Involvement of matrix metalloproteinase-9 in the development of morphine tolerance.
Matrix metalloproteinase-9 (MMP-9) is involved in tissue remodeling or neural plasticity in various clinical states (e.g. inflammation, neuropathic pain). We focused on the effect of MMP-9 on development of morphine tolerance after repeated morphine treatment. To develop morphine tolerance, mice were given morphine (10mg/kg; s.c.) once daily for 5 days. The antinociceptive effect of morphine was measured by the tail flick method. Development of morphine tolerance was significantly inhibited by daily treatment of the non-specific MMP inhibitor GM6001 (5 μg/mouse, i.c.v.). A MMP-9 inhibitor (5 μg/mouse, i.c.v.) partially, yet significantly, inhibited the development of morphine tolerance. Intrathecal treatment of a MMP-9 inhibitor did not affect morphine tolerance. In MMP-9((-/-)) mice, the development of morphine tolerance was partially, yet significantly, inhibited compared with wild-type mice. MMP-9 protein expression levels in the midbrain gradually increased 12h to 24h after morphine treatment on day 1, but were unchanged on days 3-5. In the spinal cord, MMP-9 protein expression levels were unchanged. In gelatin zymography analyses, MMP-9 activity in the midbrain gradually increased 12 to 24h after morphine treatment. Increment in MMP-9 activity in the midbrain was also observed on days 3-5. Our findings suggest that persistent MMP-9 activation observed after the transient increment in MMP-9 expression from the early phase of morphine treatment may contribute to the development of morphine tolerance.


Medication incidents related to automated dose dispensing in community pharmacies and hospitals--a reporting system study.
Automated dose dispensing (ADD) is being introduced in several countries and the use of this technology is expected to increase as a growing number of elderly people need to manage their medication at home. ADD aims to improve medication safety and treatment adherence, but it may introduce new safety issues. This descriptive study provides insight into the nature and consequences of medication incidents related to ADD, as reported by healthcare professionals in community pharmacies and hospitals. The medication incidents that were submitted to the Dutch Central Medication incidents Registration (CMR) reporting system were selected and characterized independently by two researchers. Person discovering the incident, phase of the medication process in which the incident occurred, immediate cause of the incident, nature of incident from the healthcare provider's perspective, nature of incident from the patient's perspective, and consequent harm to the patient caused by the incident. From January 2012 to February 2013 the CMR received 15,113 incidents: 3,685 (24.4%) incidents from community pharmacies and 11,428 (75.6%) incidents from hospitals. Eventually 1 of 50 reported incidents (268/15,113 = 1.8%) were related to ADD; in community pharmacies more incidents (227/3,685 = 6.2%) were related to ADD than in hospitals (41/11,428 = 0.4%). The immediate cause of an incident was often a change in the patient's medicine regimen or relocation. Most reported incidents occurred in two phases: entering the prescription into the pharmacy information system and filling the ADD bag. A proportion of incidents was related to ADD and is reported regularly, especially by community pharmacies. In two phases, entering the prescription into the pharmacy information system and filling the ADD bag, most incidents occurred. A change in the patient's medicine regimen or relocation was the immediate causes of an incident.


[Immunogenecity induced by the VA-MENGOC-BC antimeningococcal vaccine against the ATCC C11. N. meningitidis strain in adolescents 12 years after being vaccinated].
The antibodies' response induced by the VA-MENGOC-BC Cuban antimeningococcal vaccine against the ATCC C11 strain was studied by Bactericidal Serum Trial and ELISA among 184 adolescents from a polytechnic, in Ciego de Avila, that had been immnunized in mass campaings 12 years before. Blood samples were taken before administering the first dose (T0), 4 weeks later (T1), and 4 weeks after the second dose (T2). 12 years after vaccination, 25% of the adolescents presented bactericidal titers > or =1:8 against the evaluated strain. 78% showed a concentration of antibodies over the limit of detection against the meningococcus C capsular polyssacharide. The percentages of seroconversion after the first dose were 59 by Bactericidal Serum Trial and 82 by ELISA. There were no significant differences (p > 0.05) between the results obtained after the first and second dose by boths trials. The reimmnunization with 2 doses of the vaccine did not cause hyporesponse against the ATCC C11 strain in this age group.


Angiotensin-converting enzyme inhibition and renal protection in nondiabetic patients: the data of the meta-analyses.
ESRD represents a major health problem. The number of patients who enter kidney replacement programs has increased at an average of 7% per year in the past 10 yr. A large number of experimental and clinical studies have demonstrated that chronic nephropathies share common pathogenic mechanisms that contribute to renal disease progression, even independent of the original cause. Clinical studies found a significant correlation between the extent of urinary protein excretion and the rate of GFR decline in both diabetic and nondiabetic chronic nephropathies. Randomized trials, in particular the Ramipril Efficacy In Nephropathy (REIN) study, also showed that treatments that reduce proteinuria (namely angiotensin-converting enzyme [ACE] inhibitors) are renoprotective and limit progression to ESRD. Meta-analyses of randomized clinical trials also evaluated the role of proteinuria and of ACE inhibition therapy in chronic renal disease progression. Their findings were consistent with those of the REIN study and confirmed in larger series of patients the predictive value of proteinuria and the renoprotective effect of proteinuria reduction by ACE inhibition therapy. Thus, the meta-analyses may confirm and extend previous findings generated by randomized clinical trials. Conceivably, well-designed studies in properly selected and carefully monitored patients who are at increased risk continue to be the best approach to test novel hypotheses. The meta-analyses, however, represent a valuable tool to evaluate the consistency and generalizability of trial results to larger cohorts of patients.


Association between common carotid artery intima-media thickness and proteinuria in type 2 diabetic patients.
Proteinuria is the most reliable marker of diabetic nephropathy and an index of atherosclerosis and cardiovascular mortality in diabetic patients. In addition, common carotid artery intima-media thickness (CIMT) is a sensitive marker of early atherosclerosis and cardiovascular risk. The aim of this study was to evaluate the association between proteinuria and CIMT in type 2 diabetic patients. In a cross-sectional study, 154 patients with type 2 diabetes mellitus were enrolled. The CIMT was measured for all of the patients by one researcher. The 24-hour urine protein was measured using trichloroacetic acid method. A total of 154 type 2 diabetic patients were enrolled with a mean diabetes mellitus duration of 8.91 ± 6.99 years (95 women and 55 men). The mean urinary protein in the patients was 294.70 ± 525.85 mg/24 h. The mean CIMT in all of the patients was 0.84 ± 0.19 mm, and it was greater in the men than in the women (P = .03). The CIMT significantly correlated with patients' age (P < .001), systolic blood pressure (P < .001), and urinary protein excretion (P = .001). There was a marginal positive correlation between diabetes mellitus duration and the CIMT (P = .049). This study showed a significant association between CIMT, as a sensitive marker of macrovascular complication of diabetes mellitus, and proteinuria as an important index of microvascular complication of the disease.


