Viability and differential function of rainbow trout liver cells in primary culture: coculture with two permanent fish cells.
The study investigates the influence of different culture conditions on attachment, viability and functional status of rainbow trout (Oncorhynchus mykiss) liver cells in primary culture. Cells were isolated by a two-step collagenase perfusion and incubated in serum-free, chemically defined minimal essential medium (MEM), (a) as a monolayer on uncoated PRIMARIA dishes, (b) as a monolayer on culture dishes coated with calf collagen type 1, and (c) in coculture with the established fish cell lines RTH-149 or RTG-2. Cell attachment was assessed from DNA and protein concentrations per dish, viability was estimated from cellular lactate dehydrogenase release, and the metabolic status was investigated by measuring activities of the phosphoenolpyruvate carboxykinase and biotransformation enzymes as well as the total cytochrome P450 contents. Seeding of hepatocytes on collagen-coated dishes did not alter cell attachment or detachment from the (culture substrate, but had a small, but not significant effect on cell viability and metabolic parameters. Coculture of liver cells and RTG-2 cells reduced hepatocyte detachment from the culture substrate, and it was associated with a significant elevation of 7-ethoxyresorufin-O-deethylase activities in the hepatic cells. Cytochrome P450 contents, however, were not altered. The coculture effect on liver cell physiology clearly depended on the type of cell line, because coculture with RTH-149 cells led to similar, but much weaker effects than obtained in cocultures with RTG-2 cells. Electron microscopical observations revealed the existence of gap junctions and possible exocytosis-like transport between cell lines and hepatocytes. The results point to the potential of coculture systems to improve physiological parameters of trout liver cells in primary culture.


Intentional Replantation with a 2-segment Restoration Method to Treat Severe Palatogingival Grooves in the Maxillary Lateral Incisor: A Report of 3 Cases.
The palatogingival groove is a developmental anomaly that typically starts near the cingulum of the maxillary incisors and extends along the roots at varying lengths and depths. Severe grooves that extend to the root apex often lead to complex combined periodontal-endodontic lesions. There are various therapeutic options available for these cases; however, the prognosis is unfavorable. Here, we report the successful surgical treatment of 3 cases of maxillary lateral incisors with severe palatogingival grooves using intentional replantation with a 2-segment restoration method. The teeth were gently extracted, resulting in minimal damage to the periodontal ligament. Under a dental operating microscope, 3 mm of the root end was resected. The palatogingival groove was removed, and root-end preparation was performed with a #700 fissure bur. The groove cavity was connected with root-end cavity to form a class II cavity. The cavity was then filled using a 2-segment restoration method (ie, dividing the cavity into 2 parts by the cementoenamel junction, the coronal portion was filled with a flowable composite while the radicular portion, including the root-end cavity, was filled with bioceramics). The tooth was then replanted into its alveolar bone and splinted with a flexible splint for 7 days. The sinus tract was closed at the 1-week postoperative visit. During subsequent recalls, the teeth showed almost complete periapical healing. In summary, intentional replantation with a 2-segment restoration method is a viable treatment modality for single-rooted teeth with a severe palatogingival groove that extends to the root apex.


Effects of orchidectomy and dihydrotestosterone on the choline acetyltransferase activity of specific rat brain areas.
1. The choline acetyltransferase (ChAT) activity of specific brain areas was determined in adult intact, orchidectomized and dihydrotestosterone (DHT)-treated orchidectomized rats. 2. Results show that orchidectomy decreased ChAT activity in most brain areas studied. 3. However, DHT treatment of orchidectomized animals increased ChAT activity only in the cerebral cortex.


Clinical consequences of analytical variance and calculation strategy in oral busulfan pharmacokinetics.
Busulfan pharmacokinetic (PK) monitoring of the area under the concentration-time curve (AUC) is necessary to minimize adverse events associated with both under- and over-dosing of busulfan during hematopoietic stem cell transplantation (HSCT). Three strategies are frequently used to calculate the AUC including in-house polynomial methods, the trapezoidal method (also called noncompartmental analysis), and the single compartment model with first-order elimination method. We compared these 3 methods, their clinical performance, and the relationship of AUC variance to analytical variance when each of these methods is used. Clinical busulfan PK data was reviewed from 159 patients receiving the first dose of oral busulfan while undergoing HSCT. These data were used as templates to simulate AUC results and actions with varying amounts of analytical precision. Based on a predefined goal therapeutic target, the method for calculating AUC significantly changed the number of recommended busulfan dose adjustments (p<0.000001). Overall, the number of dose adjustments would be expected to drop by approximately 10% due to calibration optimization of the busulfan concentration measurement method. Analytical variance and the AUC calculation method play a considerable role in the clinical management of busulfan dosing during HSCT. With better understanding and optimization of the analytical method, the reliability of clinically actionable information from busulfan PK can increase.


Study on fluorouracil-chitosan nanoparticle preparation and its antitumor effect.
To successfully prepare fluorouracil-chitosan nanoparticles, and further analyze its anti-tumor activity mechanism, this paper makes a comprehensive study of existing preparation prescription and makes a detailed analysis of fluorouracil-chitosan in vitro release and pharmacodynamic behavior of animals. Two-step synthesis method is adopted to prepare 5-FU-CS-mPEG prodrugs, and infrared, (1)H NMR and differential thermal analysis are adopted to analyze characterization synthetic products of prepared drugs. To ensure clinical efficacy of prepared drugs, UV spectrophotometry is adopted for determination of drug loading capacity of prepared drugs, transmission electron microscopy is adopted to observe the appearance, dynamic dialysis method is used to observe in vitro drug release of prepared drugs and fitting of various release models is done. Anti-tumor effect is studied via level of animal pharmacodynamics. After the end of the experiment, tumor inhibition rate, spleen index and thymus index of drugs are calculated. Experimental results show that the prepared drugs are qualified in terms of regular shape, dispersion, drug content, etc. Animal pharmacodynamics experiments have shown that concentration level of drug loading capacity of prepared drugs has a direct impact on anti-tumor rate. The higher the concentration, the higher the anti-tumor rate. Results of pathological tissue sections of mice show that the prepared drugs cause varying degrees of damage to receptor cells, resulting in cell necrosis or apoptosis problem. It can thus be concluded that ion gel method is an effective method to prepare drug-loading nanoparticles, with prepared nanoparticles evenly distributed in regular shape which demonstrate good slow-release characteristics in receptor vitro and vivo. At the same time, after completion of drug preparation, relatively strong anti-tumor activity can be generated for the receptor, so this mode of preparation enjoys broad prospects for development.


Emergency transjugular intrahepatic portosystemic shunt for uncontrolled variceal bleeding.
This study was designed to retrospectively evaluate transjugular intrahepatic portosystemic shunt (TIPS) performed on an emergency basis in patients with hemorrhagic shock from recurrent uncontrolled variceal bleeding. Over a 3.5-year period we reviewed the medical records as well as the imaging studies of 16 patients who had uncontrolled variceal bleeding and presented to our department for an emergent placement of TIPS. In our study the technical success was 88% (14/16 patients), the overall mortality was 36% (5/14 patients), and the shunt immediately reduced the portal venous pressure gradient by a mean of 64%. Given the poor outcome of other alternatives, aggressive treatment and placement of TIPS is justified regardless of the severity of the bleeding episode.


The Baylis-Hillman reaction: a novel source of attraction, opportunities, and challenges in synthetic chemistry.
The Baylis-Hillman reaction is a successful, useful, and atom-economical carbon-carbon bond forming reaction, which has grown from an obscure level to the level of high synthetic popularity due to its operational simplicity and also due to the enormous applications of the Baylis-Hillman adducts in organic synthesis. In this tutorial review, we briefly describe the way this reaction has grown to its present heights and the opportunities, attractions, and challenges the reaction offers with respect to its asymmetric and intramolecular versions, and mechanistic aspects.


Controlled release of copper from an intrauterine device using a biodegradable polymer.
The adverse effects of copper intrauterine devices (IUDs) such as abnormal bleeding, pain and cramps may be due in part to the burst release of copper ions during the first few months of usage. This study focuses on controlling the initial burst release of copper ions. This study evaluated in vitro release rates of copper for a period of 1 year from standard CuT380 IUDs (n=6) and from CuT380 IUDs coated with poly(dl-lactide-co-glycolide) (PLGA) films (n=6). This study characterized the coated device for its morphological changes during degradation of film by scanning electron microscopy (SEM). CuT380 IUDs coated with PLGA film with a thickness of 0.10±0.02 mm showed a reduced initial copper release (40-80 mcg/day) compared with uncoated CuT380 IUDs (150-200 mcg/day). Statistically significant (p<.05) results were obtained at different time intervals during the overall study period of 1 year. SEM images showed degradation of coating. Coating a CuT380 IUD with biodegradable polymer reduced the initial copper release without affecting release at 1 year. Clinical trials are required to determine whether this could reduce side effects such as bleeding and pain associated with copper containing IUDs.


Insights into the formation and diversification of a novel chiropteran wing membrane from embryonic development.
Through the evolution of novel wing structures, bats (Order Chiroptera) became the only mammalian group to achieve powered flight. This achievement preceded the massive adaptive radiation of bats into diverse ecological niches. We investigate some of the developmental processes that underlie the origin and subsequent diversification of one of the novel membranes of the bat wing: the plagiopatagium, which connects the fore- and hind limb in all bat species. Our results suggest that the plagiopatagium initially arises through novel outgrowths from the body flank that subsequently merge with the limbs to generate the wing airfoil. Our findings further suggest that this merging process, which is highly conserved across bats, occurs through modulation of the programs controlling the development of the periderm of the epidermal epithelium. Finally, our results suggest that the shape of the plagiopatagium begins to diversify in bats only after this merging has occurred. This study demonstrates how focusing on the evolution of cellular processes can inform an understanding of the developmental factors shaping the evolution of novel, highly adaptive structures.


Genome Sequence of a Ranavirus Isolated from a Red-Eared Slider (Trachemys scripta elegans) in Poland.
The red-eared slider (RES) ranavirus (RESRV) was isolated from a free-ranging RES turtle that died with evidence of respiratory disease. The RESRV genome sequence (106,878 bp) was determined, and phylogenetic analysis revealed that it is a common midwife toad virus (CMTV) strain. This study is the first report of CMTV in RES.


