B-3'UTR complex formation by about 95%. CSFV 3'UTR was found to contain two NS5A-binding sites, located in 3'UTRSL-1 (nt 161-231) and 3'UTRSL-2 (nt 90-160), respectively, a NS5B-binding site, also located in 3'UTRSL-1. The 3'UTRSL-1 is the common binding site for NS5A and NS5B. Furthermore, competitive electrophoretic mobility shift assays indicated that binding of CSFV NS5A to 3'UTRSL-1 is more efficiently than to 3'UTRSL-2. These results suggested that the different concentrations of NS5A, the different binding activities of NS5A and NS5B to 3'UTR and binding of NS5A to different regions of 3'UTR might contribute at least partially to modulation of CSFV replication.


Localization of the corticospinal tract within the porcine spinal cord: Implications for experimental modeling of traumatic spinal cord injury.
Spinal cord injury (SCI) researchers have predominately utilized rodents for SCI modeling and experimentation. Unfortunately, a large number of novel therapies developed in rodent models have failed to demonstrate efficacy in human clinical trials which suggests that improved animal models are an important translational tool. Recently, porcine models of SCI have been identified as a valuable intermediary model for preclinical evaluation of promising therapies to aid clinical translation. However, the localization of the major spinal tracts in pigs has not yet been described. Given that significant differences exist in the location of the corticospinal tract (CST) between rodents and humans, determining its location in pigs will provide important information related to the translational potential of the porcine pre-clinical model of SCI. Thus, the goal of this study is to investigate the localization of the CST within the porcine spinal cord. Mature female domestic pigs (n=4, 60kg) received microinjections of fluorescent dextran tracers (Alexa Fluor, 10,000MW) into the primary motor cortex, using image-guided navigation (StealthStation®), to label the CST. At 5 weeks post-tracer injection animals were euthanized, the entire neuroaxis harvested and processed for histological examination. Serial sections of the brain and spinal cord were prepared and imaged using confocal microscopy to observe the location of the CST in pigs. Results demonstrate that the CST of pigs is located in the lateral white matter, signifying greater similarity to human anatomical structure compared to that of rodents. We conclude that the corticospinal tract in pigs demonstrates anatomical similarity to human, suggesting that the porcine model has importance as a translational intermediary pre-clinical model.


Pharmacokinetics and cardiovascular effect of etoricoxib in the absence or presence of St. John's Wort in rats.
The effect of chronic administration of etoricoxib (EXB), in the absence or presence of St. John's Wort (SJW), on its pharmacokinetic parameters and blood pressure was investigated in rats.Rats were divided into 3 groups, each group received daily different oral treatment for 3 weeks. Rats' blood pressures were monitored initially, after 1 and 3 weeks of treatment, and after 1 week of discontinuing dosing of both drugs. EXB pharmacokinetic parameters in the absence or presence of SJW were calculated after 3 weeks.SJW was significantly affected EXB pharmacokinetic parameters. The steady state peak plasma concentration and terminal half-life were reduced by 32% and 91%, respectively, due to a > 3 fold increase in its apparent clearance which is a concentration and time dependent effect. EXB was significantly increased (P<0.001) Rats' blood pressure while, co-administration of EXB and SJW was not significantly affect (P>0.05) rats' blood pressure as compared to the control.Monitoring blood pressure of patients anticipated taking EXB for extended period should be advised. The co-administration of SJW with EXB should be avoided since SJW would greatly reduce EXB concentrations by inducing its metabolism.


[Hereditary retinochoroidal dystrophies. Part 1: Pathogenesis, diagnosis, therapy and patient counselling].
Hereditary retinochoroidal dystrophies are a heterogeneous group of disorders characterised by progressive loss of visual acuity or visual field. They can manifest at every age of life. The basic knowledge of retinal physiology and pathophysiology, diagnostic approach, therapeutic limitations and patient counselling are summarised. Hereditary retinochoroidal dystrophies are usually monogenic disorders. The diagnosis is based on a combined assessment of patient history and the results of morphological, electrophysiological, psychophysical and molecular genetic evaluations. Patients should undergo measurement of refraction and visual acuity testing, perimetry, ophthalmoscopy, full-field and multifocal electroretinography. Additional methods, e.g. fluorescein angiography, electrooculography or laboratory testing are helpful in certain cases. For promising new methods like measurement of retinal pigment epithelium autofluorescence or optic coherence tomography further evaluation of their value for differential diagnosis is required. General molecular genetic testing is still limited due to technical and financial limitations. A detailed differential diagnosis and long-term follow-up are advisable for patient counselling and the development of new therapeutic options. To date, therapy is limited. Major tasks for the ophthalmologists are providing low vision aids and adequate patient counselling.


System map for the ionic liquid stationary phase tri(tripropylphosphoniumhexanamido)triethylamine bis(trifluoromethylsulfonyl)imide for gas chromatography.
The solvation parameter model is used to construct a system map for the retention of volatile organic compounds on the ionic liquid stationary phase tri(tripropypphosphoniumhexanamido)triethylamine bis(trifluoromethylsulfonyl)imide (SLB-IL76) over the temperature range 80-240°C. The SLB-IL76 stationary phase is moderately cohesive and strongly dipolar/polarizable and hydrogen-bond basic but only a weak hydrogen-bond acid. Electron lone pair interactions are weak and make only a minor contribution to the retention mechanism. The separation properties of SLB-IL76 highlight the difficulty of designing new stationary phases from ion structures as the presence of amide groups in the cation don't seem to contribute significantly to the hydrogen-bond acidity of SLB-IL76. The separation properties of SLB-IL76 are closest to the bis(polycyanopropyl)siloxane stationary phases with a high percentage of bis(cyanopropyl)siloxane monomer and could be used in method development when a stationary phase with similar gross retention characteristics but different selectivity is required.


Pemetrexed and Platinum Plus Pembrolizumab in Patients With Metastatic Nonsquamous NSCLC by Tumor Burden at Baseline: A Post Hoc Efficacy Analysis of KEYNOTE-189.
The aim of this study was to evaluate the efficacy of pemetrexed and platinum plus pembrolizumab by baseline tumor burden. A total of 616 patients in the intention-to-treat population of the KEYNOTE-189 study were included in this analysis. Baseline tumor burden subgroups were identified on the basis of extent of distant metastasis (M1a versus M1b), median number (≤3 versus >3) of organ systems with lesions, or symptom severity score of patient-reported lung cancer-associated symptoms (≤median versus >median). Overall survival (OS), progression-free survival (PFS), and PFS-2 were evaluated by Kaplan-Meier and univariate Cox methods. Objective response rate was analyzed using logistic regression models, and duration of response was analyzed descriptively. Efficacy outcomes were also analyzed according to the programmed death-ligand 1 expression levels. OS and PFS were significantly improved with pemetrexed and platinum plus pembrolizumab in all baseline tumor burden subgroups (M1a stage: OS hazard ratio [HR] = 0.54, p = 0.0037; PFS HR = 0.48, p = 0.0001; M1b stage: OS HR = 0.58, p ≤ 0.0001; PFS HR = 0.51, p ≤ 0.0001; number of organ systems with lesion ≤ 3: OS HR = 0.49, p ≤ 0.0001 PFS HR = 0.41, p ≤ 0.0001; >3: OS HR = 0.67, p = 0.0068; PFS HR = 0.59, p = 0.0001; symptom severity score ≤ median: HR = 0.51, p ≤ 0.0001; PFS HR 0.49, p ≤ 0.0001; > median: OS HR = 0.60, p = 0.0003; PFS HR = 0.48, p ≤ 0.0001). PFS2 and objective response rate were also improved with pemetrexed and platinum plus pembrolizumab in all baseline tumor burden subgroups. Efficacy outcomes were generally consistent regardless of programmed death-ligand 1 expression levels. Pemetrexed and platinum plus pembrolizumab were found to have relevant efficacy regardless of the extent of baseline tumor burden and the variables used to define it. These results further support pemetrexed and platinum plus pembrolizumab as the standard of care in the first-line treatment of metastatic nonsquamous NSCLC.