A phase I dose escalation study of S-1 with concurrent radiotherapy in elderly patients with esophageal cancer.
Concurrent chemoradiotherapy (CRT) with 5-fluorouracil (5-FU) and cisplatin (CDDP) are often associated with significant incidence of toxic effects in elderly patients with esophageal cancer. This phase I trial was designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of S-1, an oral 5-FU derivative, when given with radiotherapy in elderly patients. Patients who were age of 70 years or older with histologically confirmed esophageal cancer, and had an Eastern Cooperative Oncology Group (ECOG) score of 0-2 were eligible for this study. Radiotherapy was administered in 1.8 Gy fractions 5 times weekly to a total dose of 54 Gy. S-1 was administered on days 1-14 and 29-42 at the following dosages: 60, 70, and 80 mg/m(2)/day. NCT01175447 (ClinicalTrials.gov). Twelve previously untreated patients were enrolled in this study. No grade 3 or 4 toxicity was observed in six patients treated at the 60 and 70 mg/m(2) dose levels. DLT was observed in four of six patients treated at the 80 mg/m(2) dose level. Two patients developed grade 3 esophagitis, one patient developed grade 3 esophagitis and pneumonitis, and one patient developed grade 3 thrombocytopaenia. Endoscopic complete response (CR) was observed in eight patients (66.7%). The median progression free survival (PFS) was 20 months and median overall survival was 29 months. The MTD of S-1 was 80 mg/m(2), and the recommended dose (RD) for phase II studies was 70 mg/m(2). This regimen was well tolerated and active in elderly patients with esophageal cancer, meriting further investigation in phase II studies.


Effect of mineral trioxide aggregate surface treatments on morphology and bond strength to composite resin.
The aim of this study was to evaluate the micromorphologic changes that accompany different surface treatments on mineral trioxide aggregate (MTA) and their effect on the bond strength to the composite resin with 4 adhesive systems. Three types of MTA cement, ProRoot MTA (WMTA) (Dentsply, Tulsa, OK), MTA Angelus (AMTA) (Angelus, Londrina, PR, Brazil), and Endocem MTA (EMTA) (Maruchi, Wonju, Korea), were prepared and stored for a week to encourage setting. Surface treatment was performed using phosphoric acid or self-etch primer, and an untreated MTA surface was prepared as a control. The surface changes were observed using scanning electron microscopy. MTA surfaces were bonded with 4 adhesive systems, including Scotchbond Multipurpose (3M ESPE, St Paul, MN), Single Bond 2 (3M ESPE), Clearfil SE BOND (Kuraray, Osaka, Japan), and AdheSE One F (Ivoclar Vivadent, Schaan, Liechtenstein), to evaluate the adhesive effectiveness of MTA followed by composite resin restoration. The shear bond strength of the polymerized specimens was tested. For WMTA and AMTA, untreated surfaces showed an irregular crystalline plate with clusters of globular aggregate particles. For EMTA, the untreated surface presented a reticular matrix with acicular crystals. After surface treatment, superficial crystalline structures were eroded regardless of the MTA cement and adhesive system used. WMTA bonded significantly more strongly than AMTA and EMTA, regardless of the adhesive system used. In the WMTA and AMTA groups, AdheSE One F showed the highest bond strength to the composite. For EMTA, no significant differences were found across adhesive systems. Acidic treatment of the MTA surface affected the micromorphology and the bond strength to the composite. Within the limitations of this study, using a 1-step self-etch adhesive system might result in a strong bond to WMTA when the composite resin restoration is required over MTA cement.


Changing Antimicrobial Resistance Pattern of Isolates from an ICU Over a 3 Year period.
To study the changing patterns of antimicrobial resistance in gram negative bacilli esp. Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa species and Gram positive Staphylococcus aureus isolates from a 37 bedded ICU of a private hospital. Antibiotic susceptibilities were determined by using disk diffusion and Vitek-2 system. A total of 13410 clinical samples were screened over a period of 3 years, among which 16.77 percent (2250 isolates) were culture positive. In recent years there has been an increased incidence of extended-spectrum β- lactamase (ESBL). The ESBL producing Escherichia coli and Klebsiella pneumonia has shown an increase in resistance to the tune of 80-90% from 2011 to 2013. The prevalence of resistant strains of Acinetobacter species and Pseudomonas aeruginosa has shown an increase in Imipenem and Meropenem resistance at the rate of 75-80%. Antibiotic resistance has shown an increase in gram negative pathogens and thereby has created a significant problem in choosing the right antibiotic for empirical usage. Rise in resistance has left little choice for the clinicians to select antibiotics. Klebsiella pneumonia ESBL and Escherichia coli ESBL have become dominant organisms in the ICU. Piperacillin + Tazobactum, Imipenem and Amikacin have decreased sensitivity against Enterobacter. A number of old antibiotic compounds such as Polymyxins, Fosfomycin, and Aminoglycosides are re-emerging as valuable alternatives for the treatment of ESBL producing bacteria. Cases of MDR Escherichia coli and Klebsiella pneumonia bacteria have increased in recent years and are now the most frequent cause of hospital acquired infections.