Epithelial cell involvement in the estradiol-stimulated accumulation of IgA in the rat uterus.
Immunoglobulin A (IgA) and G (IgG) were analyzed in rat plasma, uterus and uterine secretions by radioimmunoassay and in tissues by immunofluorescent microscopy to determine the mechanism by which estradiol controls IgA and IgG movement from the uterus into the uterine lumen. To determine whether there was evidence for immunoglobulin transport, plasma, tissue and uterine fluid concentrations of IgA and IgG were measured in ovariectomized rats at a time when uterine fluid IgA and IgG were elevated by treatment with estradiol. The concentration of IgA in uterine fluid was 22 times greater than that in tissue indicating that, in response to estradiol, IgA accumulated in the lumen against an apparent concentration gradient. In contrast to IgA, the concentration of IgG in uterine fluid was significantly lower than that in the uterus and in plasma. Immunofluorescent analyses indicated that estradiol has a marked effect on IgA associated with uterine epithelial cells. In saline-injected controls, small amounts of IgA were found in the epithelial cells and in the basement region of these cells. In response to estradiol, IgA accumulated in these cells at a time that coincided with the known increase of IgA in the uterine lumen. No IgA increase was observed when progesterone was given along with estradiol. Similar analyses for IgG, failed to demonstrate epithelial cell involvement of IgG into the uterine lumen. These experiments indicate that in response to estradiol, IgA is moved into the uterine lumen by a mechanism that is distinctly different from that which controls IgG. Since IgA movement is against an apparent concentration gradient, it suggests that estradiol acts on epithelial cells to regulate IgA transport from the uterus into the uterine lumen.


Structure--activity relationship and mode of action of N-(6-ferrocenyl-2-naphthoyl) dipeptide ethyl esters: novel organometallic anticancer compounds.
In this article, we report the findings of a comprehensive structure-activity relationship study of N-(6-ferrocenyl-2-naphthoyl) dipeptide ethyl esters, in which novel analogues were designed, synthesized, and evaluated in vitro for antiproliferative effect. Two new compounds, 2 and 16, showed potent nanomolar activity in the H1299 NSCLC cell line, with exceptional IC(50) values of 0.13 and 0.14 μM, respectively. These compounds were also found to have significant activity in the Sk-Mel-28 malignant melanoma cell line (IC(50) values of 1.10 and 1.06 μM, respectively). Studies were also conducted to elucidate the mode of action of these novel organometallic anticancer compounds. Cell cycle analysis in the H1299 cell line suggests these compounds induce apoptosis, while guanine oxidation studies confirm that 2 is capable of generating oxidative damage via a ROS-mediated mechanism.


A Comparison of Nurse Aides and Nurses Regarding the Work Competence of Nurse Aides in a Skill-Mixed Institution.
To compare the differences between the work competencies self-reported by nurse aides' and those perceived by nurses. A cross-sectional survey was employed. The settings were units implemented a skill mix model institution in Taiwan. The instruments consisted of the participants' demographic data and a nurse aide work competence scale. The results indicated that the nurse aides had room for improvement in terms of "problem solving" and "activity design". The nurse aides and nurses differed significantly in terms of the nurse aides' competence in "activity design", as the nurse aides reported themselves to be more competent in "activity design" than reported by the nurses. Nurse aides should be incorporated into cross-disciplinary teams. Activity design should be handled by other healthcare providers such as physical therapists or senior social workers.


Endocrinologic Aspects of Hidradenitis Suppurativa.
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder of unknown etiology. The role of hormones in HS remains unclear, but the observation of premenstrual flares, female predominance, and improvement during pregnancy suggest a hormonal/metabolic background. The reported positive effects of antiandrogen therapy supports a possible role of androgens. The predominant onset of the disease years after puberty may indicate a metabolic disorder. Obesity contributes significantly to HS pathogenesis; diabetes, dyslipidemia, the metabolic syndrome, and polycystic ovarian syndrome are among the commonest comorbidities. More studies are required to clarify a potential hormonal dysregulation in HS.


Effect of intralesional and systemic BCG-application or a combined cyclophosphamide/BCG treatment on experimental bladder cancer.
Infiltrating transitional cell carcinomas of the urinary bladder were induced by ingestion of 0.188% N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (FANFT) in 145 female Wistar rats. After 8 months of carcinogen exposure, the animals were divided into different treatment groups. They received cyclophosphamide intraperitoneally as a single injection or BCG either once intralesionally or weekly subcutaneously or a combination of cyclophosphamide followed by subcutaneous BCG. The treatment effect was determined by body weight measurements and bladder tumour weight after 12 months. Compared with a control group statistically significant differences of bladder tumour weights were found after treatment with BCG alone or in combination with cyclophosphamide. Intralesional BCG resulted in an insignificant increase of tumour weights.


Cyclopedic protein expression analysis of cultured canine mammary gland adenocarcinoma cells from six tumours.
We characterised cultured canine mammary gland adenocarcinoma cells by exhaustive step protein expression analysis to identify factors associated with tumour progression or metastasis of canine mammary gland tumour. Cultured adenocarcinoma cells derived from a total of 3 primary and 3 metastatic lesions from 3 dogs (CHMp/m, CIPp/m and CNMp/m, where CHM, CIP, and CNM indicate the 3 animals) were used in this study. The expression of 24 proteins reported to be related to tumourigenesis or malignancy of human breast cancers were examined by Western blot analysis using 24 antibodies. The expression of sialyl Lewis X [sLe(x)] was only observed in CHMm cells, which were derived from pleural effusion. This expression was further confirmed by immunohistochemistry. The levels of some factors, such as 14-3-3sigma, cyclinD1 and Rb, differed among cells or between the primary and metastatic cells in the pair. Though the difference in their expression was not consistent within the cells from primary and metastatic origin, this characterisation should provide useful information for further molecular analysis of these cultured cells. Since some of the factors, such as sLe(x), 14-3-3sigma, cyclinD1 and Rb, showed different levels of expression in the pair, these cultured cells might be meaningful tools for clarification of distant metastasis in canine mammary gland tumours.


Found and missed: failing to recognize a search target despite moving it.
We present results from five search experiments using a novel 'unpacking' paradigm in which participants use a mouse to sort through random heaps of distractors to locate the target. We report that during this task participants often fail to recognize the target despite moving it, and despite having looked at the item. Additionally, the missed target item appears to have been processed as evidenced by post-error slowing of individual moves within a trial. The rate of this 'unpacking error' was minimally affected by set size and dual task manipulations, but was strongly influenced by perceptual difficulty and perceptual load. We suggest that the error occurs because of a dissociation between perception for action and perception for identification, providing further evidence that these processes may operate relatively independently even in naturalistic contexts, and even in settings like search where they should be expected to act in close coordination.


Lymphocytes proliferation kinetics and SCE variation after rubella vaccination.
The effect of anti-rubella vaccination on lymphocyte proliferation kinetics in vitro and on SCE frequency was studied in three young women. The studies were carried out by taking blood samples before vaccination (day 0) and subsequently on days 7, 14, 28 and 42. The mitotic index (MI) shows a decrease at day 14 and 28 followed at day 42 by an increase above day 0 levels. The average cell cycle (ACC) shows a decrease at day 14 followed by an increase at day 28. Complex variations were also found in the percentage distribution of cells in the various division classes. The SCE frequency showed variations inverse to the MI. The whole picture seems to indicate the existence of changes in the lymphocyte population which can be correlated with immune response.


Surgical treatment for non-parasitic liver cysts improves quality of life.
Liver cysts occur frequently. Most are harmless, however some carry a significant patient burden. Optimizing treatment strategy is complicated as needs differ between patients. The current study assesses the effect of surgery on quality of life (QoL) of patients with non-parasitic liver cysts. A retrospective cohort study of all patients who underwent surgery for non-parasitic liver cysts in three major Dutch medical centers from 1993 to 2017. Patient characteristics and surgery related variables were collected from the electronic patient file. QoL was measured before and after surgery using the EORTC QLQ-C30. Summary scores (SumSc) were calculated and compared to reference values of the general population. Multivariate analysis using logistic regression was performed for identifying outcome related factors. Increase of ≥ 10% in SumSc was defined as clinically relevant. Eighty-eight of 132 eligible patients (67%) completed two QoL assessments. Respondents demonstrated significant improvement in the global health status, on all 5 functional scales (all p ≤ 0.005), on all 9 symptom scales after surgery (all p < 0.05), and on SumSc (p < 0.001) to levels similar or better than the general population. Patients with complications demonstrated a significant QoL gain (p < 0.05), and reported a similar postoperative status compared to patients without complications (p = 0.74). QoL gain for patients who underwent open and laparoscopic cyst fenestration were similar (p = 0.08). Multivariate analysis of SumSc found mechanical complaints as significant factor for ≥ 10% SumSc increase (OR 0.11, 95% CI (0.02-0.55). Surgery is a safe and effective strategy to significantly improve QoL in patients with symptomatic liver cysts.


Dyslipidemia is not associated with cardiovascular disease risk in an animal model of mild chronic suboptimal nutrition.
Previous studies performed in an experimental model of nutritional growth retardation (NGR) have observed metabolic adaptation. We hypothesized that changes in lipid-lipoprotein profile, glucose, and insulin levels occur, whereas overall body growth is reduced.The aim of this study was to assess serum lipid-lipoprotein profile, hepatogram, insulinemia and glycemia, and CVD risk markers in rats fed a suboptimal diet. Weanling male rats were assigned either to control (C) or NGR group. In this 4-week study, C rats were fed ad libitum a standard diet, and NGR rats received 80% of the amount of food consumed by C. Zoometric parameters, body fat content, serum lipid-lipoprotein profile, hepatogram, insulinemia, and glycemia were determined, and the cardiovascular disease (CVD) risk markers homeostasis model assessment-insulin resistance and homeostasis model assessment and β-cell function were calculated. Suboptimal food intake induced a significant decrease in body weight and length, which were accompanied by a reduction of 50% in body fat mass. Serum lipoproteins were significantly higher in NGR rats, with the exception of high-density lipoprotein cholesterol, which remained unchanged. Nutritional growth retardation rats had decreased triglycerides compared with C rats. No significant differences were detected in liver function parameters. The CVD risk markers homeostasis model assessment (HOMA)-insulin resistance and homeostasis model assessment and β-cell function were significantly lower in NGR rats. Mild chronic suboptimal nutrition in weanling male rats led to growth retardation and changes in the lipid-lipoprotein profile, glucose, and insulin levels while preserving the integrity of liver function. These data suggest a metabolic adaptation during suboptimal food intake, which ensures substrates flux to tissues that require constant energy-in detriment to body growth. The CVD risk markers suggested that mild chronic food restriction of approximately 20% could provide protection against this degenerative disease.


Management of facial fractures.
This article presents up-to-date information for the emergency medicine community on several patterns of facial fractures and their associated injuries. The article contains information about the anatomic structure and pathologic injuries that occur in the setting of facial trauma and guides the emergency medicine community in the thorough physical and diagnostic evaluation, emergent treatment, and proper surgical or outpatient treatment.