Fabrication and characterization of bilayer scaffolds - nanocellulosic cryogels - for skin tissue engineering by co-culturing of fibroblasts and keratinocytes.
This study focuses on developing a microarchitectural bilayer structure for stimulating the two top layers of skin tissue (epidermis and dermis) fabricated using a one-step freeze-drying method. Cellulose nanofibers (CNFs) and poly (vinyl) alcohol (PVA) were used as a biocompatible scaffolding material, and the composition was designed in such a way that it provides physical and biological property attributes. In this work, scaffolding materials with integrated layer structures and well interconnected and open pore structures were obtained. This bilayer structure had porosity with a pore size of 19.72 μm and 90.71 μm for the simulation of the epidermis and dermis, respectively. The production and expression of laminin, collagen IV, and keratin 10 proteins in the bilayer cryogel scaffolds obtained from the immunofluorescence study were 49.7 %, 63.8 %, and 49.3 %, respectively. The extracellular matrix (ECM) was produced in each scaffold layer. The observations confirmed that the porosity and pore size of both N1 and N2 layers were appropriate for the fibroblast and keratinocyte cells, respectively. H&E stained cross-sections of bilayer cryogel scaffolds illustrated epidermal and dermal layers produced by co-culturing keratinocytes and fibroblasts. Based on the results, the bilayer CNF/PVA scaffold can be used in skin tissue engineering applications. However, more experiments and in vivo evaluations are needed to express this conclusion more accurately.


Small tissue chips with big opportunities for space medicine.
The spaceflight environment, including microgravity and radiation, may have considerable effects on the health and performance of astronauts, especially for long-duration and Martian missions. Conventional on-ground and in-space experimental approaches have been employed to investigate the comprehensive biological effects of the spaceflight environment. As a class of recently emerging bioengineered in vitro models, tissue chips are characterized by a small footprint, potential automation, and the recapitulation of tissue-level physiology, thus promising to help provide molecular and cellular insights into space medicine. Here, we briefly review the technical advantages of tissue chips and discuss specific on-chip physiological recapitulations. Several tissue chips have been launched into space, and more are poised to come through multi-agency collaborations, implying an increasingly important role of tissue chips in space medicine.


Post-intensive care syndrome: A concept analysis.
Post-intensive care syndrome is a term used to describe new or worsening multidimensional impairments in physical, psychological cognitive and social status arising from critical illness and persisting beyond hospital discharge. It is associated with high morbidity among patients discharged from intensive care units. However, due to its complexities, which encompass physical, psychological, cognitive and social impairments, the exact nature of this condition has not been fully conceptualized. The aim of this analysis therefore was to define the concept of post-intensive care syndrome. This conceptual clarity provides a general definition that is essential for practitioners and researchers to gain a comprehensive understanding of the syndrome and provide for accurate measurement of its incidence and prevalence. The Walker and Avant approach to concept analysis guided this investigation. An electronic search of the literature using PubMed, CINHAL, PsycArticles, Academic search complete, Science Direct, MEDLINE and Health Source databases informed the analysis. The search included both quantitative and qualitative studies related to post-intensive care syndrome published in English between 2010 and 2020. Of the 3948 articles identified, 24 ultimately met the inclusion criteria. Analysis identified the defining attributes of post-intensive care syndrome as: (1) new or worsening multidimensional impairments; (2) physical dysfunction; (3) psychological disorder; (4) cognitive impairment; (5) failed social reconstruction; and (6) persistent impaired multidimensional symptoms extending beyond intensive care and hospital discharge. Antecedents were divided into two categories: pre-existing and those related to the intensive care admission. Consequences were identified as both positive (for example the establishment of coping processes) and adverse (for example decreased quality of life and caregiver burden). Post-intensive care syndrome affects more than half of patients discharged from intensive care units. This operational definition and conceptual understanding of this syndrome will help improve understanding and inform the design of preventative strategies to improve long-term consequences of the syndrome. Future research and standardized instrument development will serve to better understand the scope and characteristics of this syndrome and inform the development of possible preventative interventions.


Colorectal Cancer Surgery: Influence of Psychosocial Factors.
(1) Background: In the treatment of colorectal cancer, it is important to consider different psychosocial factors. Our first objective was to measure the levels of perceived stress in subjects diagnosed with colorectal cancer awaiting potentially curative surgery. Also, we aimed to analyse what coping styles these patients used, how they perceived their illness, and the subsequent influence of these factors on their levels of stress. (2) Methods: Stress, coping styles and illness perception were assessed in a sample of 107 patients. The instruments used were the Perceived Stress Scale (PSS-14), the Stress Coping Questionnaire (SCQ) and the Brief Illness Perception Questionnaire (BIPQ-R). (3) Results: Patients using active coping styles have lower levels of perceived stress (p = 0.000; p = 0.002) than patients making use of passive coping styles (p = 0.000; p = 0.032; p = 0.001). A multi-linear regression model found that the perception of illness and the use of the negative approach coping style (p = 0.000; p = 0.001) influence an increase in perceived stress, and that a decrease in stress levels was influenced by the problem solving coping style (p = 0.001). (4) Conclusions: Based on our results, we recommend preventive interventions in care patients undergoing colorectal cancer surgery.


Detection of enhancer repeats in the long terminal repeats of feline leukemia viruses from cats with spontaneous neoplastic and nonneoplastic diseases.
Enhancer duplication in the long terminal repeat of feline leukemia virus (FeLV) was examined in primary cells from naturally FeLV-infected cats with various neoplastic and nonneoplastic diseases using the polymerase chain reaction. In all cases, a 170-bp band, corresponding to a standard exogenous FeLV with one copy of enhancer, was detected. Repeated enhancer sequences were found in all 8 cases of thymic-form lymphosarcoma, in some cases of lymphosarcoma of other forms (3/8) and myeloid tumors (2/3), and in only 1 of 6 cases with nonneoplastic diseases. The copy number of FeLV proviruses with a repeated enhancer seemed higher than that of those with one copy of enhancer in 3 cases of thymic form lymphosarcoma. In 5 cases of thymic form lymphosarcoma and in 1 case of erythroleukemia, coexistent FeLVs with double and triple enhancers of different sizes were found. Of the enhancer elements, only the SV40 core binding site was found in all the enhancer direct repeats of these FeLVs. All the provirus clones with single and duplicated enhancer sequences from a single tumor showed mutations or deletions characteristic to that tumor, indicating that enhancer repeats may arise in individual animals after infection with a single virus clone. The present findings indicate that FeLV with enhancer repeats generated in the cat is associated with the induction of neoplastic diseases in natural conditions.