Healthcare and community stakeholders' perceptions of barriers and facilitators to implementing a behavioral activation intervention for people with dementia and depression: a qualitative study using Normalization Process Theory.
Depression is commonly experienced by people with dementia, and associated with lower quality of life and functional decline. However, access to evidence-based psychological interventions for people with dementia and depression is limited. One potential solution is guided low-intensity behavioral activation. Following the new Medical Research Council Framework, considering factors such as potential barriers and facilitators to implementation is recommended during the development of new interventions. Aims of this study were to: (1) develop an understanding of existing healthcare and community support in the Swedish context for people with dementia and their informal caregivers; and (2) identify barriers and facilitators to intervention uptake informed by Normalization Process Theory. Semi-structured interviews and focus groups were held with healthcare (n = 18) and community (n = 7) stakeholders working with people with dementia and/or informal caregivers. Interview questions were informed by Normalization Process Theory. Data was analysed utilizing a two-step deductive analysis approach using the Normalization Process Theory coding manual, with inductive categories applied to data related to the main mechanisms of the theory, but not captured by its sub-constructs. Twelve deductive and three inductive categories related to three Normalization Process Theory primary mechanisms (Coherence, Cognitive Participation, and Collective Action) were identified. Identified barriers to intervention uptake included: (1) additional burden for informal caregivers; (2) lack of appropriate workforce to provide guidance; (3) lack of time and financial resources; (4) people with dementia not recognising their diagnosis of dementia and/or a need for support; and (5) stigma. Identified facilitators to intervention uptake included: (1) intervention has potential to fill a large psychological treatment gap in Sweden; (2) objectives and potential benefits understood and agreed by most stakeholders; and (3) some healthcare professionals recognized their potential role in providing intervention guidance. Several barriers and facilitators for future implementation, specific to the intervention, individuals and families, as well as professionals, were identified during intervention development. Barriers were mapped into evidence-based implementation strategies, which will be adopted to overcome identified barriers. A feasibility study further examining implementation potential, acceptability and feasibility, alongside clinical, methodological, and procedural uncertainties associated with the intervention will be conducted. Not applicable.


Phylogenomic Mining of the Mints Reveals Multiple Mechanisms Contributing to the Evolution of Chemical Diversity in Lamiaceae.
The evolution of chemical complexity has been a major driver of plant diversification, with novel compounds serving as key innovations. The species-rich mint family (Lamiaceae) produces an enormous variety of compounds that act as attractants and defense molecules in nature and are used widely by humans as flavor additives, fragrances, and anti-herbivory agents. To elucidate the mechanisms by which such diversity evolved, we combined leaf transcriptome data from 48 Lamiaceae species and four outgroups with a robust phylogeny and chemical analyses of three terpenoid classes (monoterpenes, sesquiterpenes, and iridoids) that share and compete for precursors. Our integrated chemical-genomic-phylogenetic approach revealed that: (1) gene family expansion rather than increased enzyme promiscuity of terpene synthases is correlated with mono- and sesquiterpene diversity; (2) differential expression of core genes within the iridoid biosynthetic pathway is associated with iridoid presence/absence; (3) generally, production of iridoids and canonical monoterpenes appears to be inversely correlated; and (4) iridoid biosynthesis is significantly associated with expression of geraniol synthase, which diverts metabolic flux away from canonical monoterpenes, suggesting that competition for common precursors can be a central control point in specialized metabolism. These results suggest that multiple mechanisms contributed to the evolution of chemodiversity in this economically important family.


Molecular studies on bromovirus capsid protein. III. Analysis of cell-to-cell movement competence of coat protein defective variants of cowpea chlorotic mottle virus.
To determine whether the role of coat protein (CP) in cell-to-cell movement of dicot-adapted cowpea chlorotic mottle bromovirus (CCMV) is distinct from that of monocot-adapted brome mosaic bromovirus (BMV), two reporter genes, beta-glucuronidase (GUS) and enhanced green fluorescent protein (EGFP), were substituted for the CP in a biologically active clone of CCMV RNA3 (C3). Primary leaves of Nicotiana benthamiana, Chenopodium quinoa, and cowpea were co-inoculated with wild-type (wt) CCMV RNA 1 and -2 and either C3/delta CP-GUS or C3/delta CP-EGFP and analyzed for GUS activity or the presence of green fluorescence. The visual appearance of infections caused by GUS or EGFP variants indicated that, in CCMV, epidermal cell-to-cell movement can occur without a functional CP. By contrast, inoculation of MP defective variants of C3/delta CP-GUS or C3/delta CP-EGFP resulted in subliminal infections. Additional experiments examining the infectivity of wt BMV RNA 1 and -2 and a BMV RNA3 variant bearing the EGFP in the place of CP (B3/delta CP-EGFP) confirmed previous observations that, unlike CCMV, epidermal cell-to-cell movement of BMV is dependent on the expression of a functional CP. Taken together, the results demonstrate that BMV and CCMV use different mechanisms for initial epidermal cell-to-cell spread, and the individual role played by the respective CP genes in this active process is discussed.


[Timing of administration of sulfonyl urea derivatives].
In daily practice the optimal time of administration of sulphonylurea derivatives is not always clear. Administration 30 minutes prior to meals allegedly offers the advantage that an active plasma level has been reached when food enters the gastrointestinal tract. Alleged disadvantages are higher risk of hypoglycaemia and poor compliance. In publications from Medline 1966-1999 the 24-hour availability of sulphonylurea derivates was the same after administration at different times. The absorption rate of glibenclamide and tolbutamide was not affected by food. Study results concerning gliclazide were contradictory. The absorption rate of glipizide was reduced after ingestion during breakfast. In several, partly the same, small studies the findings concerning the variation of the glucose level in time in patients with type 2 diabetes mellitus were equivocal. The pharmacokinetic and pharmacodynamic evidence that sulphonylurea derivatives should be taken 30 minutes before meals appears to be so limited that in our opinion it is out-weighed by the potential risk that this advice may compromise the drug compliance of users.


MATRIX SEARCH 1.0: a computer program that scans DNA sequences for transcriptional elements using a database of weight matrices.
The information matrix database (IMD), a database of weight matrices of transcription factor binding sites, is developed. MATRIX SEARCH, a program which can find potential transcription factor binding sites in DNA sequences using the IMD database, is also developed and accompanies the IMD database. MATRIX SEARCH adopts a user interface very similar to that of the SIGNAL SCAN program. MATRIX SEARCH allows the user to search an input sequence with the IMD automatically, to visualize the matrix representations of sites for particular factors, and to retrieve journal citations. The source code for MATRIX SEARCH is in the 'C' language, and the program is available for unix platforms.