Insulin detemir improves glycaemic control without weight gain in insulin-naïve patients with type 2 diabetes: subgroup analysis from the PREDICTIVE study.
Predictable Results and Experience in Diabetes through Intensification and Control to Target: an International Variability Evaluation (PREDICTIVE) is a multi-national, open-label, prospective, observational study assessing the safety and efficacy of insulin detemir in clinical practice. This post hoc subanalysis evaluates insulin-naïve patients on oral antidiabetic drugs (OADs) who were initiated on insulin detemir as basal therapy (+/- OADs). The European cohort of the PREDICTIVE study currently includes 20,531 patients (12,981 with type 2 diabetes) who were prescribed insulin detemir and followed up for 12, 26 or 52 weeks. Here, we report data from a subgroup of 2377 OAD-treated, insulin-naïve type 2 diabetes patients for a mean follow-up of 14.4 weeks. Patients were prescribed insulin detemir as basal therapy (+/- OADs) by their physician, as part of routine clinical care. Results were reported in comparison with baseline observations. One serious adverse drug reaction was reported, which was a major hypoglycaemic episode. Treatment with insulin detemir (+/- OADs) significantly reduced mean haemoglobin A(1c) (HbA(1c)) (-1.3%; p < 0.0001), fasting glucose (-3.7 mmol/l; p < 0.0001), and within-patient fasting glucose variability (-0.5 mmol/l; p < 0.0001). In the majority of patients (82%), these improvements in glycaemic control were achieved with once daily administration of insulin detemir. There was a small reduction in mean body weight (-0.7 kg; p < 0.0001), which was most apparent in patients with a higher body mass index (BMI) at baseline. A significant negative relationship between weight change and baseline BMI was observed (greater the BMI, greater the weight reduction). Multiple regression analysis showed that BMI and HbA(1c) at baseline, and change in HbA(1c), were all predictors for weight change (p < 0.0001 for all), with BMI being the strongest predictor. Patients with type 2 diabetes naïve to insulin can be effectively treated with once-daily insulin detemir (+/- OADs) to achieve improved glycaemic control with no adverse effect on weight and a low risk of hypoglycaemia. These short-term results are consistent with the findings of clinical trials.


Functional recovery after surgical stabilization and postoperative radiotherapy due to metastases of long bones.
To reinvestigate the functional recovery after combined treatment with surgery and postoperative irradiation of complete or impending pathologic fractures of long bones. We retrospectively evaluated the results of external beam radiation therapy (EBRT) carried out after 68 orthopedic stabilization procedures (femur, n = 55, 80.8%; humerus, n = 13, 19.2%) for actual or impending pathological fracture of long bone in 61 patients with skeletal metastases. The mean normalized total dose was 34.7 ± 7.8 Gy. Endpoints were patient's functional status (FS; 1 = normal pain free status; 2 = normal use with pain; 3 = significantly limited used; 4 = nonfunctional status), a need for a secondary procedure to the same site and overall survival following surgery. Overall, 75% of patients achieved normal functional status (FS 1-2) within 12 weeks after surgery. Functional recovery in surviving patients reached 93%. Median survival was 17 months (95% confidence interval 13.7-20.2). Secondary surgical intervention at the same location was necessary in 3 patients (4.4%). On multivariate analysis, only general status (p = 0.011) and growing potential of primary tumor (p = 0.049) were associated with achieving normal functional status within 12 weeks after surgery and radiotherapy. The applied radiation schemes demonstrated a comparable impact on functional recovery. Our results confirm the effectiveness of stabilizing surgery and fractionated postoperative radiotherapy in terms of functional recovery, supporting prior results assessing postsurgical radiotherapy versus follow-up. The patient's general status is a strong prognostic factor for functional recovery. Rapidly growing tumors may hinder achievement of a normal functional status.


The incidence of hepatic pseudolesions caused by focal rib compression as seen on multidetector row CT in patients of different hepatic function.
To determine whether the incidence of pseudolesions of the liver caused by rib compression is correlated with liver function. Multidetector row CT images of 150 consecutive cases were evaluated for the presence of pseudolesions caused by rib compression. Liver function was categorized into two groups mainly using the Child-Pugh classification: Group I-normal liver function and Grade A; Group II-Grades B and C. The number of focal deformities of the liver caused by rib compression was also counted. The incidence of pseudolesions based on number of patients or focal deformities of liver parenchyma by rib compression were compared between the two groups. There were 108 and 42 patients in Groups I and II, respectively. 169 and 41 focal deformities of the liver caused by rib compression were found in Groups I and II, respectively. Patient-based and deformity-based incidences of pseudolesions were 10.7% (16/150) and 7.6% (16/210), respectively. All pseudolesions were seen in patients of Group I. Both patient-based and deformity-based incidences of pseudolesions were significantly higher in Group I as compared with those in Group II. Pseudolesions of the liver caused by focal rib compression may be seen more frequently in patients with preserved liver function than in those with impaired function.


Eliminating epigenetic barriers induces transient hormone-regulated gene expression in estrogen receptor negative breast cancer cells.
In breast cancer, approximately one-third of tumors express neither the estrogen receptor (ERalpha) nor estrogen-regulated genes such as the progesterone receptor gene (PR). Our study provides new insights into the mechanism allowing hormone-activated expression of ERalpha target genes silenced in ERalpha-negative mammary tumor cells. In cell lines derived from ERalpha-negative MDA-MB231 cells, stable expression of different levels of ERalpha from a transgene did not result in transcription of PR. A quantitative comparative analysis demonstrates that inhibiting DNA methyltransferases using 5-aza-2'-deoxycytidine or specific disruption of DNMT1 by small interfering RNAs and treatment with the histone-deacetylase inhibitor trichostatin A enabled ERalpha-mediated hormone-dependent expression of endogenous PR. We show that demethylation of a CpG island located in the first exon of PR was a prerequisite for ERalpha binding to these regulatory sequences. Although not a general requirement, DNA demethylation is also necessary for derepression of a subset of ERalpha target genes involved in tumorigenesis. PR transcription did not subsist 4 days after removal of the DNA methyltransferase blocking agents, suggesting that hormone-induced expression of ERalpha target genes in ERalpha-negative tumor cells is transient. Our observations support a model where an epigenetic mark confers stable silencing by precluding ERalpha access to promoters.


Multibatch Cytometry Data Integration for Optimal Immunophenotyping.
High-dimensional cytometry is a powerful technique for deciphering the immunopathological factors common to multiple individuals. However, rational comparisons of multiple batches of experiments performed on different occasions or at different sites are challenging because of batch effects. In this study, we describe the integration of multibatch cytometry datasets (iMUBAC), a flexible, scalable, and robust computational framework for unsupervised cell-type identification across multiple batches of high-dimensional cytometry datasets, even without technical replicates. After overlaying cells from multiple healthy controls across batches, iMUBAC learns batch-specific cell-type classification boundaries and identifies aberrant immunophenotypes in patient samples from multiple batches in a unified manner. We illustrate unbiased and streamlined immunophenotyping using both public and in-house mass cytometry and spectral flow cytometry datasets. The method is available as the R package iMUBAC (https://github.com/casanova-lab/iMUBAC).


Renal length z-score for the detection of dysfunction in children with solitary functioning kidney.
To evaluate whether renal length z-scores predict renal dysfunction in children with a solitary functioning kidney (SFK). In a single-centre retrospective cohort of children with SFK, we correlated body mass index z-scores, extracellular volume and lean body mass to renal length z-scores. We grouped these z-scores to other markers of renal dysfunction (proteinuria, hypertension, extracellular volume and abnormal estimated glomerular function rate [eGFR]) and analysed renal length z-score with multivariate analysis, receiver-operated characteristics (ROC) plots and Youden's index to determine an appropriate cut-off. 111 children had a median follow-up 5.08 years, eGFR 80.8 mL/min/1.73 m2 , and age at last follow-up 7.4 (3.8-13.4 years). The median renal length z-scores of those without any renal dysfunction (n = 37, 25.1%) were greater (+3.66, interquartile range 3.02-4.47) than those with renal dysfunction (median 3.11, interquartile range 1.76-4.11, P = .0107, Mann-Whitney test). Using a cut-off of z-score of >+1.911, the odds ratio for having no renal dysfunction was 0.07 (95% CI 0.002-0.459, P = .0010). However, accuracy of the renal length z-score was poor (ROC curve 0.6488). In this cohort of children with SKF, using the renal length z-score as a biomarker of renal dysfunction at 7 years of age is not recommended.


Ammonia fiber expansion pretreatment and enzymatic hydrolysis on two different growth stages of reed canarygrass.
Plant materials from the vegetative growth stage of reed canarygrass and the seed stage of reed canarygrass are pretreated by ammonia fiber expansion (AFEX) and enzymatically hydrolyzed using 15 filter paper units (FPU) cellulase/g glucan to evaluate glucose and xylose yields. Percent conversions of glucose and xylose, effects of temperature and ammonia loading, and hydrolysis profiles are analyzed to determine the most effective AFEX treatment condition for each of the selected materials. The controls used in this study were untreated samples of each biomass material. All pretreatment conditions tested enhanced enzyme digestibility and improved sugar conversions for reed canarygrass compared with their untreated counterparts. Based on 168 h hydrolysis results using 15 FPU Spezyme CP cellulase/g glucan the most effective AFEX treatment conditions were determined as: vegetative growth stage of reed canarygrass--100 degrees C, 60% moisture content, 1.2:1 kg ammonia/kg of dry matter (86% glucose and 78% xylose) and seed stage of reed canarygrass--100 degrees C, 60% moisture content, 0.8:1 kg ammonia/kg of dry matter (89% glucose and 81% xylose). Supplementation by commercial Multifect 720 xylanase along with cellulase further increased both glucose and xylose yields by 10-12% at the most effective AFEX conditions.


A comparison of the natural and groomed fingermark lipid composition of different donors using GC/MS.
The lipid composition of natural fingermarks was studied and compared with the composition of groomed residue. Approximately 100 specimens were collected from 6 donors over three sessions (in October, December and July) and analysed using gas chromatography / mass spectrometry (GC/MS). The measured lipid content was generally lower and more variable in natural fingermarks than in groomed fingermarks. Some significant variability was noticed. Relative standard deviations were the highest between donors (generally above 100%) but were also relatively high within donor within a session (from 21% to 80%) and between sessions (from 34% to 126%). The fingermarks from one of the donors generally contained higher relative amounts of lipids in both groomed and natural residue compared to the others. All other fingermarks led to very variable amounts and did not allow classifying the other donors as constantly "good" or "poor" donors. Squalene was the major compound in all marks, particularly in groomed specimens. A correlation between squalene, cholesterol, myristic acid, palmitoleic acid, stearyl palmitoleate and pentadecanoic acid was highlighted. Oleic and stearic were also correlated together but generally more in natural than groomed marks. The obtained results may be particularly useful to better understand the detection mechanisms for techniques targeting lipids and to develop artificial fingermark secretions to further support the development of detection techniques.