Pharmacokinetics of the new proton pump inhibitor ilaprazole in Chinese healthy subjects in relation to CYP3A5 and CYP2C19 genotypes.
PPIs are widely used in peptic diseases, and this paper is to investigate the kinetic characteristics of a new PPI ilaprazole in Chinese healthy subjects and the association with CYP3A5 and CYP2C19 polymorphisms. 21 subjects were selected and treated with 10mg ilaprazole according to their CYP3A5*3 genotypes (including 7 of CYP3A5*1/*1, 7 of *1/*3, and 7 of *3/*3). The plasma concentrations of ilaprazole and its metabolites were monitored by LC-MS/MS method. The C(max), AUC((0-6)), AUC((0-48)) and AUC((0-infinity)) of ilaprazole were all significantly different across the 3 CYP3A5 genotypes (including 4 of CYP3A5*1/*1, 4 of *1/*3, 3 of *3/*3; P<0.05) in CYP2C19 wild-type subjects (CYP2C19 wt/wts), similar variety of C(max) and AUC((0-6)) among CYP3A5 genotypes (including 3 of CYP3A5*1/*1, 3 of *1/*3, 4 of *3/*3; P<0.05) were also observed in CYP2C19 heterozygous subjects (CYP2C19 wt/mts). The sulfoxidation metabolic index (measure of collective CYP3A activity) indicates that the CYP3A5*1/*1, (high-expressers), *1/*3, (low-expressers), and *3/*3 (no-expressers) groups have medium, lowest and highest activities on ilaprazole metabolism, inconsistent with genotype-based CYP3A5 enzymatic activity. Further analysis showed no correlation between ilaprazole metabolism and CYP2C19 genotypes, evidenced by that the AUC((0-infinity)) of ilaprazole from either CYP3A5*1/*1 or CYP3A5*1/*3 groups was much higher in CYP2C19 wt/wts (n=4) than that in CYP2C19 wt/mts (n=3) (P<0.001), but the C(max) and AUC((0-6)) of ilaprazole from CYP3A5*3/*3 groups, were significantly lower in CYP2C19 wt/wts (n=3) compared to CYP2C19 wt/mts (n=4) (P<0.01). There was no demonstrated relationship between ilaprazole metabolism and CYP3A5 polymorphisms.


Evaluation of Anti-diabetic Property on Streptozotocin-Induced Diabetic Rats.
The diabetes-inducing agent streptozotocin (STZ) is a glucosamine-nitrosourea compound produced by Streptomyces achromogenes, which specifically induces DNA strand breakage in β-cells causing diabetes mellitus. The destruction of pancreatic β-cells by STZ is associated with a huge release of insulin in their first phase, and then in the second phase, the destruction has lead to deficiency of insulin causes hyperglycaemia. A detailed method on selection of diabetic animals, investigation of blood glucose levels, body weight, biochemical and histopathological parameters is presented in this chapter.


Soluble RANKL expression in Lactococcus lactis and investigation of its potential as an oral vaccine adjuvant.
To initiate mucosal immune responses, antigens in the intestinal lumen must be transported into gut-associated lymphoid tissue through M cells. Recently, it has been increasingly recognized that receptor activator of NF-kB ligand (RANKL) controls M cell differentiation by interacting with RANK expressed on the sub-epithelium of Peyer's patches. In this study, we increased the number of M cells using soluble RANKL (sRANKL) as a potent mucosal adjuvant. For efficient oral delivery of sRANKL, we constructed recombinant Lactococcus lactis (L. lactis) IL1403 secreting sRANKL (sRANKL-LAB). The biological activity of recombinant sRANKL was confirmed by observing RANK-RANKL signaling in vitro. M cell development in response to oral administration of recombinant L. lactis was determined by 1.51-fold higher immunohistochemical expression of M cell marker GP-2, compared to that of non-treatment group. In addition, an adjuvant effect of sRANKL was examined by immunization of mice with M-BmpB as a model antigen after treatment with sRANKL-LAB. Compared with the wild-type L. lactis group, the sRANKL-LAB group showed significantly increased systemic and mucosal immune responses specific to M-BmpB. Our results show that the M cell development by sRANKL-LAB can increase the antigen transcytotic capability of follicle-associated epithelium, and thereby enhance the mucosal immune response, which implies that oral administration of sRANKL is a promising adjuvant strategy for efficient oral vaccination.


Beneficial effects of luseogliflozin on lipid profile and liver function in patients with type 2 diabetes mellitus (BLUE trial): a single-center, single-arm, open-label prospective study.
Arteriosclerosis and non-alcoholic fatty liver disease are major complications of diabetes mellitus. Hyperglycemia, insulin resistance, obesity, and metabolic syndrome are associated with the progression of these complications. Sodium-glucose transporter 2 inhibitors such as luseogliflozin are oral hypoglycemic agents that reduce glucose levels, induce loss of weight or body fat, and improve liver function. However, the effects of these agents on lipid profiles are unclear. Therefore, this study aimed to investigate these effects and their relationship with arteriosclerosis and non-alcoholic fatty liver disease. This single-center, single-arm, open-labeled prospective study enrolled 25 outpatients with type 2 diabetes mellitus who visited Minami Osaka Hospital. Laboratory tests and body measurements were performed at weeks 0 and 24. Luseogliflozin was started at 2.5 mg/day after breakfast, and data from weeks 0 and 24 were evaluated. There were no changes in the doses of other antidiabetic and dyslipidemia drugs a month prior to or during the study. The patients showed significant reductions in the levels of triglycerides, remnant-like particle cholesterol, and triglyceride/high-density lipoprotein cholesterol ratio, along with significant increases in the levels of high-density lipoprotein cholesterol and apolipoprotein A-1. Alanine aminotransferase, γ-glutamyl transpeptidase, and the fatty liver index were significantly reduced. Luseogliflozin-induced changes in the lipid profile were related to the suppression or improvement of arteriosclerosis and liver function, respectively. Patients who received this drug also showed improvements in the levels of liver enzymes and reductions in the fatty liver index. Earlier use of luseogliflozin might prevent diabetic complications. Trial registration This study was registered in the University Hospital Medical Information Network Clinical Trial Registry (UMIN 000043595) on April 6th, 2021.