Promoting vaccinations - an analysis of measures taken by German statutory health insurers.
Prophylactic vaccinations play a significant role in health care. As a relatively cost-effective preventive measure they can help to avert transmissible diseases and thus protect not only the vaccinated individuals themselves but also those who have not been vaccinated. In order to achieve this, a high vaccination rate is necessary; for many prophylactic vaccinations this rate is not reached in Germany. In order to counteract this trend the importance of prophylactic vaccinations was upgraded in 2007 within the scope of the reform of the health system. The reimbursement of patients' vaccination fees was made compulsory for the statutory health insurance companies and statutory requirements were imposed on the insurers to ensure a nationwide provision of prophylactic vaccinations for insured persons. The objective of this paper is to evaluate to what extent the health insurance companies promote the increasing of vaccination coverage rate today and what measures are being used to present this topic to the public. In order to assess the public presentation of the topic "prophylactic vaccinations" we have examined the websites of 68 statutory health insurance companies. We have assessed the attitude of the companies towards the promotion of participation in vaccination programs by conducting qualitative, structured interviews with representatives of 8 health insurers. Measures to promote vaccinations, such as information, recall offers, projects to educate people or even monetary incentives, are employed relatively extensively by the health insurers and are considered important. However, it became clear that the discussion about prophylactic vaccinations, in particular concerning the costs and benefits thereof, had not been completed yet within the companies. Vaccination-specific data is not collected or evaluated on a regular or even isolated basis. There are no concrete targets concerning specific vaccination rates and incentives are neither evaluated nor compared with one another. The relatively extensive range of measures used to promote the vaccination rate contrasts with insufficient knowledge about their efficacy and efficiency. There is an urgent requirement for more research here.


Detection of autosomal dominant polycystic kidney disease by NMR spectroscopic fingerprinting of urine.
Autosomal dominant polycystic kidney disease (ADPKD) is a frequent cause of kidney failure; however, urinary biomarkers for the disease are lacking. In a step towards identifying such markers, we used multidimensional-multinuclear nuclear magnetic resonance (NMR) spectroscopy with support vector machine-based classification and analyzed urine specimens of 54 patients with ADPKD and slightly reduced estimated glomerular filtration rates. Within this cohort, 35 received medication for arterial hypertension and 19 did not. The results were compared with NMR profiles of 46 healthy volunteers, 10 ADPKD patients on hemodialysis with residual renal function, 16 kidney transplant patients, and 52 type 2 diabetic patients with chronic kidney disease. Based on the average of 51 out of 701 NMR features, we could reliably discriminate ADPKD patients with moderately advanced disease from ADPKD patients with end-stage renal disease, patients with chronic kidney disease of other etiologies, and healthy probands with an accuracy of >80%. Of the 35 patients with ADPKD receiving medication for hypertension, most showed increased excretion of proteins and also methanol. In contrast, elevated urinary methanol was not found in any of the control and other patient groups. Thus, we found that NMR fingerprinting of urine differentiates ADPKD from several other kidney diseases and individuals with normal kidney function. The diagnostic and prognostic potential of these profiles requires further evaluation.


Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents.
Protein tyrosine phosphatases are often exploited and subverted by pathogenic bacteria to cause human diseases. The tyrosine phosphatase mPTPB from Mycobacterium tuberculosis is an essential virulence factor that is secreted by the bacterium into the cytoplasm of macrophages, where it mediates mycobacterial survival in the host. Consequently, there is considerable interest in understanding the mechanism by which mPTPB evades the host immune responses, and in developing potent and selective mPTPB inhibitors as unique antituberculosis (antiTB) agents. We uncovered that mPTPB subverts the innate immune responses by blocking the ERK1/2 and p38 mediated IL-6 production and promoting host cell survival by activating the Akt pathway. We identified a potent and selective mPTPB inhibitor I-A09 with highly efficacious cellular activity, from a combinatorial library of bidentate benzofuran salicylic acid derivatives assembled by click chemistry. We demonstrated that inhibition of mPTPB with I-A09 in macrophages reverses the altered host immune responses induced by the bacterial phosphatase and prevents TB growth in host cells. The results provide the necessary proof-of-principle data to support the notion that specific inhibitors of the mPTPB may serve as effective antiTB therapeutics.


Efficacy of oral calcium pentosan polysulphate for the treatment of osteoarthritis of the canine stifle joint secondary to cranial cruciate ligament deficiency.
The efficacy of calcium pentosan polysulphate (CaPPS) as a slow-acting drug for the treatment of osteoarthritis of the canine stifle joint, secondary to cranial cruciate ligament deficiency, was tested in a double-blind, placebo-controlled clinical trial over a period of one year. Dogs with the deficiency were treated surgically, matched for bodyweight, and randomly assigned to treatment or placebo groups. Active treatment began six weeks postoperatively and consisted of 10 mg/kg CaPPS orally, once weekly for four weeks, repeated every 12 weeks. The outcome was assessed in terms of function by the dogs' owners, by the radiographical grading of the osteoarthritis, and by the measurement of total sulphated glycosaminoglycans and the 5D4 epitope of keratan sulphate in the synovial fluids of affected joints. There were no differences either in functional outcome or in the radiographical progression of osteoarthritis between the two groups. Fifty-four weeks after surgery, the concentration of 5D4 in synovial fluid (expressed as change from baseline values) had decreased significantly in the treatment group compared with the placebo group (P=0.03).


On the implication of structural zeros as independent variables in regression analysis: applications to alcohol research.
In alcohol studies, drinking outcomes such as number of days of any alcohol drinking (DAD) over a period of time do not precisely capture the differences among subjects in a study population of interest. For example, the value of 0 on DAD could mean that the subject was continually abstinent from drinking such as lifetime abstainers or the subject was alcoholic, but happened not to use any alcohol during the period of interest. In statistics, zeros of the first kind are called structural zeros, to distinguish them from the sampling zeros of the second type. As the example indicates, the structural and sampling zeros represent two groups of subjects with quite different psychosocial outcomes. In the literature on alcohol use, although many recent studies have begun to explicitly account for the differences between the two types of zeros in modeling drinking variables as a response, none has acknowledged the implications of the different types of zeros when such modeling drinking variables are used as a predictor. This paper serves as the first attempt to tackle the latter issue and illustrate the importance of disentangling the structural and sampling zeros by using simulated as well as real study data.