Long-term follow-up of ACL reconstruction with hamstring autograft.
To investigate the differences in the incidence and severity of knee osteoarthritis (OA), joint space narrowing, knee laxity, and knee flexion and extension strength between an anterior cruciate ligament (ACL)-reconstructed knee and the contralateral non-reconstructed limb. Retrospective case series of patients from a single surgeon that had an ACL reconstruction with a semitendinosus/gracilis autograft more than 12 years ago. Outcome measures included radiographic analysis, International Knee Documentation Committee Subjective Knee Evaluation Form (IKDC), KT-1000, Tegner Activity Level Scale, Lysholm Knee Score, ACL quality of life score (ACL-QOL) and knee flexor/extensor strength. Seventy-four patients consented and sixty-eight (43 male, 25 female) were included for analysis. Average age (SD) at the time of surgery was 31.2 (±9.1) years. At follow-up of 14.6 (1.9) years, 9% had re-ruptured their ACL, whereas 5% ruptured the contralateral ACL. Reconstructed knees had a greater incidence and severity of OA (P < 0.01). Medial meniscus surgery was a strong predictor of OA. Seventy-five per cent scored a normal or nearly normal knee on the IKDC. The mean Lysholm score was 75.8% and Tegner Activity Level Scale scores decreased (P < 0.001) from the time of surgery. Knee extension strength was greater in the contralateral knee at speeds of 60°/s (P = 0.014) and 150°/s (P = 0.012). Reconstructed knees have a greater incidence and severity of OA than non-reconstructed knees, which suggests degenerative changes are secondary to ACL rupture. Medial meniscus surgery is a strong predictor of OA. Despite this, 75% of patients reported good outcomes.


Left ventricular pseudoaneurysm after mitral valve replacement: Review of pseudoaneurysms late after mitral valve replacement.
Left ventricular pseudoaneurysm (LVPA) due to incomplete or late rupture after mitral valve replacement is a rare condition but can be life threatening if it develops into perdicardial tamponade. LVPA may develop de novo after the surgical procedure or may be a sequela of an earlier rupture. Clinical presentation includes shortness of breath, heart failure, chest pain, endocarditis, and pericardial tamponade. However, it can also have an asymptomatic course. The recommended treatment for LVPA is surgical repair. Conservative follow-up is an alternative for patients who refuse surgical treatment or are considered high risk for re-operation. We conducted a review of all the available literature on cases of LVPA after mitral valve replacement and present the findings here.


Microwave sterilization of Candida on underwear fabric. A preliminary report.
Candida-contaminated underwear might not be sterilized by ordinary laundering. The effectiveness of microwaving against Candida albicans on fabric was therefore determined. Swatches of Candida-impregnated cotton underpants fabric were subjected to domestic microwaving at the high setting for up to 30 minutes. If the fabric was microwaved dry, the Candida organisms survived. If the fabric was moistened, sterilization occurred within five minutes. Microwaving wet, freshly laundered cotton underpants should sterilize residual Candida and reduce the risk of reinfection.


Highly transparent, self-healing, injectable and self-adhesive chitosan/polyzwitterion-based double network hydrogel for potential 3D printing wearable strain sensor.
A purely physically crosslinked double network (DN) hydrogel, poly(sulfobetaine-co-acrylic acid)/chitosan-citrate (P(SBMA-co-AAc)/CS-Cit) DN hydrogel, was prepared based on electrostatic interaction and hydrogen bonding between the polymer chains. The hydrogel is highly stretchable, transparent, anti-fatigue, self-adhesive and has good self-healing properties with a self-healing efficiency as high as 95.4%. Furthermore, the resistance of the P(SBMA-co-AAc)/CS-Cit DN hydrogel is sensitive to a wide strain window and the relative resistance shows stable and reliable change during deformation. Herein, the hydrogel was demonstrated as a strain sensor to detect human motions, such as joint bending and swallowing. More excitingly, before ionic crosslinking, the P(SBMA-co-AAc)/CS-Cit composite hydrogel is injectable, thus the P(SBMA-co-AAc)/CS-Cit DN hydrogel sensor can be made into various complex shapes by injecting the P(SBMA-co-AAc)/CS-Cit composite hydrogel into citrate solution, including multilayer structures, exhibiting a great potential for applications as 3D printing strain sensors.


[The reciprocity of gastrin and cholecystokinin effects on the motor and evacuatory functions of the proximal section of the gastrointestinal tract in dogs].
In dogs with fistulas in fundal and antral parts of the stomach and in the proximal part of jejunum, subcutaneous and i.v. administration of pentagastrin and i.v. administration of cholecystokinin caused reciprocal reactions in the stomach: pentagastrin suppressed the motility of fundal part and activated the contractions of antral part, whereas cholecystokinin activated the contractions of fundal part and suppressed the motility of antral part of the stomach. Excepting a more complex character of pentagastrin and cholecystokinin effects on the jejunum contractions, the responses were reciprocal as well. Pentagastrin exerts mainly a suppressing effect whereas cholecystokinin--an activating one. Possible biological significance of the hormones interactions while maintaining evacuatory function of the stomach, is discussed.


In vitro analysis of the effect of contrast agents on the antiaggregant effects of P2Y12 inhibitors.
The contrast agents have different molarities and ionic structures. The high osmolar contrast agents could increase platelet aggregation but the ionic contrast agents decrease platelet aggregation. However there is insufficient data on whether the antiaggregan effect of P2Y12 inhibitors used during coronary interventions are affected by the contrast agents. This study aimed to evaluate the in vitro effects of different contrast agents on the antiaggregant activity of P2Y12 inhibitors (clopidogrel, ticagrelor and prasugrel). Thirty patients (who underwent percutaneous coronary interventions and were treated with a P2Y12 inhibitor for a minimum of 10 days) and five healthy volunteers were divided into four groups: the clopidogrel (10 patients), ticagrelor (10 patients), prasugrel (10 patients) and control (five volunteers) groups. Antiaggregant activity was measured by using the Verify-Now method and was represented as P2Y12 reaction unit (PRU) values. Three tubes of blood were collected from the participants in the three patient groups and in the control group; as the contrast material, 10% iohexol was added to a second tube, and 10% iodixanol was added to a third tube. PRU values of the control and the contrast tubes were measured at 5 min and at 30 min after the contrast material was added. Iohexol and iodixanol led to a significant decrease in the PRU values in the control group (iohexol: 188.4 ± 39.2 vs 142.4 ± 17.0, p = .04; iodixanol: 188.4 ± 39.2 vs 159.2 ± 33.7, p = .04) and in the clopidogrel group (iohexol: 140.8 ± 50.8 vs 106.3 ± 44.4, p = .04; iodixanol: 140.8 ± 50.8 vs 109.4 ± 47.6, p = .009) but not in the ticagrelor and prasugrel groups. The PRU values were significantly lower in the ticagrelor (23.1 ± 26.2) and prasugrel (23.4 ± 27.5) groups than in the clopidogrel (140.8 ± 50.8) and control (188.4 ± 39.2) groups (p < .01), and the PRU values for the ticagrelor and prasugrel groups were similar for both the 5-min and 30-min time periods (p > .05). The antiaggregant activities of iohexol and iodixanol were observed to be similar at the 5- and 30-minute time points for all of the groups (p > .05). Iohexol and iodixanol had in vitro antiaggregant effects, and their antiaggregant effects were similar. Iohexol and iodixanol increased the clopidogrel antiaggregant activity in vitro, but they did not significantly alter the antiaggregant activities of prasugrel and ticagrelor.


Striosome-based map of the mouse striatum that is conformable to both cortical afferent topography and uneven distributions of dopamine D1 and D2 receptor-expressing cells.
The striatum is critically involved in execution of appropriate behaviors, but its internal structures remain unmapped due to its unique structural organization, leading to ambiguity when interpreting heterogeneous properties of striatal neurons that differ by location. We focused on site-specific diversity of striosomes/matrix compartmentalization to draw the striatum map. Five types of striosomes were discriminated according to diverse immunoreactivities for the µ-opioid receptor, substance P (SP) and enkephalin, and each type occupied a particular domain inside the striatum. Furthermore, there was an additional domain lacking striosomes. This striosome-free space was located at the dorsolateral region and received afferents preferentially from the primary motor and sensory cortices, whereas the striosome-rich part received afferents from associational/limbic cortices, with topography inside both innervations. The proportion of dopamine D1 receptor-expressing, presumptive striatonigral neurons was approximately 70% in SP-positive striosomes, 40% in SP-deficient striosomes, 30% in the striosome-free space, and 50% in the matrix. In contrast, the proportion of D2 receptor-expressing, presumptive striatopallidal neurons was complementary to that of D1 receptor-expressing cells, indicating a close relationship between the map and the direct and indirect parallel circuitry. Finally, the most caudal part of the striatum lacked compartmentalization and consisted of three lamina characterized by intense and mutually exclusive immunoreactivities for SP and enkephalin. This tri-laminar part also received specific afferents from the cortex. The newly obtained map will facilitate broad fields of research in the basal ganglia with higher resolution of the three-dimensional anatomy of the striatum.


LncRNAs as biomarkers for predicting radioresistance and survival in cancer: a meta-analysis.
The effect of long noncoding RNAs (lncRNAs) on the radiotherapy response has been gradually revealed. This systematic review and meta-analysis aimed to evaluate the association between the function and underlying mechanism of lncRNAs in regulating the radiosensitivity and radioresistance of different tumors. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were calculated to estimate the effect of lncRNAs on cancer patient prognosis, including overall survival (OS), recurrence-free survival (RFS), disease-free survival (DFS) and progression-free survival (PFS). Collectively, 23 lncRNAs in 11 cancer types were enrolled. Of them, 13 lncRNAs were downregulated and related to radiosensitivity, 11 lncRNAs were upregulated and related to radioresistance, and 3 lncRNAs were upregulated and related to radiosensitivity in cancers. Furthermore, 17 microRNAs and 20 pathways were targeted by different lncRNAs and contributed to the cancer radiotherapy response in this meta-analysis. The individual pooled HRs (95% CIs) of downregulated radiation-resistant and upregulated radiation-resistant lncRNAs for OS were 0.49 (0.40-0.60) and 1.88 (1.26-2.79), respectively. Our results showed that lncRNAs could modulate tumor radioresistance or sensitivity by affecting radiation-related signaling pathways and serve as potential biomarkers to predict radiotherapy response.