Reading skill and neural processing accuracy improvement after a 3-hour intervention in preschoolers with difficulties in reading-related skills.
This study aimed at determining whether an intervention game developed for strengthening phonological awareness has a remediating effect on reading skills and central auditory processing in 6-year-old preschool children with difficulties in reading-related skills. After a 3-hour training only, these children made a greater progress in reading-related skills than did their matched controls who did mathematical exercises following comparable training format. Furthermore, the results suggest that this brief intervention might be beneficial in modulating the neural basis of phonetic discrimination as an enhanced speech-elicited mismatch negativity (MMN) was seen in the intervention group, indicating improved cortical discrimination accuracy. Moreover, the amplitude increase of the vowel-elicited MMN significantly correlated with the improvement in some of the reading-skill related test scores. The results, albeit obtained with a relatively small sample, are encouraging, suggesting that reading-related skills can be improved even by a very short intervention and that the training effects are reflected in brain activity. However, studies with larger samples and different subgroups of children are needed to confirm the present results and to determine how children with different dyslexia subtypes benefit from the intervention.


The influence of pulsed electromagnetic field therapy (PEMFT) on cutaneous blood flow in healthy volunteers1.
The biophysical interaction induced by low energy pulsed electromagnetic field therapy (PEMFT) on the capillary microcirculation is not well understood. Several studies indicate a significant effect of PEMFT in patients with chronic medical conditions. The aim of this study was to evaluate the influence of PEMFT on skin microcirculation in healthy volunteers. 15 healthy participants were included. Nine PEMF treatments were applied over three weeks in an 48-hour interval. The PEMFT system (BEMER) was placed beneath one of the participants' leg with the contralateral side serving as a control. A forty-minute application period was preceded by a 10-minute resting phase. Measuring was done using two Laser Doppler probes (LEA) placed on each anterior lateral thigh. All outcome parameters including flow, mixed venous oxygen saturation and relative venous hemoglobin showed a significant increase during the experiment when compared to the baseline values of the resting phase in both groups (p < 0.01). Comparing both groups, the measurement values during the experiment did not differ (p > 0.05) except for higher flow values in the control group (P = 0.03). Over time, baseline values of both groups showed no significant difference (p > 0.05). We found a significant increase of all measurement parameters during the study compared to the baseline values with no difference between the PEMF and control group.


Left Atrial Myopathy is Associated With Exercise Incapacity and Ventilatory Inefficiency in Hypertrophic Cardiomyopathy.
Left atrial (LA) myopathy is an established component of hypertrophic cardiomyopathy (HCM); however, the data about its association with exercise incapacity or ventilatory inefficiency that may be seen in HCM patients are limited. This study aimed to explore the association between LA myopathy, evaluated by echocardiography LA strain, and exercise capacity and ventilatory efficiency, evaluated by cardiopulmonary exercise testing (CPET), in HCM patients. This study included 241 consecutive HCM patients (aged 51.2±15.7 years 67.2% male) in sinus rhythm who underwent CPET and transthoracic echocardiography at the same visit. Exercise incapacity (maximal/predicted oxygen consumption [%peakVO2] <80%) and ventilatory inefficiency (ventilation/carbon dioxide output [VE/VCO2] slope >34) were assessed by CPET. Left atrial myopathy was examined by speckle-tracking myocardial deformation parameters: LA reservoir, conduit and booster strain. All three LA strain values were univariate predictors of exercise capacity and ventilatory efficiency. Among them, LA reservoir strain had the higher r correlation coefficient for predicting both %peakVO2 and VE/VCO2 slope. Left atrial reservoir strain, presence of angina and family history of HCM were independent predictors of exercise capacity. Left atrial reservoir strain, male gender and non-sustained ventricular tachycardia were independent predictors of ventilatory efficiency. Left atrial reservoir strain was a significant predictor of %peakVO2<80% with an optimal cut-off value of 27% (sensitivity 87% and specificity 31%) and VE/VCO2>34 with an optimal cut-off value of 18% (sensitivity 71% and specificity 83%). Left atrial myopathy, as reflected by the LA strain values, was associated with exercise incapacity and ventilatory inefficiency in HCM individuals. Left atrial reservoir strain was the only common independent predictor of %peakVO2 and VE/VCO2 slope.


The structure and function of oxidized albumin in hemodialysis patients: Its role in elevated oxidative stress via neutrophil burst.
Oxidized albumin is a reliable marker of oxidative stress in hemodialysis (HD) patients. However, oxidized albumin in vivo and its possible clinical significance has been rarely investigated. In the present study, the qualitative modification of albumin in HD patients (n = 20) was examined and their results were compared with healthy age-matched controls (n = 10). The increase in plasma protein carbonyl levels in HD patients was largely due to an increase in oxidized albumin. Human serum albumin (HSA) of HD patients, HSA of HD patients (HD-HSA) and normal subjects (Normal-HSA) were purified on a blue Sepharose CL-6B column. Spectroscopic analysis confirmed that the HD-HSA samples contained higher levels of carbonyls than Normal-HSA. An HPLC analysis also suggested that the state of the purified HSA used throughout the experiments accurately reflects the redox state of albumin in blood. HD-HSA was found to have a decreased the antioxidant activity, and was able to trigger the oxidative burst of human neutrophils, compared to Normal-HSA. HD-HSA was conformationally altered, with its hydrophobic regions more exposed and to have a negative charge. In binding experiments, HD-HSA showed impaired Site II-ligand binding capabilities. Collectively, the oxidation of plasma proteins, especially HSA, might enhance oxidative stress in HD patients.


A colorimetric and fluorescent dual-modal displacement probe based on host-assisted modulation of intramolecular charge transfer and deaggregation.
A new colorimetric and fluorescent dual-modal displacement probe was developed based on a supramolecular host-guest complex of cucurbit[8]uril (CB8) and a new functionalized perylene derivative involving macrocycle encapsulation that modulated intramolecular charge transfer and deaggregation.


Abnormalities in the face primary motor cortex in oromandibular dystonia.
To comprehensively investigate excitability in face and hand M1 and sensorimotor integration in oromandibular dystonia (OMD) patients. Short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), short (SAI) and long (LAI) afferent inhibition were investigated in face and hand M1 using transcranial magnetic stimulation protocols in 10 OMD patients. Data were compared with those obtained in 10 patients with focal hand dystonia (FHD), in 10 patients with blepharospasm (BSP), and 10 matched healthy subjects (HS). Results demonstrated that in OMD patients SICI was reduced in face M1 (p < 0.001), but not in hand M1, compared to HS. In FHD, SICI was significantly impaired in hand M1 (p = 0.029), but not in face M1. In BSP, SICI was normal in both face and hand M1 while ICF and LAI were normal in all patient groups and cortical area tested. SAI was significantly reduced (p = 0.003) only in the face M1 of OMD patients. In OMD, SICI and SAI were significantly reduced. These abnormalities are specific to the motor cortical area innervating the muscular district involved in focal dystonia. In OMD, the integration between sensory inflow and motor output seem to be disrupted at cortical level with topographic specificity.