Identification of new hub genes associated with bladder carcinoma via bioinformatics analysis.
Bladder carcinoma (BC) is one of the most common malignant cancers worldwide. Several genes related to the mechanism of BC have been studied in recent years, but the current understanding of BC is still rather limited. This study aimed to find new differentially expressed genes (DEGs) associated with the occurrence and development of BC. In this work, we downloaded gene expression data from Gene Expression Omnibus under accession number GSE27448, which included 10 GeneChips from urinary BC tissues and 5 from normal tissues. DEGs were identified by the LIMMA package in R. Then the protein-protein interactions (PPIs) networks were analyzed with the database of Search Tool for the Retrieval of Interacting Genes, and gene ontology (GO) was applied to explore the underlying function of the DEGs using the Database for Annotation, Visualization and Integrated Discovery. A total of 2,068 DEGs were found between BC and normal tissues. These genes were involved in 49 functional clusters. The top 10 highest degree nodes, such as POLR2F/2H (DNA directed RNA polymerase II polypeptide F/polypeptide H) and RPS14/15 (ribosomal protein S14/S15), were proven to be hub nodes in the PPIs network. ITGA7 (integrin, alpha 7), GRB14 (growth factor receptor-bound protein 14), CDC20 (cell division cycle 20) and PSMB1 (proteasome subunit, beta type, 1) were significant DEGs identified in the functional clusters. Genes such as POLR2F/2H, RPS14/15, ITGA7, GRB14, CDC20 and PSMB1 were forecast to play important roles in the occurrence and progression of BC.


[The inhibiting effect of cimetidine on a number of enzymes].
The results of the comparative study on the contents and activity of the enzymes of the system of oxidases of mixed function in the lungs and liver in rabbits, the specific features of phospholipid spectrum in the supernatant and microsomal fractions of the lungs and liver tissues are presented. The same parameters were investigated in experimental chronic inflammatory diseases of the lungs. The degree of the damage of the monoxygenase capacity of the lungs and the degree of the liver involvement in the process were established. The peculiarities of the inhibitory action of cimetidine on the detoxication capacity of the lungs and liver and on the disorder of the reproduction of phospholipids in these organs were revealed. The substrate specificity of cimetidine in inhibition of microsomal NADPN-cytochrome-C-reductase both in the liver and in the lungs, the probability of blocking the synthesis of phospholipids at the level of phosphatide acid and citidinephosphatecholine were noted. The results obtained should be taken into consideration during drug therapy.


Interrelationships among lipoprotein levels, sex hormones, anthropometric parameters, and age in hypogonadal men treated for 1 year with a permeation-enhanced testosterone transdermal system.
Serum lipoproteins and cardiovascular risk are affected by endogenous and exogenous sex hormones. As part of a multicenter evaluation of a permeation-enhanced testosterone transdermal system (TTD), the interrelationships among serum lipoproteins, hormone levels, anthropometric parameters, and age were investigated in 29 hypogonadal men. Subjects (aged 21-65 yr) were first studied during prior treatment with im testosterone esters (IM-T), then during an 8-week period of androgen withdrawal resulting in a hypogonadal state (HG), and finally during a 1-yr treatment period with the TTD. Compared with treatment with IM-T, the HG period produced increases in high density lipoprotein [HDL; 12.0 +/- 1.6% (+/-SEM); P<0.001] and total cholesterol (4.2 +/- 1.9%; P: = 0.02) and a decrease in the cholesterol/HDL ratio (-9.7 +/- 2.8%; P = 0.02). Compared with the HG period, TTD treatment produced decreases in HDL (-7.6 +/- 2.5%; P = 0.002) and increases in the cholesterol/HDL ratio (9.0 +/- 2.5%; P = 0.01) and triglycerides (20.7 +/- 6.4%; P: = 0.03). Small decreases in total cholesterol (-1.2 +/- 1.8%; P: = 0.1) and low density lipoprotein (-0.8 +/- 2.6%; P = 0.07) were also observed during TTD, but did not reach statistical significance. Likewise, there were no significant differences between the IM-T and TTD treatments. Serum HDL levels showed a strong negative correlation with body mass index and other obesity parameters in all three study periods (r < -0.45; P < 0.02). During treatment with TTD, serum testosterone levels also correlated negatively with body mass index (r = -0.621; P < 0.001). As a consequence of these relationships, a positive trend was observed between HDL and testosterone levels during TTD treatment (r = 0.336; P = 0.07). Interestingly, the changes in lipoprotein levels during TTD treatment indicated a more favorable profile (decrease in cholesterol and low density lipoprotein levels) with increasing age of the patients. In hypogonadal men the effects of transdermal testosterone replacement on serum lipoproteins appear consistent with the physiological effects of testosterone in eugonadal men.


Expression profile analysis of the transient receptor potential (TRPM) channel, a possible target of praziquantel in Schistosoma japonicum.
The WHO considers schistosomiasis, which is controlled by the mass administration of the drug praziquantel (PZQ), to be a neglected tropical disease. Despite its clinical use for over four decades, PZQ remains the only choice of chemotherapy against this disease. Regarding the previous studies that demonstrated that PZQ activates the transient receptor potential (TRP) channel in Schistosoma mansoni (Sm.TRPMPZQ), the expression profile of the ortholog of this channel gene (Smp_246790.5) in S. japonicum (EWB00_008853) (Sj.TRPMPZQ) was analyzed. The relative expression of this gene in various stages of the parasite lifecycle was analyzed by quantitative real-time reverse transcription-PCR (qRT-PCR), and the expression of Sj.TRPMPZQ was observed by immunohistochemical staining using anti-serum against the recombinant Sj.TRPMPZQ protein. qRT-PCR revealed the significantly lower mRNA expression in the snail stage in comparison to other stages (p < 0.01). The relative quantity of the Sj.TRPMPZQ expression for paired females, unpaired males, and eggs was 60%, 56%, and 68%, respectively, in comparison to paired males that showed the highest expression (p < 0.05). Interestingly, immunostaining demonstrated that Sj.TRPMPZQ is expressed in the parenchyma which contains muscle cells, neuronal cells and tegument cells in adult worms. This may support the two major effects of PZQ-worm paralysis and tegument disruption-induced by channel activation. Moreover, the channel was expressed in both the eggshell and the miracidia inside, but could not be observed in sporocyst. These results suggest that the expression of Sj.TRPMPQZ corresponds to the known sensitivity of S. japonicum to PZQ.


Triplane fractures in the hand.
Two new cases of triplane fracture of the distal tibia are reported in the proximal phalanx of the thumb and the distal radius, respectively, of a 12-year-old girl and a 13-year-old boy. Neither fracture showed any displacement, achieving healing at 4 weeks of external immobilization. Triplane fractures can occur across growth plates other than the distal tibia. Because of the rapid physiologic physeal arrest, the potential for growth deformity is null. In cases without displacement, these fractures should be treated conservatively by external immobilization, as one would treat a one-plane fracture.