Pituitary gland involvement by a gamma delta hepatosplenic lymphoma, a mimicker of pituitary adenoma: report of a rare case.
The authors report an unusual case of hepatosplenic T-cell lymphoma in a 41-year-old male patient. He presented initially with low grade fever, hepatosplenomegaly and pancytopenia. Splenectomy was done which showed infiltration of red pulp by monomorphic lymphocytes. Liver was also infiltrated with similar cells. A provisional diagnosis of hairy cell leukemia was made. Subsequently, after 6 months he was found to have a sellar mass, which on microscopy revealed lymphoma cells. These cells were positive for leukocyte common antigen and T-cell markers. Finally, based on overall clinical, histomorphological and immunophenotypic features, a diagnosis of hepatosplenic T-cell lymphoma, possibly gamma delta type, involving pituitary gland was established. On follow up, this patient showed evidence of bone marrow involvement and died after 1.5-year of diagnosis. This case highlights the involvement of rare site by a rare lymphoma and should be kept in mind in the differential diagnoses of pituitary tumors.


Exposure to pyrogallol impacts the hemato-biochemical endpoints in catfish (Clarias gariepinus).
Pyrogallol is widely used in several industrial applications and can subsequently contaminate aquatic ecosystems. Here, we report for the first time the presence of pyrogallol in wastewater in Egypt. Currently, there is a complete lack of toxicity and carcinogenicity data for pyrogallol exposure in fish. To address this gap, both acute and sub-acute toxicity experiments were conducted to determine the toxicity of pyrogallol in catfish (Clarias gariepinus). Behavioral and morphological endpoints were evaluated, in addition to blood hematological endpoints, biochemical indices, electrolyte balance, and the erythron profile (poikilocytosis and nuclear abnormalities). In the acute toxicity assay, it was determined that the 96 h median-lethal concentration (96 h-LC50) of pyrogallol for catfish was 40 mg/L. In sub-acute toxicity experiment, fish divided into four groups; Group 1 was the control group. Group 2 was exposed to 1 mg/L of pyrogallol, Group 3 was exposed to 5 mg/L of pyrogallol, and Group 4 was exposed to 10 mg/L of pyrogallol. Fish showed morphological changes such as erosion of the dorsal and caudal fins, skin ulcers, and discoloration following exposure to pyrogallol for 96 h. Exposure to 1, 5, or 10 mg/L pyrogallol caused a significant decrease in hematological indices, including red blood cells (RBCs), hemoglobin, hematocrit, white blood cells (WBC), thrombocytes, and large and small lymphocytes in a dose-dependent manner. Several biochemical parameters (creatinine, uric acid, liver enzymes, lactate dehydrogenase, and glucose) were altered in a concentration dependent manner with short term exposures to pyrogallol. Pyrogallol exposure also caused a significant concentration-dependent rise in the percentage of poikilocytosis and nuclear abnormalities of RBCs in catfish. In conclusion, our data suggest that pyrogallol should be considered further in environmental risk assessments of aquatic species.


Distribution of arsenic, silver, cadmium, lead and other trace elements in water, sediment and macrophytes in the Kenyan part of Lake Victoria: spatial, temporal and bioindicative aspects.
This is the first detailed report on the distribution of Ni, As, Sr and Ag in water, sediments and macrophytes from Lake Victoria, complemented with recent data on the heavy metals Cr, Cu, Zn, Cd and Pb. The study was conducted over an 11-month period at five sites in the Kenyan part of Lake Victoria: four sites in the Winam Gulf influenced by various anthropogenic pressures including a site near Kisumu City, and one in the main lake, perceived to have lesser direct anthropogenic influence. Compared with the main lake site, the water in Winam Gulf had significantly higher values for electrical conductivity and concentrations of dissolved components: organic carbon and bound nitrogen, as well as major and most trace elements. This contamination is also evident in surface sediments, which contained significantly higher levels of Cr, Zn, As, Ag, Cd and Pb compared with the main lake site. The mean levels of Cr, Cu, Zn, Ag and Pb exceeded probable effect levels at least at one of the gulf sites. The sediments at the Kisumu City site were classified as severely polluted with Cu (up to 259 mg/kg dw) and Pb (up to 1188 mg/kg dw). The sediment cores showed significantly higher levels of Cu, Zn, Ag, Cd and Pb in the surface (0-3 cm) versus subsurface (22-25 cm) layer at the Kisumu City site, indicating increasing pollution by these elements within the last 15 years. This is also the first report on trace elements in the emergent water plant Vossia cuspidata and submerged plant Ceratophyllum demersum from this lake. Even though the accumulation of most elements is comparable between C. demersum (whole plant) and V. cuspidata roots, the latter shows a better bioindicative potential. Contamination of the gulf with Ni, Cu, Zn, Ag, Cd and Pb is well mirrored in V. cuspidata roots. V. cuspidata strongly restricts the acropetal transport of trace elements, and hence using the shoots as fodder does not pose a risk to livestock.


The feasibility and efficacy of the home-based exercise programs in patients with cognitive impairment: A pilot study.
To examine the feasibility and efficacy of home-based aerobic and resistance exercise interventions for geriatric individuals with cognitive impairment. Fourteen participants with cognitive impairment were allocated to either the aerobic group (n = 8) or the resistance group (n = 6), after which they implemented a two-month home-based training program. Feasibility and efficacy outcomes were evaluated. A semi-structured interview was performed after the intervention. All fourteen participants completed the two-month training program. The adherence rate was 0.94 for the aerobic group and 0.96 for the resistance group. No adverse events occurred. The results revealed a trend of group×time interaction effect on delayed recall. Significant group×time interaction effects were revealed on simple physical performance and body composition. Semi-structured interviews identified four motivators for participating in this program, four facilitators for and three barriers to keeping exercising, and some perceived benefits. Home-based aerobic and resistance exercise programs are feasible for geriatric individuals with cognitive impairment. The efficacy needs to be further examined.


CRISPR/Cas9 Editing of Glia Maturation Factor Regulates Mitochondrial Dynamics by Attenuation of the NRF2/HO-1 Dependent Ferritin Activation in Glial Cells.
Microglial cells are brain specific professional phagocytic immune cells that play a crucial role in the inflammation- mediated neurodegeneration especially in Parkinson's disease (PD) and Alzheimer's disease. Glia maturation factor (GMF) is a neuroinflammatory protein abundantly expressed in the brain. We have previously shown that GMF expression is significantly upregulated in the substantia nigra (SN) of PD brains. However, its possible role in PD progression is still not fully understood. The Clustered-Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR Associated (Cas) protein9 (CRISPR/Cas9) system is a simple, rapid and often extremely efficient gene editing tool at desired loci, enabling complete gene knockout or homology directed repair. In this study, we examined the effect of GMF editing by using the CRISPR/Cas9 technique in BV2 microglial cells (hereafter referred to as BV2-G) on oxidative stress and nuclear factor erythroid 2-related factor 2 (NRF2)/Hemeoxygenase1 (HO-1)-dependent ferritin activation after treatment with (1-methyl-4-phenylpyridinium) MPP+. Knockout of GMF in BV2-G cells significantly attenuated oxidative stress via reduced ROS production and calcium flux. Furthermore, deficiency of GMF significantly reduced nuclear translocation of NRF2, which modulates HO-1 and ferritin activation, cyclooxygenase 2 (COX2) and nitric oxide synthase 2 (NOS2) expression in BV2 microglial cells. Lack of GMF significantly improved CD11b and CD68 positive microglial cells as compared with untreated cells. Our results also suggest that pharmacological and genetic intervention targeting GMF may represent a promising and a novel therapeutic strategy in controlling Parkinsonism by regulating microglial functions. Targeted regulation of GMF possibly mediates protein aggregation in microglial homeostasis associated with PD progression through regulation of iron metabolism by modulating NRF2-HO1 and ferritin expression.


A distinctive cutaneous malignant neoplasm expressing the Langerhans cell phenotype. Synchronous occurrence with B-chronic lymphocytic leukemia.
The authors describe a 63-year-old woman who developed a histologically distinctive malignant cutaneous neoplasm composed of large pleomorphic cells with abundant cytoplasm and multilobate, often clefted nuclei that occasionally contained small nucleoli. This neoplastic cell population metastasized to a regional lymph node already involved by a B-cell derived chronic lymphocytic leukemia expressing surface IgMk, BA-1, and OKT1. The large metastatic tumor cells lacked surface immunoglobulin, B-lymphocyte associated antigen BA-1, T-lymphocyte associated antigens OKT1 and OKT3, and the monocyte/macrophage markers lysozyme and alpha 1-antichymotrypsin. These tumor cells expressed HLA-DR antigens, adenosine triphosphatase (ATPase), OKT6, and contained S-100 protein, i.e., they expressed the phenotype peculiar to epidermal Langerhans cells. The typical clinical and histologic features of Histiocytosis X were absent. Thus, this case appears to represent a distinctive cutaneous neoplasm composed entirely of malignant cells of dendritic cell origin which, by immunophenotypic and histochemical analysis, appear to be related to epidermal Langerhans cells.


Knowledge Is Power, but Is Ignorance Bliss? Optimising Conversations About Disease Progression in Multiple Sclerosis.
Communication about multiple sclerosis (MS) disease progression between healthcare professionals (HCPs) and people with MS (PwMS) has historically been considered difficult, and attention to improving it has been neglected. However, a growing number of studies have shown that this is a key area to get right, since negative experiences can affect patient satisfaction, treatment adherence, and clinical outcomes. This article reports on a symposium at the European Charcot Foundation, 2018, led by a panel of leading clinicians and patient experts from MS in the 21st Century, who debated the benefits, drawbacks, and challenges of communicating about disease progression, for both HCPs and PwMS, and potential ways to optimise these discussions. PwMS' preferences and priorities regarding conversations about disease progression vary widely. While the majority want to have these conversations, some will be reluctant and/or emotionally unready. Communication therefore needs to be personalised, and HCPs should always be prepared to have such conversations in an appropriate and sensitive manner. Clinical information can be opaque for PwMS, so HCPs also need to use language that is clear, easily understandable, and patient-friendly. MS in the 21st Century is in the process of developing several resources and programmes to help improve disease progression communication between HCPs and PwMS. FUNDING: Merck KGaA, Darmstadt, Germany. Plain language summary available for this article.