Reliability and validity of assessing lower-limb muscle architecture of patients with cerebral palsy (CP) using ultrasound: A systematic review.
To investigate the reliability, validity, and level of evidence of applying ultrasound in assessing the lower-limb muscles of patients with cerebral palsy (CP). Publications in Medline, PubMed, Web of Science, and Embase were searched on May 10, 2023, to identify and examine relevant studies investigating the reliability/validity of ultrasound in evaluating the architecture of CP lower-limb muscles systematically, following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis 2020 guidelines. Out of 897 records, 9 publications with 111 CP participants aged 3.8-17.0 years were included (8 focused on intra-rater and inter-rater reliability, 2 focused on validity, and 4 were with high quality). The ultrasound-based measurements of muscle thickness (intra-rater only), muscle length, cross-sectional area, muscle volume, fascicle length, and pennation angle showed high reliability, with the majority of intraclass correlation coefficient (ICC) values being larger than 0.9. Moderate-to-good correlations between ultrasound and magnetic resonance imaging measurements existed in muscle thickness and cross-sectional area (0.62 ≤ ICC ≤ 0.82). Generally, ultrasound has high reliability and validity in evaluating the CP muscle architecture, but this is mainly supported by moderate and limited levels of evidence. More high-quality future studies are needed.


[Hematuria in cases of bladder cancer].
In the majority of cases, painless macroscopic hematuria is a typical initial symptom of bladder carcinoma. The time of occurrence (early and late symptom) neither correlates with tumor size and degree nor with infiltration depth. The respective testing method and threshold value exert a significant influence on frequency and constancy of a potential microscopic hematuria. Without sufficient standardization, however, it is understandable that even the existing guidelines for diagnosis of hematuria recommend different methods and threshold values. This paper provides an overview of the various testing methods and threshold values in microscopic hematuria, their influence on the diagnosis of bladder carcinoma as well as the possibility of differentiating the source of hematuria morphologically.


Morphometric analysis of thoracic muscles in wildtype and in bithorax Drosophila.
The tergotrochanteral (TTM) "jump" muscles in the second (T2) and third (T3) thoracic segments of the fruit fly, Drosophila melanogaster, were analyzed morphologically and morphometrically in wildtype (Canton-S) and bithorax mutants (abx bx3 pbx/Df(3R)P2). In the transformed T3 segments of mutant flies, the TTMs were greatly increased in fiber number (330% of wildtype), length (141%), and volume (460%), thus manifesting both hyperplasia and hypertrophy. In contrast, TTMs in the "untransformed" T2 segments of mutant flies were both hypoplastic and hypotrophic, in that significant decreases in fiber number (93% of wildtype), length (90%), and volume (80%) were observed. Two relationships emerged from analysis of the morphometric data: 1) Although the fiber numbers and volumes of the transformed T3 TTMs in bithorax flies were greatly increased, the total combined volumes of the TTMs in T2 + T3 remained approximately the same in bithorax compared to wildtype flies. 2) The changes in TTM volumes in bithorax flies compared to those in wildtype were proportional to the relative changes in fiber numbers times the relative changes in muscle lengths. These observations suggest that the genes of the bithorax complex influence the number and the length of tubular muscles fibers of the TTMs, but do not significantly affect the mean cross-sectional areas of these fibers. Fibrillar muscle fibers, which are not found at all in T3 segments in wildtype flies, were observed in the transformed T3 segments of bithorax mutants in 11 of 18 cases (61%), but typically as wisps, not in complete muscles. We suggest that, in the T3 segment of the bithorax flies, the relative differences between the massive transformation of tubular TTMs vs. the minimal appearance of fibrillar muscles may be related, in part, to the relative availability of muscle precursors.


Results of transurethral resection of the prostate in renal transplant recipients: a single center experience.
The aim of this study was to retrospectively evaluate the early and long-term results of renal transplantation (RT) patients undergoing transurethral resection of the prostate (TURP) due to benign prostate hyperplasia (BPH). Eighty-nine patients with RT performed in our hospital underwent TURP between November 2008 and March 2016. Results were evaluated along with early and long-term complications. Patients were followed up for a minimum of 12 months. The mean age of the patients was 61.4 ± 7.4 years. The median duration of dialysis was 28 (0-180) months. The median duration between transplantation and TURP was 13 (0-84) months. Before TURP, the mean serum creatinine (sCr) was 1.99 ± 0.83 mg/dL and the mean prostate volume was 33.3 ± 14.6 cm3. The mean Q max, Q ave and PVR values were 9.5 ± 3.7, 5.2 ± 2.2 ml/s and 85(5-480) mL, respectively. None of the patients developed perioperative and postoperative major complications. Twelve patients (13.4%) developed urinary tract infections in the postoperative period. The sCr, IPSS and PVR values significantly decreased, while Q max and Q ave significantly increased at the 1-month follow-up. At the 6-month follow-up, 63 (70.8%) patients had retrograde ejaculation. Patients were followed up for a median of 42 (12-96) months. Three patients (3.3%) were re-operated for bladder neck contracture and eight (8.9%) patients were re-operated for urethral stricture. TURP can be safely and successfully applied for the treatment of BPH after RT. LUTS and renal functions significantly improve after the operation. Patients should be followed up for UTIs in the short term and for urethral stricture in the long term.


Expression of endogenous murine leukaemia viruses in AKR/J streaker mice.
MICE of the AKR/J strain show high rates of spontaneous thymic lymphoma and are chronically infected with murine leukaemia viruses. Total thymectomy in young mice of this strain results in a marked decrease in the incidence of leukaemia. The finding of athymic mutant mice on the AKR/J background (referred to as streaker mice) is of importance in the study of genetic factors which influence virus expression and leukaemogenesis. Here we report that mice of both normal and mutant genotypes vary in the expression of a particular class of murine leukaemia virus. This lower virus expression in conjunction with the absence of a thymus leads to a lower tumour incidence in streaker mice.


Interaction of benzo [A] pyrene and a hyperplastic agent in epidermal nuclear enlargement in the mouse. A dose response study.
Experiments were conducted on the effects of various dose levels of benzo [a]pyrene (BP) on nuclear size in mouse interfollicular epidermis over a 3-day period. Topical application of BP was made with or without croton oil (CO) (0.1 or 0.5%) in the vehicles acetone, toluene and methyl ethyl ketone (MEK). Nuclear size was measured on histological sections either manually or by Quantimet Image Analyser. Vehicle controls treated with 0.1 or 0.5% CO in acetone or MEK gave rise to epidermal hyperplasia with some nuclear enlargement and toluene without CO produced a similar response. It was found that when BP was applied in a vehicle capable of inducing hyperplasia, the nuclear enlargement produced was greater than that produced by either the vehicle control or BP in a non-irritant vehicle. The enhancement of response to BP when tested in the presence of a hyperplastic agent resulted in lower concentrations of BP being detectable. As the levels of BP detectable by nuclear enlargement under these conditions compared reasonably well with those detectable in long-term tests, this system might be usable as a basis for a short-term test for carcinogens.