[Multimodality evoked potentials and brain death. Prerequisites, findings and problems].
According to the recommendations of the medical board of the FRG the clinical diagnosis of cerebral death in adults requires an observation period of 12 hours. Evoked cerebral potentials have been accepted as a technical method of confirmation of clinical signs. In 32 patients with the signs of apneic brain-stem areflexia acoustic evoked brain-stem potentials and median-evoked somatosensory potentials were recorded. In supratentorial lesions evoked potentials are adequate to confirm complete cessation of brain function. In three cases of primary brain-stem disease evoked potentials were abolished, however, unequivocal EEG activity was preserved. The registration of evoked potentials is sufficient to confirm the brain death syndrome in primary supratentorial lesions, in infratentorial disease, however, demonstration of isoelectric EEG is necessary.


Cystatin C is associated with inflammation but not atherosclerosis in systemic lupus erythematosus.
Even mild renal impairment is associated with increased atherosclerosis and cardiovascular mortality. Cystatin C, a novel measure of renal function, is more sensitive than conventional creatinine-based measures for the detection of subtle renal impairment. Increased cystatin concentrations are also associated with cardiovascular risk, independently of conventional measures of renal function. This study examined the hypothesis that cystatin C is elevated in systemic lupus erythematosus (SLE) and is associated with coronary atherosclerosis. Serum cystatin C, creatinine, tumor necrosis factor (TNF)-α, interleukin (IL)-6, coronary artery calcium score (CACS), Framingham risk score (FRS), Modified Diet in Renal Disease estimated glomerular filtration rate (MDRD-eGFR), and other clinical parameters were measured in 118 patients with SLE and 83 control subjects. The independent association between concentrations of cystatin C and SLE was evaluated using multivariable linear regression models, and the relationship between renal measures and coronary calcium was assessed with multivariable proportional odds logistic regression models. Cystatin C, but not other measures of renal function, was significantly higher in patients with SLE than in controls (1.09 [interquartile range, IQR: 0.85-1.28] mg/l vs. 0.89 [IQR: 0.76-0.99] mg/l; p < 0.001 after adjustment for age, race, sex and MDRD-eGFR). Cystatin C was significantly associated with SLICC (p = 0.04), erythrocyte sedimentation rate (ESR) (p = 0.02), TNF-α (p = 0.008) and IL-6 (p = 0.01) after adjustment for age, race, and sex. Cystatin C was not significantly correlated with coronary calcium score in SLE (rho=0.096, p = 0.31) and the association remained non-significant after adjustment for age, race, sex, and Framingham risk score (p = 0.99). Cystatin C was higher in patients with SLE than in control subjects even after adjustment for conventional measures of renal function. Cystatin C was significantly correlated with several markers of inflammation in SLE but was not associated with coronary atherosclerosis. Subtle renal dysfunction does not appear to be directly associated with accelerated atherosclerosis in SLE.


[Clinical and experimental study of danfukang granule in treating cholecystitis and cholelithiasis].
In order to evaluate the clinical effect of Danfukang Granule (DFKG) in treating cholecystitis and cholelithiasis, 200 patients were treated with DFKG and observed with ultrasonography before and after treatment. Results showed 48 cases (24%) among the 200 patients were cured, 76 (38%) were marked effective, 70(35%) were improved and 6 (3%) ineffective, the effective rate being 97%. The lithagogue rate of cholelithiasis patients with diameter of gallstone < 0.5 cm, or those with sandy stone was 62%. In 50 post-operative patients received DFKG treatment, 28 (56%) were cured, 18 (36%) marked effective, 2 (4%) improved and 2 (4%) were ineffective, the total effective rate being 96%, while in the other 50 cases did not receive DFKG, the numbers were 8 (16%), 12(24%), 15 (30%), 15 (30%) and 70% respectively. The difference of total effective rate between the two groups were significant (analyzed by chi 2 test, P < 0.05). Experimental study-showed that the flow of hepatic bile in experimental group of guinea-pig was 3.7 +/- 0.4 ml/h, which was significantly higher than that of control group (2.7 +/- 0.1 ml/h), P < 0.05. The bile stone formation rate in experimental group was 32.4%, which was markedly lower than that of control group (93.8%), P < 0.01, suggesting the bile stone formed in experimental guinea-pigs could be evacuated by the rinsing effect of DFKG.


Beaching process of floating marine debris associated with the evolution of the nearshore wave.
Floating marine debris (FMD) is a pervasive problem in marginal seas worldwide. Driven by the nearshore waves, the FMD gradually accumulates shoreward and has a large chance of being beached, posing a direct threat to the coastal environment. Thus, investigating the nearshore drifting and beaching process of the FMD is of paramount importance. In this article, the trajectories of the FMD on a sloping beach are simulated by the Smoothed Particle Hydrodynamics (SPH) method, which is pre-verified through laboratory experiments. A series of sensitivity tests are conducted numerically on the influence of attributes of FMD as well as varied wave height (H0), and wave period (T0) on its beaching process. It is found that the beaching process of the FMD can be divided into three steps: drifting in front of surf zones, surfing and leaping with plunging waves, and advancing via wave runup. The density of the FMD combined with wave steepness determines whether the FMD can enter into the surf zone where it has a large chance to beach. Finally, this article proposed a semi-analytical model with improved Morison's equations considering the second-order Lagrangian transport on a sloping beach. This semi-analytical model is much faster and is comparable in computational accuracy to the high-resolution SPH model. It has the potential to be incorporated into the existing marine models and replace the stochastic process assumed for the FMD's tracking in the nearshore, in order to achieve more accurate assessment on the stranded FMD.


Metastasis-Initiating Cells in Renal Cancer.
Metastasis is a complex process that propagates cells from the primary or initial site of the cancer occurrence to distant parts of the body. Cancer cells break from the cancer site and circulate through the bloodstream or lymph vessels, allowing them to reach nearly all parts of the body. These circulating tumour cells (CTCs) contain specialized metastasis-initiating cells (MICs) that reside in the biological heterogeneous primary tumour. Researchers have hypothesized that metastasis of renal cell carcinoma is initiated by circulation of MICs in patients' blood and bone marrow. Based on the cancer stem/progenitor cell concept of carcinogenesis, understanding the molecular phenotypes of metastasis-initiating cells (MICs) in renal cancer could play a vital role in developing strategies for therapeutic interventions in renal cancer. Existence of MICs among CTCs in renal carcinoma has not been proven in large scale. However, some studies have reported that specialized markers are found on the surface of circulating cells from the primary tumour. In mice, MICs have been isolated from CTCs using such markers, which have then been transplanted into xenograft model to show whether they give rise to metastasis in different organs. Considering these findings, in this review we have attempted to summarize the studies connected with MICs and their gene expression profiles that are responsible for metastasis in renal cancer.