Benefits of multi-session balance and gait training with multi-modal biofeedback in healthy older adults.
Real-time balance-relevant biofeedback from a wearable sensor can improve balance in many patient populations, however, it is unknown if balance training with biofeedback has lasting benefits for healthy older adults once training is completed and biofeedback removed. This study was designed to determine if multi-session balance training with and without biofeedback leads to changes in balance performance in healthy older adults; and if changes persist after training. 36 participants (age 60-88) were randomly divided into two groups. Both groups trained on seven stance and gait tasks for 2 consecutive weeks (3×/week) while trunk angular sway and task duration were monitored. One group received real-time multi-modal biofeedback of trunk sway and a control group trained without biofeedback. Training effects were assessed at the last training session, with biofeedback available to the feedback group. Post-training effects (without biofeedback) were assessed immediately after, 1-week, and 1-month post-training. Both groups demonstrated training effects; participants swayed less when standing on foam with eyes closed (EC), maintained tandem-stance EC longer, and completed 8 tandem-steps EC faster and with less sway at the last training session. Changes in sway and duration, indicative of faster walking, were also observed after training for other gait tasks. While changes in walking speed persisted post-training, few other post-training effects were observed. These data suggest there is little added benefit to balance training with biofeedback, beyond training without, in healthy older adults. However, transient use of wearable balance biofeedback systems as balance aides remains beneficial for challenging balance situations and some clinical populations.


Distinct frequency dependent effects of whole-body vibration on non-fractured bone and fracture healing in mice.
Low-magnitude high-frequency vibration (LMHFV) provokes anabolic effects in non-fractured bone; however, in fracture healing, inconsistent results were reported and optimum vibration conditions remain unidentified. Here, we investigated frequency dependent effects of LMHFV on fracture healing. Twelve-week-old, female C57BL/6 mice received a femur osteotomy stabilized using an external fixator. The mice received whole-body vibrations (20 min/day) with 0.3g peak-to-peak acceleration and a frequency of either 35 or 45 Hz. After 10 and 21 days, the osteotomized femurs and intact bones (contra-lateral femurs, lumbar spine) were evaluated using bending-testing, µ-computed tomography, and histomorphometry. In non-fractured trabecular bone, vibration with 35 Hz significantly increased the relative amount of bone (+28%) and the trabecular number (+29%), whereas cortical bone was not influenced. LMHFV with 45 Hz failed to provoke anabolic effects in trabecular or cortical bone. Fracture healing was not significantly influenced by whole-body vibration with 35 Hz, whereas 45 Hz significantly reduced bone formation (-64%) and flexural rigidity (-34%) of the callus. Although the exact mechanisms remain open, our results suggest that small vibration setting changes could considerably influence LMHFV effects on bone formation in remodeling and repair, and even disrupt fracture healing, implicating caution when treating patients with impaired fracture healing.


Influences of cerebral stent implantation on CD4+ CD25+ FOXP3+ Treg, Th1 and Th17 cells.
Stent implantation is primarily used for the treatment of artery stenosis. However, the application and use of stent struts induces local and systemic inflammation, leading to intractable neointimal hyperplasia. CD4(+) T cells are involved in artery stenosis diseases, but little is known about the influence of the CD4(+) T cells on the inflammation reaction after stent implantation. In this study, we analyzed the frequency of signature transcription factors and proinflammatory cytokine expression from each subtype of CD4(+) T cells in 50 patients receiving intracranial or cervical stent implantations from December 2011 to June 2012. The results showed that the frequency of signature transcription factor/cytokine production in Treg cells was reduced in the first week and returned to control levels at 3 months after stent implantation. However, we observed opposite trends for Th17 cells, showing increased signature transcription factor/cytokine production during the acute phase, which returned to control levels after 3 months. No significant difference in the frequency of signature transcription factor/cytokine expression was observed in Th1 cells from patients before and after stent implantation. We speculate that the maintenance of the frequency and function of Tregs controls the inflammatory response, which otherwise induces acute inflammation after stent implantation.


Unintegrated HIV-1 DNAs are loaded with core and linker histones and transcriptionally silenced.
Upon delivery into the nucleus of the host cell, linear double-stranded retroviral DNAs are either integrated into the host genome to form the provirus or act as a target of the DNA damage response and become circularized. Little is known about the chromatinization status of the unintegrated retroviral DNAs of the human immunodeficiency virus type 1 (HIV-1). In this study, we used chromatin immunoprecipitation to investigate the nature of unintegrated HIV-1 DNAs and discovered that core histones, the histone variant H3.3, and H1 linker histones are all deposited onto extrachromosomal HIV-1 DNA. We performed a time-course analysis and determined that the loading of core and linker histones occurred early after virus application. H3.3 and H1 linker histones were also found to be loaded onto unintegrated DNAs of the Moloney murine leukemia virus. The unintegrated retroviral DNAs are potently silenced, and we provide evidence that the suppression of extrachromosomal HIV-1 DNA is histone-related. Unintegrated DNAs were marked by posttranslational histone modifications characteristic of transcriptionally inactive genes: high levels of H3K9 trimethylation and low levels of H3 acetylation. These findings reveal insights into the nature of unintegrated retroviral DNAs.


Effects of polyethylene microplastics on properties, enzyme activities, and the succession of microbial community in Mollisol: At the aggregate level.
Soil, as a heterogeneous body, is composed of different-sized aggregates. There is limited data available on the potential role of microplastics (MPs) in microbial properties at the soil aggregate level. In this study, changes in microbial construction and diversity in farmland bulk soil and aggregates induced by polyethylene MPs (PE-MPs) were investigated at a dose of 0.5% (w/w) through 16s rDNA sequencing and enzyme activity measurements of different particle size aggregates in incubated soil. The presence of low-dose PE-MPs increased the proportion of >1 mm soil aggregates fraction, and decreased soil available nitrogen and available phosphorus in bulk soils. Furthermore, low-dose PE-MPs increased bacterial richness and diversity in 1-0.5 and < 0.25 mm fractions and decreased operational taxonomic unit, abundance-based coverage estimator, and Chao1 indices in bulk soil and >1 mm fractions. The levels of predicted functional genes taking part in the biodegradation and metabolism of exogenous substances also increased. At the phylum level, PE-MPs changed the proportion of Proteobacteria and Actinobacteria. The variations in soil aggregate properties were significantly correlated with the bacterial communities' composition and diversity. This study deepens our perception of the soil microenvironment, microbial community composition, and diversity in response to PE-MPs.


The antihypertensive profile of the angiotensin AT1 receptor antagonist, GR138950, and the influence of potential homeostatic compensatory mechanisms in renal hypertensive rats.
The cardiovascular profile of the angiotensin AT1 receptor antagonist, GR138950, and the influence of potential compensatory homeostatic mechanisms on this profile, were investigated in renal artery ligated hypertensive (RALH) rats. GR138950 caused a marked reduction in blood pressure associated with immediate tachycardia in conscious RALH rats. The antihypertensive action of GR138950 appeared biphasic; an immediate fall in blood pressure, which plateaued within 1 h, and which was followed by a further slow decline that reached maximum between 5-7 h after administration. The tachycardia caused by GR138950 was attenuated by atenolol and was abolished by combined pretreatment with atenolol and atropine methyl nitrate. However, the antihypertensive profile of GR138950 was unchanged by these pretreatments. The resting blood pressure and the antihypertensive effect of GR138950, in RALH rats, were unaffected by the vasopressin V1 receptor antagonist, [beta-mercapto-beta,beta-cyclopentamethylene propionyl(1)-O-Me-Tyr2,Arg8]-vasopressin. Thus, vasopressinergic mechanisms are not involved in either maintaining blood pressure in RALH rats, or in compensating for the fall in blood pressure caused by GR138950. In anaesthetized RALH rats, GR138950 caused a marked fall in blood pressure that was accompanied by an increase in heart rate along with sustained increases in renal and splanchnic sympathetic nerve activity. In summary, the biphasic fall in blood pressure evoked by GR138950 in RALH rats can not be explained on the basis of changes in autonomic control of the heart, alteration of vasopressin-mediated vasoconstrictor mechanisms or overall suppression of central sympathetic outflow. Rather, increased vasoconstrictor tone might serve to oppose the initial fall in blood pressure.


Diet-induced thermogenesis in man: thermic effects of single protein and carbohydrate test meals in lean and obese subjects.
Postprandial thermogenesis of 8 healthy males of normal body weight and 17 healthy obese subjects with a body weight gain of more than 10 kg per year was measured continuously by means of a respiratory chamber over 10 h after test meals of 1 and 2 MJ protein (casein) and 2 MJ carbohydrate (hydrolized starch). The total thermic response to all test meals was reduced by about 50% in the obese subjects. The thermic response was related to body weight, energy intake, resting metabolic rate and weight loss during restricted energy intake. The necessity for a careful characterization of the obese subjects in studies of thermogenesis and of efficiency of energy utilization in obesity is pointed out. It is suggested that thermic response to food can be considered as a suitable indicator for the distinction between people of different metabolic efficiency.


Assessing the effectiveness of a diabetes group visit training for health center staff: a pilot study of five Midwestern community health centers.
Diabetes group visits are shared appointments that include diabetes education in a group setting and individual visits with a medical provider. An 18-month pilot study was designed to evaluate organizational capacity and staff preparedness in implementing and sustaining diabetes group visits. Data were collected and analyzed from pre-post assessments and key informant interviews with community health center (CHC) staff (N = 26) from teams across five Midwestern states. Overall, participants demonstrated high baseline knowledge and awareness about diabetes group visit implementation. Changes in attitudes and practices did occur pertaining to familiarity with billing and increased awareness about potential barriers to diabetes group visit implementation. Key assets to diabetes group visit implementation were access to pre-designed resources and materials, a highly motivated team, and supportive leadership. Key obstacles were socioeconomic challenges experienced by patients, constraints on staff time dedicated to group visit implementation, and staff turnover. Results of the study provide a framework for implementation of diabetes group visit trainings for CHC staff. Future research is needed to assess the training program in a larger sample of CHCs.