Turbidity regimes over fringing coral reefs near a mining site at Lihir Island, Papua New Guinea.
An extensive sediment transport survey took place at Lihir Island (Papua New Guinea), where mining operations involve disposal of waste rocks and soil in nearshore waters. To investigate the potential impact of these practices over neighbouring fringing reefs, turbidity and sediment accumulation were measured continuously for extended periods. Turbidity records provided a map of observed impact zones based on turbidity thresholds. The main zoning features were (a) that an extreme turbidity gradient persists between the inner harbour (turbidity levels of 100-1000 mg l(-1)) and the adjacent reefs (turbidity levels in the order of 10 mg l(-1)), and (b) that observed zones conform with pre-operations impact predictions. Accumulation measurements unveiled no significant sediment accumulation over fringing coral reefs. This study contributes to the understanding of the potential impact of sediment discharge to nearshore waters.


Justification of 150 mg clopidogrel in patients with high on-clopidogrel platelet reactivity.
The GRAVITAS trial showed that 150 mg clopidogrel did not improve outcome in patients with high on-clopidogrel platelet reactivity (HPR) screened by the VerifyNow assay. We aimed to determine the impact of 150 mg clopidogrel in stable angina patients with HPR identified with conventional aggregometry (LTA). Clopidogrel-naive stable angina patients before ad hoc percutaneous coronary intervention were recruited into a randomized, double-blind, placebo-controlled trial (NCT00638326). Twelve to 24 h after the 600-mg loading dose of clopidogrel, ADP(5μM)-stimulated maximal (AGGmax), late platelet aggregation (AGGlate) and vasodilator-stimulated phosphoprotein phosphorylation (VASP-PRI) were evaluated. Patients with HPR (AGGmax ≥ 34%) were randomly allocated to 75 or 150 mg clopidogrel after 4 weeks. After control platelet function measurements at day 28, 75 mg clopidogrel was administered to all patients until 1 year. The study was prematurely terminated at the stage of 200 enroled patients. Administration of 150 mg clopidogrel significantly reduced platelet aggregation (AGGmax: 45·0 ± 6·8 vs. 33·8 ± 15·1, P < 0·01; AGGlate: 27·1 ± 14·7 vs. 13·8 ± 18·0, P < 0·01) and VASP-PRI (57·5 ± 15·2 vs. 37·2 ± 17·1; P < 0·01), while platelet reactivity remained unchanged in patients with HPR receiving 75 mg clopidogrel. The higher maintenance dose of clopidogrel was associated with a significant reduction in cardiovascular (CV) death and myocardial infarction (MI) (0% vs. 11·4%, P = 0·04) and in CV death, MI or target vessel revascularization (24·6% vs. 3·1%; P = 0·01) during 1 year. One-month administration of 150 mg maintenance dose of clopidogrel reduces platelet reactivity and might decrease the risk of thrombo-ischaemic complications in stable angina patients with HPR identified by LTA.


Influence of a vitamin E-deficient diet on prostacyclin production by mesometrial triangles and aortic rings from nondiabetic and diabetic pregnant rats.
We investigated the effect of a vitamin E-deficient diet on the synthesis of prostacyclin in nondiabetic and diabetic pregnant rats. In both groups the diet reduced fetal growth and prostacyclin production by mesometrial triangles; it also increased serum lipid peroxides, which are known to inhibit prostacyclin synthesis. Independently of the diet, mesometrial triangles of diabetic rats produced more prostacyclin than those of control rats, whereas an opposite tendency was found in the aortic rings. Our model seems useful for fundamental and pharmacologic studies of the vascular pathology of pregnancy.


Lysosomal glycogen storage disease with normal acid maltase with early fatal outcome.
In a male infant who had cardiomyopathy, generalized muscle weakness and increased serum creatine kinase levels, his muscle biopsy revealed myopathic changes with tiny intracytoplasmic vacuoles containing PAS-positive material and high acid phosphatase activity, but had normal acid maltase activity biochemically. These findings were consistent with those seen in lysosomal glycogen storage disease with normal acid maltase (Danon disease). Sarcolemmal indentations commonly seen in this disease were missing, but a complement membrane attack complex, C5b-9 was positive along the surface membrane of the muscle fibers as seen in X-linked vacuolar myopathy. The patient was on a respirator and died at 27 months of age from pneumonia and hypertrophic cardiomyopathy. Lysosomal glycogen storage disease with normal acid maltase may be manifested at birth with marked skeletal and cardiac involvement leading to death in early infancy.


Mild anemia and 11- to 15-year mortality risk in young-old and old-old: Results from two population-based cohort studies.
Mild anemia is a frequent although often overlooked finding in old age. Nevertheless, in recent years anemia has been linked to several adverse outcomes in the elderly population. Objective of the study was to investigate the association of mild anemia (hemoglobin concentrations: 10.0-11.9/12.9 g/dL in women/men) with all-cause mortality over 11-15 years and the effect of change in anemia status on mortality in young-old (65-84 years) and old-old (80+ years). The Health and Anemia and Monzino 80-plus are two door-to-door, prospective population-based studies that included residents aged 65-plus years in Biella municipality and 80-plus years in Varese province, Italy. No exclusion criteria were used. Among 4,494 young-old and 1,842 old-old, mortality risk over 15/11 years was significantly higher in individuals with mild anemia compared with those without (young-old: fully-adjusted HR: 1.35, 95%CI, 1.15-1.58; old-old: fully-adjusted HR: 1.28, 95%CI, 1.14-1.44). Results were similar in the disease-free subpopulation (age, sex, education, smoking history, and alcohol consumption adjusted HR: 1.54, 95%CI, 1.02-2.34). Both age groups showed a dose-response relationship between anemia severity and mortality (P for trend <0.0001). Mortality risk was significantly associated with chronic disease and chronic kidney disease mild anemia in both age groups, and with vitamin B12/folate deficiency and unexplained mild anemia in young-old. In participants with two hemoglobin determinations, seven-year mortality risk was significantly higher in incident and persistent anemic cases compared to constant non-anemic individuals in both age groups. In participants without anemia at baseline also hemoglobin decline was significantly associated with an increased mortality risk over seven years in both young-old and old-old. Limited to the Monzino 80-plus study, the association remained significant also when the risk was further adjusted also for time-varying covariates and time-varying anemia status over time. Findings from these two large prospective population-based studies consistently suggest an independent, long-term impact of mild anemia on survival at older ages.


Human Blastocyst Secreted microRNA Regulate Endometrial Epithelial Cell Adhesion.
Successful embryo implantation requires synchronous development and communication between the blastocyst and the endometrium, however the mechanisms of communication in humans are virtually unknown. Recent studies have revealed that microRNAs (miRs) are present in bodily fluids and secreted by cells in culture. We have identified that human blastocysts differentially secrete miRs in a pattern associated with their implantation outcome. miR-661 was the most highly expressed miR in blastocyst culture media (BCM) from blastocysts that failed to implant (non-implanted) compared to blastocysts that implanted (implanted). Our results indicate a possible role for Argonaute 1 in the transport of miR-661 in non-implanted BCM and taken up by primary human endometrial epithelial cells (HEECs). miR-661 uptake by HEEC reduced trophoblast cell line spheroid attachment to HEEC via PVRL1. Our results suggest that human blastocysts alter the endometrial epithelial adhesion, the initiating event of implantation, via the secretion of miR, abnormalities in which result in implantation failure.