Policies affecting the supply and access of opioid analgesics: a scoping review protocol.
This scoping review aims to describe and map the range of evaluated policies that affect the supply and access of opioids for analgesic therapy. There has been increasing concern regarding the rise in opioid analgesic misuse and related harms, including overdose deaths. In response, policies have been developed and implemented to reduce the burden of opioid-related problems, including strategies that aim to affect the supply and/or access of opioid analgesics. However, little is known about the range and nature of these policies, including whether they have been evaluated for effectiveness and how. Studies to be included must evaluate the effectiveness of policies directly designed to affect the supply and/or access of opioids for analgesic therapy, and measure clinical and health services outcomes quantitatively. Studies that assessed interventions or factors impacting the use of these policies, measured only utilization of the policy itself, and/or measured outcomes regarding attitudes and behaviors towards these policies will be excluded. Literature on policies for the treatment and management of opioid abuse, overdose, or addiction will be excluded. Multiple databases will be searched including MEDLINE, Embase, PsycINFO, Scopus, and Web of Science using keywords, indexed terms, and phrases for the following concepts: opioid, policy, evaluation, and clinical context. Each included study will be rated using a modified version of the JBI Levels of Evidence framework. Details on included policies and their assessment will be extracted, and results presented in diagrams and tables.


2015 Update on Acute Adverse Reactions to Gadolinium based Contrast Agents in Cardiovascular MR. Large Multi-National and Multi-Ethnical Population Experience With 37788 Patients From the EuroCMR Registry.
Specifically we aim to demonstrate that the results of our earlier safety data hold true in this much larger multi-national and multi-ethnical population. We sought to re-evaluate the frequency, manifestations, and severity of acute adverse reactions associated with administration of several gadolinium- based contrast agents during routine CMR on a European level. Multi-centre, multi-national, and multi-ethnical registry with consecutive enrolment of patients in 57 European centres. During the current observation 37,788 doses of Gadolinium based contrast agent were administered to 37,788 patients. The mean dose was 24.7 ml (range 5-80 ml), which is equivalent to 0.123 mmol/kg (range 0.01 - 0.3 mmol/kg). Forty-five acute adverse reactions due to contrast administration occurred (0.12%). Most reactions were classified as mild (43 of 45) according to the American College of Radiology definition. The most frequent complaints following contrast administration were rashes and hives (15 of 45), followed by nausea (10 of 45) and flushes (10 of 45). The event rate ranged from 0.05% (linear non-ionic agent gadodiamide) to 0.42% (linear ionic agent gadobenate dimeglumine). Interestingly, we also found different event rates between the three main indications for CMR ranging from 0.05% (risk stratification in suspected CAD) to 0.22% (viability in known CAD). The current data indicate that the results of the earlier safety data hold true in this much larger multi-national and multi-ethnical population. Thus, the "off-label" use of Gadolinium based contrast in cardiovascular MR should be regarded as safe concerning the frequency, manifestation and severity of acute events.


Mood changes related to antidepressants: a longitudinal study of patients with bipolar disorder in a naturalistic setting.
This prospective, longitudinal study investigated the frequency and pattern of mood changes between outpatients receiving usual care for bipolar disorder who were either taking or not taking antidepressants. Eighty patients with bipolar disorder self-reported mood and psychiatric medications daily for 3 months using a computerized system (ChronoRecord) and returned 8662 days of data. Of the total group of 80 patients, 47 took antidepressants; 33 did not. Patients taking antidepressants reported depression twice as frequently (29% of days vs. 13.8% of days). In both groups, two-thirds of all mood changes over a 1-, 2- and 3-day period were small, between -5 and 5 on a 100-point scale. No statistically significant difference was found in the frequency of large mood changes (>10 on a 100-point scale) or in switches between depression and mania (0.7% if not taking antidepressants vs. 0.9% if taking), independent of diagnosis of bipolar I or II. Eighty-nine percent of patients taking antidepressants were also taking mood stabilizers. In this naturalistic setting, no significant difference between the rate of switches to mania or rapid cycling was found between those taking and not taking antidepressants, regardless of diagnosis. The primary difference in pattern between the groups was the time spent in depressed or normal mood, with minor daily mood variations.


Examining the Priorities, Needs and Preferences of Men with Metastatic Prostate Cancer in Designing a Personalised eHealth Exercise Intervention.
Few individuals with metastatic prostate cancer have access to prostate cancer-specific exercise support, despite demonstrated benefits. eHealth tools, such as websites, may be viable options for increasing access. To be effective and acceptable, future eHealth websites need to consider end-users' perspectives, capacity and needs. We aim to provide insight into these factors by exploring daily priorities, activities and health literacy of individuals with metastatic prostate cancer and their perspectives towards exercise and exercise-based web-based eHealth interventions. Semi-structured interviews explored participant's experiences and understanding of their disease, exercise levels, advice received from health care providers, as well as acceptability of and suggested content for an eHealth tool. A thematic analysis was undertaken. Interviews were conducted with eighteen Australians (55-83 years; M = 71.5, SD = 8.9) living with metastatic prostate cancer. Needing to perform daily responsibilities was a key priority. Participants had limited understanding of the benefits of prostate cancer-specific exercise, and less than half discussed exercise with their health team. Fourteen men felt they could report metastases location, but only four could provide detailed information, which has clinical implications for exercise prescription. A potential web-based intervention was considered acceptable by seventeen men for reasons such as affordability, accessibility and convenience. User-friendly design and practitioner support were important. Results identified key aspects useful for person-centred design of exercise programs. Participants were positive towards the proposed web-based tool and expressed the need for individualised, user-friendly and reliable information with support from a professional embedded. Lastly, not all participants could accurately report metastasis locations.