Molecular characterization of minichromosome maintenance protein (MCM7) in Scylla paramamosain and its role in white spot syndrome virus and Vibrio alginolyticus infection.
The minichromosome maintenance protein (MCM7) is a member of the MCM protein family which participates in the MCM complex by playing a role in the cell replication cycle and chromosome initiation in eukaryotes. The 2270 bp cDNA sequence of MCM7, including a 2127-bp open reading frame (ORF) encoding a 709-aa protein, was cloned from Scylla paramamosain using RT-PCR and RACE. Data showed that MCM7 was highly expressed in the digestive organ and hepatopancreas of S. paramamosain. Furthermore, MCM7 expression was down-regulated by infection with white spot syndrome virus (WSSV) or Vibrio alginolyticus. When MCM7 was knocked down, immune genes such as Janus kinase (JAK) and crustin antimicrobial peptide (CAP) were down-regulated, and C-type-lectin (CTL) was up-regulated in hemocytes. The mortality of WSSV-infected or V. alginolyticus-infected crabs was enhanced following MCM7 knockdown. It was demonstrated that MCM7 is very important in the progression of WSSV and V. alginolyticus infection. We also investigated the effect of MCM7 on apoptosis rate and phagocytic rate in S. paramamosain. MCM7 knockdown caused higher levels of apoptosis in the hemocytes of the control, WSSV, and V. alginolyticus groups. MCM7 knockdown influenced the activity of phenoloxidase (PO) and superoxide dismutase (SOD), and total hemocyte count (THC) after infection with WSSV or V. alginolyticus, which indicated that MCM7 plays a regulatory role in innate immunity of crabs. Thus, we conclude that MCM7 may participate in the anti-WSSV and V. alginolyticus immune response in crabs by regulating apoptosis and the activity of PO and SOD.


Pathophysiologic features of "thin" endometrium.
To characterize pathophysiologic features of a "thin" endometrium. A prospective observational study. University Hospital and City General Hospital. Patients with normal-thickness endometrium (Normal-Em group: endometrial thickness >or=8 mm; n = 57) and thin endometrium (Thin-Em group: endometrial thickness <8 mm; n = 17). Blood flow impedance of the uterine radial artery (RA) was assessed as resistance index (RI) by transvaginal color-pulsed Doppler ultrasonography. The area of glandular epithelium, the number of blood vessels, and vascular endothelial growth factor (VEGF) expression were examined in the midluteal-phase endometrium. The RA-RI in the Thin-Em group was significantly higher than in the Normal-Em group throughout the menstrual cycle. Endometrial thickness was significantly correlated with RA-RI. Growth of glandular epithelium, the number of blood vessels, and VEGF expression were significantly lower in the Thin-Em group than in the Normal-Em group. A "thin" endometrium was characterized by high blood flow impedance of RA, poor epithelial growth, decreased VEGF expression, and poor vascular development.


Biomechanical simulation of forces and moments of initial orthodontic tooth movement in dependence on the used archwire system by ROSS (Robot Orthodontic Measurement & Simulation System).
Aim of this study was to determine the forces and moments during simulated initial orthodontic tooth movements using a novel biomechanical test setup. The test setup consisted of an industrial precision robot with a force-torque sensor, a maxillary model and a control computer and software. Forces and moments acting on the corresponding experimental tooth during the motion simulations were dynamically measured for two 0.016" NiTi round archwires (Sentalloy Light/Sentalloy Medium). Intrusive (#1), rotational (#2) and angular (#3) tooth movements were simulated by a control program based on the principle of force control and executed by the robot. The results were statistically analysed using K-S-test and Mann-Whitney U test with a significance level of α = 5%. Sentalloy Medium archwires generated higher forces and moments than the Sentalloy Light archwires in all simulations. In simulation #1 the mean initial forces/moments reached 1.442 N/6.781 Nmm for the Light archwires and 1.637 N/9.609 Nmm for the Medium archwires. In movement #2 Light archwires generated mean initial forces/moments of 0.302 N/-8.271 Nmm whereas Medium archwires generated 0.432 N/-9.653 Nmm. Simulation #3 showed mean initial forces/moments of -0.122 N/8.477 Nmm from the Light archwires compared to -0.300 N/11.486 Nmm for the Medium archwires. The measured forces and moments were suitable for initial orthodontic tooth movement in simulations #2 and #3, however inadequate in simulation #1. Reduced archwire dimensions (<0.016″) should be selected for initial leveling of vertical malocclusions.


Two-Dimensional and 3-Dimensional MRI Assessment of Progressive Collapsing Foot Deformity-Adult Acquired Flat Foot Deformity.
This article is meant to serve as a reference for radiologists, orthopedic surgeons, and other physicians to enhance their understanding of progressive collapsing foot deformity, also known as adult acquired flat foot deformity. Pathophysiology, imaging findings, especially on MRI and 3-dimensional MRI are discussed with relevant illustrations so that the readers can apply these principles in their practice for better patient managements.


Variation in estrogen-related genes associated with cardiovascular phenotypes and circulating estradiol, testosterone, and dehydroepiandrosterone sulfate levels.
Younger age at the onset of menopause and lower circulating levels of estrogen are risk factors for cardiovascular disease. Several studies have detected associations between variations in genes encoding estrogen receptors alpha (ESR1) and beta (ESR2), and enzyme aromatase (CYP19A1), which regulates the estrogen to testosterone ratio, and cardiovascular phenotypes in the Framingham Heart Study. To explore potential mechanisms by which these gene variants may contribute to cardiovascular disease, we tested the hypothesis that the polymorphisms were associated with endogenous steroid hormone levels. Multiple regression analysis was used to assess the relation between reported polymorphisms and total serum estradiol, testosterone, and dehydroepiandrosterone sulfate levels in 834 men and 687 women who attended the third and fourth Framingham Heart Study examination cycles. In men, significant associations were detected between CYP19A1 polymorphisms and estradiol and testosterone levels, and the estradiol to testosterone ratio (P ranges 0.0005-0.01). Specifically, carriers of common haplotype rs700518[G]-(TTTA)(n) [L]-rs726547[C] had higher estradiol levels (5% per copy; P = 0.0004), lower testosterone levels (17% per copy; P = 0.036), and a higher estradiol to testosterone ratio (24% per copy; P < 0.0001) compared with the rs700518[A]-(TTTA)(n) [S]-rs726547[C] carriers. In addition, postmenopausal carriers of the ESR2 (CA)(n) long allele and rs1256031 [C] allele had moderately higher estradiol levels (P < or = 0.03). No significant associations with the ESR1 variants were detected. Our findings suggest that variations in CYP19A1 correlate with steroid hormone levels in men. Knowledge that a specific carrier status may predispose to altered steroid hormone levels may lead to targeted intervention strategies to reduce health risks in genetically susceptible individuals.


The sensitivity and specificity of direct immunofluorescence testing in disorders of mucous membranes.
Direct immunofluorescence testing is frequently used to diagnose inflammatory mucosal disorders, but its accuracy relative to histologic and clinical diagnosis has not been reported. Our purpose was to compare diagnoses made on the basis of direct immunofluorescence, histologic features, and clinical impression and define optimal immunofluorescence criteria. Direct immunofluorescence findings and diagnostic impressions for 500 unselected mucosal biopsy specimens were recorded, as were the histologic diagnosis, initial clinical impression, and final diagnosis made on the basis of all studies and follow-up. Sensitivity and specificity were calculated for each parameter by diagnosis and site. Direct immunofluorescence testing was superior for diagnosing pemphigus and pemphigoid and was slightly inferior to histologic evaluation for diagnosing lichen planus. Optimal criteria were IgG and C3 intercellular substance staining for pemphigus, linear C3 basement membrane zone deposits for pemphigoid, and shaggy fibrinogen basement membrane zone staining plus IgM cytoids for lichen planus. Direct immunofluorescence testing was diagnostic for several extraoral mucosal biopsy specimens. Direct immunofluorescence is a valuable diagnostic tool for diseases of the oral mucosa and other mucosal sites.


Establishment of an appropriate method for determining multiple heterocyclic amines in soy products processed with various methods.
A method using UPLC-MS/MS and a core-shell C18 column was developed to simultaneously determine 21 heterocyclic amines (HAs) in 15 min. Appropriate QuEChERS conditions were also established to conveniently extract HAs from soy products cooked with various methods. These conditions presented good analytical performance; limit of detection, limit of quantification, recovery (%), repeatability (coefficient of variation (CV) %) and intermediate precision (CV%) were 0.008 ∼ 0.150 ng/g, 0.025 ∼ 0.500 ng/g, 62 ∼ 91%, ≤ 28% and ≤ 23% for tofu sample, and 0.003 ∼ 0.100 ng/g, 0.010 ∼ 0.350 ng/g, 64 ∼ 93%, ≤ 19% and ≤ 20% for soy milk sample, respectively. HAs contents in the samples increased with cooking temperature and time. The tofu samples cooked by frying had much higher HAs content than those cooked by boiling and roasting. Norharman and Harman mainly contributed HAs content in all samples. For the general population in Taiwan, the highest estimated level of HAs consumed from the samples is 373.67 ng/day.


Prenatal exposure to perfluoroalkyl substances and inflammatory biomarker concentrations.
Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants that induce immunotoxicity in experimental studies; however, epidemiological evidence-particularly during pregnancy-is scarce. We quantified associations between first trimester plasma perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and perfluorohexane sulfonate (PFHxS) concentrations and third trimester concentrations of inflammatory biomarkers and determined if these associations were modified by fetal sex. We analyzed data from 1411 participants, recruited between 2008 and 2011, in the Maternal-Infant Research on Environmental Chemicals study. Our primary outcome was a composite inflammatory index derived by summing the z-scores of eight proinflammatory biomarkers. Using multivariable linear regression models, we quantified associations between each PFAS and the inflammatory index and individual biomarkers. We quantified the effects of the PFAS mixture using weighted quantile sum regression, and evaluated effect modification using product terms and sex-stratified models. Each doubling of PFOA and PFHxS was associated with a 0.38 (95% CI, 0.09, 0.67) and 0.21 (95% CI, 0.01, 0.41) SD increase in the proinflammatory index, respectively. A one-quartile increase in the PFAS mixture was associated with a 0.40 (95% CI, 0.09, 0.71) SD increase in the proinflammatory index. In individual models, we observed positive associations between PFAS and concentrations of monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and matrix metalloproteinases-9; however, the magnitude and precision varied according to the specific PFAS. Sex-specific findings were identified in few PFAS-biomarker associations. PFOA, PFOS, and PFHxS, individually and as a mixture, were positively associated with proinflammatory biomarkers during pregnancy.


Response of cancer cells to molecular interruption of the CK2 signal.
Protein kinase CK2 is one of the key cellular signals for cell survival, growth, and proliferation. It is has been observed to be elevated in various cancers that have been examined. Various observations suggest that moderate dysregulation of CK2 may profoundly influence the cell response. We have examined the effects of interfering with the CK2 signal in various cancer cell lines by employing antisense oligodeoxynucleotides (ODN) against the alpha and beta subunits of CK2. Our results demonstrate that antisense CK2-alpha and antisense CK2-beta ODNs markedly influence cell viability of these cancer cells in a dose and time-dependent manner. Antisense CK2-alpha was slightly more effective than antisense CK2-beta in most of the cells tested. The efficacy of the antisense ODN seemed to vary with the cell type; however, in all cases potent induction of apoptosis was observed. Significantly, the effects of the antisense ODN on the CK2 activity in the nuclear matrix were relatively small compared to the much stronger induction of apoptosis in cells. This suggests that modest downregulation of CK2 can evoke a much greater apoptotic response in cancer cells.