Genome modification in two lines of baby hamster kidney fibroblasts (BHK-21).
Reasons for the different levels of 5-methyl cytosine encountered in the DNA of two baby hamsters kidney fibroblast lines, BHK-21/C13 and BHK-21/PyY have been investigated. From enzymic studies it does not seem that there are large numbers of potentially methylatable cytosine residues in the C13 line DNA which contains a lower level of 5-methyl cytosine. Rather it is possible that the difference may be due to the reiteration in the PyY strain of certain sequences containing 5-methyl cytosine which simply occur less frequently in the other line.


Systematic review of the pharmacological treatment of alcohol use disorders in individuals infected with hepatitis C.
Treating alcohol use disorders (AUD) is critical in individuals suffering from hepatitis C infection (HCV). Aside from psychosocial interventions, pharmacological treatment is effective for decreasing alcohol consumption and promoting abstinence. However, unique factors belonging to HCV-infected individuals, such as baseline hepatic vulnerability and possible ongoing hepatitis C treatment, complicate AUD drug therapy. The goal of this review is to systematically identify, summarize, and evaluate the existing evidence on the pharmacological management of AUD in HCV-infected individuals. MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials were searched for English- and French-language articles published from 1993 to December 2013. The search criteria focused on clinical trials and observational studies assessing the efficacy and/or safety of pharmacological management of AUD in patients infected with HCV. Of 421 identified studies, three were included for analysis. Two were observational studies assessing the safety of disulfiram. One was a randomized controlled trial assessing the efficacy and safety of baclofen. There is paucity of data regarding the efficacy and safety of pharmacological treatment of AUD in HCV-infected individuals, with studies being small series and showing significant heterogeneity. No strong recommendations can be made based on the current studies as to which pharmacological option should be preferred in this sub-population.


Methacholine delays pulmonary absorption of inhaled β(2)-agonists due to competition for organic cation/carnitine transporters.
The aim of the present investigation was to compare the pulmonary absorption of the novel long-acting β(2)-agonist GW597901 with salbutamol and to determine the influence of an induced bronchoconstriction on the pharmacokinetics of the compounds using a human lung reperfusion model. In an initial study with six lung perfusions the pharmacokinetic properties of the β(2)-agonists were determined. We then investigated the influence of an induced bronchoconstriction on the pulmonary absorption in six lung lobes for each drug. Therefore, methacholine (MCh) challenge agent was nebulised prior to administration of the β(2)-agonists. As expected, the extent of pulmonary absorption of salbutamol into the perfusate was more pronounced than for the more lipophilic GW597901. Although the observed differences were not statistically significant they were further supported by analysis of tissue concentrations. In contrast, we observed a statistically significant influence of the bronchoprovocation with MCh on the pulmonary absorption of both β(2)-agonists, but this effect was not limited to a successfully induced bronchoconstriction. A prominent decline of salbutamol distribution into perfusion fluid was also observed when the organic cation transporter substrate carnitine was nebulised prior to the bronchodilator. Nebulised methacholine had a significant influence on the pharmacokinetics of bronchodilators. Since we observed this effect independently of a successfully induced bronchoconstriction and also after nebulisation of carnitine we suggest a significant delay of pulmonary absorption of inhaled salbutamol and GW597901 due to competition for a cation/carnitine drug transporter, most likely OCTN2.


[Benign mesenchymal tumors of the spinal canal. Clinical aspects and long-term results].
22 patients were operated on because of a benign mesenchymal tumor in the spinal canal. 14 women and 8 men were affected, the average age being 37 years. Preoperatively 7 patients showed an incomplete or complete transverse lesion with a mean duration of the disease being 30 months. After the operation 19 patients showed an improvement, of these 17 were able to walk by themselves. 10 patients became again fit to work. One patient died after the operation.


Analysis of the protovirus hypothesis.
Cancer may be endogenous to all mankind. Its activity is dependent upon the absence of anti cancer gene agent or agents.


Two-column sequential injection chromatography for fast isocratic separation of two analytes of greatly differing chemical properties.
This paper deals with a novel approach to separate two analytes with different chemical properties and different lipophilicity. The newly described methodology is based on the two column system that was used for isocratic separation of two analytes with very different lipophilicity-dexamethasone and cinchocaine. Simultaneous separation of model compounds cinchocaine and dexamethasone was carried under the following conditions in two-column sequential injection chromatography system (2-C SIC). A 25×4.6 mm C-18 monolithic column was used in the first dimension for retention and separation of dexamethasone with mobile phase acetonitrile:water 30:70 (v/v), flow rate 0.9 mL min(-1) and consumption of 1.7 mL. A 10×4.6 mm C-18 monolithic column with 5×4.6 mm C-18 precolumn was used in the second dimension for retention and separation of cinchocaine using mobile phase acetonitrile:water 60:40 (v/v), flow rate 0.9 mL min(-1) and consumption 1.5 mL. Whole analysis time including both mobile phase's aspirations and both column separations was performed in less than 4 min. The method was fully validated and used for determination of cinchocaine and dexamethasone in pharmaceutical otic drops. The developed 2-C SIC method was compared with HPLC method under the isocratic conditions of separation on monolithic column (25×4.6 mm C-18). Spectrophotometric detection of both compounds was performed at wavelength 240 nm. System repeatability and method precision were found in the range (0.39-3.12%) for both compounds. Linearity of determination was evaluated in the range 50-500 μg mL(-1) and coefficients of determination were found to be r(2)=0.99912 for dexamethasone and r(2)=0.99969 for cinchocaine.


Three-dimensional knee model: constrained by isometric ligament bundles and experimentally obtained tibio-femoral contacts.
The purpose of this study is to investigate the effect of anterior portion of anterior cruciate ligament, posterior cruciate ligament, anterior and deep portions of medial collateral ligament and the tibio-femoral articular contacts on passive knee motion. A well-accepted reference model for a normal tibio-femoral joint is reconstructed from the literature. The proposed three-dimensional dynamic tibio-femoral model includes the isometric fascicles, ligament bundles and irregularly shaped medial-lateral contact surfaces. With the approach we aim to analyze bone shape and ligament related abnormalities of knee kinematics. The rotations, translations and the contact forces during passive knee flexion were compared against a reference model and the results were found in close accordance. This study demonstrated that isometric ligament bundles play an important role in understanding the femur shape from contact points on tibia. Femoral condyles are not necessarily spherical. The surgical treatments should consider both ligament bundle lengths and contact surface geometries to achieve a problem free knee kinematics after a knee surgery.


Coccidiosis in Sudanese camels (Camelus dromedarius): 1--First record and description of Eimeria spp. harboured by camels in the eastern region of Sudan.
Coccidial oocysts were detected in 40 (17.4%) out of 230 faecal samples obtained from camels in the Eastern Region of Sudan during June 1985-June 1986. These oocysts were identified as Eimeria rajasthani, Eimeria dromedarii and Eimeria cameli. A detailed description of sporulated oocysts is given in this study and variations from previous authors' findings are discussed.