Cytochrome c oxidase from bakers' yeast. Photolabeling of subunits exposed to the lipid bilayer.
Yeast mitochondria and purified yeast cytochrome c oxidase incorporated into micelles of the nonionic detergent Tween 80 were equilibrated with the hydrophobic aryl azides 5-[125I]iodonaphthyl-1-azide or S-(4-azido-2-nitrophenyl)-[35S]thiophenol. The azides were then converted to highly reactive nitrenes by flash photolysis or by illumination for 2 min and the derivatized cytochrome c oxidase subunits were identified by gel electrophoresis and radioactivity measurements. 5-[125I]Iodonaphthyl-1-azide labeled mainly the three mitochondrially made Subunits I to III and the cytoplasmically made Subunit VII. Subunits IV to VI or cytochrome c bound to the purified enzyme were labeled 9- to 90-fold less. Essentially the same result was obtained with S-(4-azido-2-nitrophenyl)-[35S]thiophenol except that Subunit V was labeled as well. In contrast, all seven subunits as well as cytochrome c were heavily labeled when the enzyme was dissociated with dodecyl sulfate prior to photolabeling with either of the two probes. These data indicate that all subunits of yeast cytochrome c oxidase except Subunits IV and VI are at least partly embedded in the lipid bilayer of the mitochondrial inner membrane.


Effectiveness of a 4-Day Mindfulness-Based Intervention in a 2-Month Follow-Up for Chinese Incarcerated People.
Mindfulness-based interventions, an evidence-based stress reduction approach, may help incarcerated people cope with stress-related problems in the challenging environment of prison. However, due to their unique living environment, the duration and instructor guidance required by standard mindfulness-based interventions would be infeasible in most prisons. Therefore, the aims of the current study were to test the effects of two different 4-day interventions (i.e., instructor-guided and audio-based) with content similar to Mindfulness-Based Cognitive Therapy for newly incarcerated males, and to compare the effectiveness of the two interventions relative to a no-intervention control group. Using daily assessments, we explored changes in perceived stress, insomnia, and negative affect in the 56 days following the instructor-guided (N = 25), audio-based (N = 21), and control (N = 44) intervention; length of mindfulness practice during the follow-up was also compared between the two intervention groups. Hierarchical linear model results showed significantly greater linear decreases in perceived stress after both mindfulness interventions during the 56-day follow-up (γ11 = -0.011, p < .001, 95% CI [-0.017, -0.004] for instructor-guided intervention; γ12 = -0.013, p < .001, 95% CI [-0.018, -0.006] for audio-based intervention), as compared to the control group. Compared to the control group, the instructor-guided group reported a significantly greater decrease in insomnia (γ11 = -0.007, p < .001, 95% CI [-0.014, -0.002]), but the audio-based group did not (γ12 = -0.002, p = .160, 95% CI [-.007, .004]). Neither mindfulness-based intervention group reported a significantly greater decrease in negative affect compared to the control group (γ11 = -0.002, p = .170, 95% CI [-0.005, 0.001] for instructor-guided intervention; γ12 = -0.002, p = .150, 95% CI [-0.006, 0.002] for audio-based intervention). No significant difference between the two intervention groups was found in the change of outcomes (γ11 = 0.002, -0.005 and 0.000, p = .350, .130 and .390, 95% CI [-0.008, 0.011], 95% CI [-0.014, 0.004] and 95% CI [-0.004, 0.006] subsequently for perceived stress, insomnia and negative affect). Daily mindfulness practice was significantly longer for the audio-based group on the first day of follow-up (γ02 = -0.758, p < .05, 95% CI [-1.333, -0.129]), but it gradually decreased to the same amount as the instructor-guided group (t (32) = 0.051, p = .959). Short-term mindfulness interventions, either instructor-guided or audio-based, appear to be beneficial for Chinese prisoners in reducing stress. Live instruction may have potential benefit in reducing insomnia and sustaining daily practice.


A novel amino acid substitution in the reactive site of a congenital variant antithrombin. Antithrombin pescara, ARG393 to pro, caused by a CGT to CCT mutation.
Antithrombin is a plasma protein inhibitor that can be grouped within a serine proteinase inhibitor superfamily. Antithrombin Pescara is a functional variant of antithrombin found in a family with a high incidence of thrombosis. Preliminary functional analysis has suggested that the abnormality resides in the reactive site rather than in the heparin binding domain of the molecule. Accordingly, we have isolated the variant from plasma using heparin-Sepharose chromatography, followed by chromatography upon thrombin-Sepharose to remove the normal antithrombin that is present (the propositus is heterozygous for the variant). The variant protein was reduced, S-carboxy-methylated, and fragmented with CNBr. A pool ("CNBr pool 4") containing the reactive site region was isolated by reverse-phase high performance liquid chromatography and sequentially treated with trypsin and V8 protease. Fast atom bombardment-mass spectrometric analysis of this subdigest identified a novel peptide of mass 1708. Four steps of Edman degradation together with further analysis by fast atom bombardment-mass spectroscopy identified the NH2-terminal sequence of this peptide as Ala-Ala-Ala-Ser. The mass of the novel peptide and its changing mass in response to Edman degradation are only compatible with its identity as Ala382-Arg399, with the reactive site Arg393 replaced by Pro. Using specific oligonucleotide hybridization, we demonstrated that the molecular defect of antithrombin Pescara is caused by a CGT to CCT mutation in codon 393. These findings may be of broad interest, as other members of the serine protease inhibitor superfamily contain arginine at their reactive sites and may be expected to undergo a similar mutation.


Post-trial administration of vasopressin in humans does not enhance memory formation (vasopressin and memory consolidation).
Many animal studies show an enhancing effect of vasopressin (VP) on memory, but not all human studies could confirm this finding. This study examined the influence of post-learning administration of VP (40 IU, intranasally) on the consolidation of declarative memories in healthy humans during different intervals of sleep and waking. We could not find any effect of VP on memory consolidation, but EEG activity indicated a significant arousing influence of VP. Results suggest that if VP affects memory function it might do so primarily at the stage of encoding of the materials to be learned but it leaves unaffected processes of consolidation.


Cyclophosphamide, Bortezomib, and Dexamethasone Consolidation in Patients with Multiple Myeloma after Stem Cell Transplantation: The KMM130 Study.
A three-drug combination of cyclophosphamide, bortezomib, and dexamethasone (CVD) shows significant efficacy and manageable toxicity as induction therapy in patients with multiple myeloma. In this phase II study, we enrolled 45 patients who achieved a very good partial response (VGPR) or partial response (PR) after autologous stem cell transplantation (ASCT) and evaluated the efficacy and toxicity of CVD consolidation. CVD consolidation comprised three cycles of cyclophosphamide 300 mg/m2 orally on days 1, 8, and 15, and bortezomib 1.3 mg/m2 subcutaneously on days 1, 8, 15, and 22, along with dexamethasone 20 mg orally or intravenously on days 1 and 2, 8 and 9, 15 and 16, and 22 and 23. At enrollment, 39 patients (86.7%) showed VGPR, and nine (13.3%) presented with PR. Nineteen patients (45.2%) achieved a complete response or better as their best response after the end of consolidation. Overall, 22 of 42 patients (52.4%) experienced an improved response status with CVD consolidation. Three-year overall survival and progression-free survival rates were 89.0% and 42.7%, respectively. The most common non-hematologic toxicities were peripheral neuropathy and infection (20.5%), with no grade ≥ 3 neuropathy observed. These results showed that CVD consolidation therapy improved the response with reasonable toxicity in patients with residual disease after ASCT. This trial was registered with the Clinical Research Information Service, Republic of Korea (KCT0001327).


Interval between neoadjuvant chemoradiotherapy and surgery for esophageal squamous cell carcinoma: does delayed surgery impact outcome?
Although esophagectomy traditionally is recommended to perform within 8 weeks after neoadjuvant chemoradiotherapy (nCRT), data from neoadjuvantly treated rectal cancer patients demonstrate that delayed surgery ([8 weeks) can maximize the effect of CRT. Despite these promising data, investigators are concerned that delayed surgery may lead to tumor repopulation. We report the impact of delayed surgery in patients with esophageal cancer who were treated with nCRT. We retrospectively studied 276 esophageal cancer patients treated with nCRT and surgery between 2002 and 2008. We compared perioperative complication, rate of pathological complete response (pCR), distribution of tumor regression grade (TRG), and overall survival (OS) in patients who underwent surgery within 8 weeks (group A) and after 8 weeks (group B) after nCRT. There were 138 patients in each group with similar pre/post-nCRT characteristics. Delayed surgery did not result in lower surgical risk or higher pCR rate. Survival outcome also did not improve following a longer surgery interval (5-year OS: group A vs. group B, 29 vs. 23 %; P = 0.3). On the contrary, a subgroup analysis showed that delayed surgery might be hazardous, especially in patients who demonstrate a good response after nCRT. The amount of residual cancer, as measured by TRG, increased significantly after a longer surgical interval (P = 0.024). Survival also decreased after a longer surgical interval (5-year OS B8 vs. [8 weeks, 50 vs. 35 %; P = 0.038). After nCRT, esophagectomy should be performed within 8 weeks, especially in patients with good response.


Spatial distribution and historical input of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) in sediments from a subtropical estuary (Guaratuba Bay, SW Atlantic).
This study evaluated the occurrence and distribution of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) in 22 surface sediment samples and one core collected in Guaratuba Bay, a large and well-preserved estuary in Southern Atlantic, Brazil. The concentration of PCBs in the superficial sediment samples ranged from <LQ (below the limit of quantification) to 5.62 ng g⁻¹, while the concentration of OCPs ranged from <LQ to 0.74 ng g⁻¹. The spatial distribution of the organochlorine compounds (OCs) suggested that the sources of these contaminants are located outside the bay and are related to human activities on the margins of the two main rivers that discharge in the region. The OCs in the sediment core ranged from <LQ to 0.52 ng g⁻¹ and from <LQ to 1.52 ng g⁻¹ for PCBs and OCPs, respectively. Despite their usage worldwide, the low concentrations of OCs in Guaratuba Bay suggest low input levels, which may represent the background levels for this region.