Screening for intra-anal squamous intra-epithelial lesions in women with a history of human papillomavirus-related vulvar or perianal disease: results of a screening protocol.
Women with a history of human papillomavirus (HPV)-related cervical, vaginal or vulvar high-grade squamous intra-epithelial lesions (HSILs) or cancer are at increased risk of developing anal squamous intra-epithelial lesions (SILs) or a squamous cell carcinoma of the anus (SCCA). Screening for intra-anal SILs with high-resolution anoscopy (HRA) in high-risk populations is a subject of debate. In this study we aimed to answer the following question: what is the prevalence of intra-anal (H)SIL in women with HPV-related vulvar and/or perianal disease using HRA for screening? A retrospective study was performed to evaluate the prevalence of intra-anal (H)SIL in women with a history of vulvar and/or perianal HSIL or (superficially invasive) squamous cell carcinoma (SCC). This study was performed between 2015 and 2018 following implementation of a protocol for intra-anal screening using HRA. Twenty-seven patients, 10 with a history of (superficially invasive) SCC (four vulvar, five perianal, one multizonal) and 17 with HSIL as the worst diagnosis (two perianal, 15 multizonal) were screened for intra-anal lesions using HRA. No anal cancer was found at screening, 6 (22%) patients were diagnosed with intra-anal HSIL and 12 (44%) patients with intra-anal low-grade SIL. We found a high prevalence of intra-anal HSIL in women previously diagnosed with vulvar and perianal HSIL. Given the clear link between HSIL and SCCA, screening for intra-anal lesions in women with HPV-related genital pathology seems warranted. Future studies should focus on the effect of HSIL treatment on the prevention of anal cancer.


Photoreceptor membrane breakdown in the spider Dinopis: localisation of acid phosphatases.
The ultrastructural localisation of acid phosphatases (AcPhs) during the normal daily breakdown of rhabdomere membrane in Dinopis has been examined using beta-glycerophosphate and p-nitrophenyl phosphate as substrates. Results are related to the classification of organelles in the receptors given by Blest, Powell and Kao (1978). Weak and infrequent reactions are obtained in multivesicular bodies (mvbs) and multilamellar bodies (mlbs) derived from them. Residual bodies (rbs) begin to react strongly as they lyse. Source of AcPhs is endoplasmic reticulum which has barely differentiated towards the GERL configuration; it becomes reactive as it is incorporated into secondary lysosomes. GERL tubules, Y-bodies and vesicles respond erratically and weakly, and are also incorporated into rbs. No evidence was found for a significant participation of Golgi bodies in these processes, and acid phosphatase cytochemistry fails to reveal a topographical relationship between GERL in these cells and Golgi saccules. Coated vesicle clusters found in the predawn receptive segments are AcPh-negative; this implies that their previous identification as GERL-derived "Nebenkerne" carrying hydrolytic enzymes to newly-formed mvbs (Blest, Kao and Powell, 1978) is dubious. Isolation bodies and autophagic vacuoles enclosing other organelles in pathological receptors give strong reactions while adjacent secondary lysosomes derived from rhabdomere membrane and associated GERL give weak ones. It is concluded that rhabdomere-derived rb lysis is more tightly regulated than other autophagic processes, and it is suggested that a high degree of control is necessary in a receptor which may repeat the autophagy of a large mass of transductive membrane at least 60--100 times in the course of its working life.


Co-occurrence of multiple sclerosis and cancer in a BRCA1 positive family.
Multiple sclerosis is not known to be a risk factor for subsequent development of cancer. Recently, a multiple sclerosis locus was mapped adjacent to BRCA1 gene. We present a familial case affected by multiple sclerosis and cancer. We identified a c.5266dupC (5382insC) frameshift mutation in a 33-year-old woman with breast cancer, multiple malignant melanomas and multiple sclerosis. The patient's family history shows further cases of multiple sclerosis in BRCA1 mutation carriers. Therefore the presented family may carry a monogenic predisposition for multiple sclerosis nearby to BRCA1.


Cervical Instability and Quadriparesis Requiring Stabilization in Pediatric Patient Caused by a Mutation in COL2A1.
A 3-year-old male with no past medical history presented with flaccid plegia of his upper extremities and significant weakness in his lower extremities after wrestling with his brother. Cervical spine magnetic resonance imaging was consistent with cord edema and intraparenchymal hemorrhage at C1-C2. A nonossified tissue mass at the expected location of the upper dens created narrowing of the canal at the C1-2 level and mass effect on the cord. Head computed tomography showed periventricular leukomalacia. Initial findings favored dysplasia of the odontoid with associated soft tissue mass/pannus caused by a possible underlying genetic or metabolic bone dyscrasia. The patient underwent suboccipital craniotomy/C1 laminectomy and occiput to C4 fusion, for decompression and stabilization. Genetic testing showed a COL2A1 collagen disorder, with the child harboring a de novo mutation for c.3455 G>T (p.G1152V). The patient was discharged to inpatient acute rehabilitation, with gradual improvement in strength in all 4 extremities.


Human immunodeficiency virus-associated vitiligo: expression of autoimmunity with immunodeficiency?
Persistent viral infections have been postulated to be trigger factors for the development of autoimmune disease. We report the development of vitiligo in four patients with human immunodeficiency virus (HIV)-related conditions and in one patient with hepatitis who later developed both psoriasis and acquired immunodeficiency syndrome (AIDS). Other common features were hepatitis and multiple other viral infections. Ribavirin was associated with repigmentation in one patient. Vitiligo may be an example of an autoimmune disease triggered by viral infection in a genetically predisposed host.


Liver transplantation for hepatocellular carcinoma: a single European centre experience.
With respect to deficient donor grafts and the risk of tumour recurrence, indication for orthotopic liver transplantation (OLT) is still controversial. OLT offers the only chance for both the tumour and the underlying liver disease to be eliminated in patients with hepatocellular carcinoma (HCC) and cirrhosis. The aim of this study was to assess survival and related factors of recurrence. This retrospective study analyses data from 45 patients with HCC (UICC stage I/II, n=16; III, n=13; IV, n=12) treated with OLT between 1992 and 2002 in our centre. There were 39 primary tumours and two recurrent ones after previous surgical resection. Four perioperative deaths were excluded from analysis. Mean follow-up was 50.4 months. Five-year rates after OLT were 64% for overall survival, 78% for disease-specific survival, 73% for recurrence-free survival, and 22% for tumour recurrence. No tumour recurrence has been observed so far in patients with tumours of UICC stage I/II. None of the patient characteristics had a significant impact on survival, while tumour stage was significantly correlated with freedom from recurrence. Our results demonstrate that the risk of recurrent HCC in liver transplanted patients is low for small and solitary tumours with no vascular invasion (UICC I/II). Even in advanced tumour stages (UICC III/IV), there is a real chance of cure or at least a survival benefit in selected patients.