Correlation between Dynamics of Polaronic Photocarriers and Photoelectrochemical Performance in Mo-Doped Bismuth Vanadate.
Bismuth vanadate (BiVO4) has received intense research interest due to its outstanding performance for solar water splitting, and doping it with molybdenum (Mo) ions can effectively boost photoelectrochemical performance. In this material, highly localized polarons play a key role in the photoconversion process. Herein, we uncovered the influence of Mo dopants on the dynamics of polaronic transient species using transient absorption spectroscopy. We find that the preexisting electron small polarons stemming from the thermal ionization of dopants provide additional centers to capture itinerant holes, which significantly decrease the hole lifetime. However, the introduction of dopants increases the lifetime of self-trapped excitons that arise from the binding of electron polarons and holes. The dependence of the photoelectrochemical performance of BiVO4 photoelectrodes on doping levels can be well explained by combining the dopant effects on the lifetimes of delocalized and self-trapped transient species. Our findings provide guidance for rational optimization of dopant concentration to maximize the PEC efficiency.


The role of the vitreous in the intraocular pressure rise after neodymium-YAG laser capsulotomy.
Autologous liquid vitreous injected into the anterior chamber of the phakic owl monkey eye leads to markedly increased intraocular pressure (IOP) peaking at one to two hours. In contrast, neodymium-YAG laser shock waves focused in the center of the anterior chamber of the same animal led to a mild decrease in IOP. Debris produced by laser pulses focused on the residual cortex of owl monkey eyes that had undergone extracapsular surgery failed to increase the IOP. Similarly, injection of dialyzed vitreous did not have any significant influence on IOP. We conclude that the disruption of the integrity of the anterior cortical gel and the subsequent release of a dialyzable intravitreal substance with a molecular weight of less than 10,000 daltons into the anterior chamber may contribute to the IOP rise after surgical discission, including neodymium-YAG laser posterior capsulotomy.


Cytological detection of telomerase activity using an in situ telomeric repeat amplification protocol assay.
A previously reported highly sensitive assay for measuring telomerase activity on cell and tissue extracts indicates that most human tumor tissues, but not cells adjacent to tumors, have detectable telomerase activity. Although this assay has provided a significant amount of information about the presence or absence of telomerase activity, it does not indicate whether all cells within a tumor have telomerase activity or whether only a subset does. The present report demonstrates the ability to advance this technology to an in situ assay. Using fluorescent telomerase primers and in situ PCR, we show that telomerase activity can be detected at the cellular level. This study demonstrates that telomerase activity is not detected in normal cells but is detected in tumor cells of clinical specimens and in tumor-derived cell lines.


[Smoking-related interstitial lung diseases].
The most important smoking-related interstitial lung diseases (ILD) are respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, and Langerhans' cell histiocytosis. Although traditionally considered to be discrete entities, smoking-related ILDs often coexist, thus accounting for the sometimes complex patterns encountered on high-resolution computed tomography (HRCT). Further studies are needed to elucidate the causative role of smoking in the development of pulmonary fibrosis.


The Effect of a Park-Based Physical Activity Program on Cardiovascular, Strength, and Mobility Outcomes Among a Sample of Racially/Ethnically Diverse Adults Aged 55 or Older.
Many older adults are not physically active despite the well-documented health benefits of regular exercise. We examined cardiovascular, strength, and mobility outcomes among a sample of racially/ethnically diverse adults aged 55 or older participating in a community park-based physical activity program. We assessed the following among adults aged 55 or older who attended a 1-hour park-based fitness class 2 or 3 times per week for 21 weeks: 1) 3 fitness outcomes, 2) systolic and diastolic blood pressure, 3) height and weight (to assess body mass index), and 4) pulse. We collected data at baseline (August-September 2016) and follow-up (January-February 2017). Linear regression analysis, adjusting for sex, age, and race/ethnicity, examined the association between program participation and changes in outcomes. Adjusted models showed a mean decrease in systolic blood pressure (-3.80 mm Hg; 95% CI, -6.75 to -0.84 mm Hg) and diastolic blood pressure (-1.54 mm Hg; 95% CI, -3.01 to -0.06 mm Hg) and a mean increase in number of arm curls completed in 30 seconds (1.66; 95% CI, 0.71-2.61) from baseline to follow-up among all participants. Hispanic participants, compared with non-Hispanic white and non-Hispanic black participants, showed greater improvements in mean body mass index (-2.48; 95% CI, -4.60 to -0.34), systolic blood pressure (8.59 mm Hg; 95% CI, -16.82 to -0.36 mm Hg), diastolic blood pressure (-7.06 mm Hg; 95% CI, -11.16 to -2.97 mm Hg), and pulse (-6.53 beats per minute; 95% CI, -11.38 to -1.67 beats per minute). Park-based fitness classes tailored to older, racially/ethnically diverse adults can improve cardiovascular health and strength.


Comparative analysis of potency of splenic dendritic and adherent cells (macrophages) as alloantigen presenters in vivo.
Dendritic cells and macrophages have been attributed with stimulatory capacity for in vivo and in vitro immune responses. However, the relative contribution of each of these cell types has long been in dispute. Therefore, the differential ability of dendritic cells and macrophages (splenic adherent cells [SACs]) to stimulate pancreatic islet allograft rejection in reversed alloxan-induced diabetic rats was examined. Rats bearing established allografts were challenged with various dosages of donor-strain dendritic cells or SACs, and graft rejection was assessed by analysis of plasma glucose levels and/or histological criteria. Marked differences in the ability to stimulate allograft rejection were observed at the 10(5)-cell dosage; 10(5) dendritic cells induced graft rejection in five of six rats (1 rat required 2 injections), whereas 10(5) SACs failed to induce rejection in four of four rats (P less than 0.10, chi 2 test). Challenge stimuli consisting of less than or equal to 10(5) SACs or less than or equal to 10(4) dendritic cells failed to induce graft rejection. These findings indicate that dendritic cells are potent stimulator cells for in vivo immune responses. Previous studies indicated that as few as 10(3) dendritic cells initiate allograft rejection in nondiabetic recipients. That more dendritic cells were required to stimulate rejection in reversed diabetic recipients compared with nondiabetic recipients suggests that other factors, such as the diabetic state and the production of a tolerant status achieved by larger amounts of grafted tissue, may influence graft survival.


Complement opsonization is required for presentation of immune complexes by resting peripheral blood B cells.
Complement receptor 2 (CD21, CR2) is a B cell receptor for complement degradation products bound to Ag or immune complexes. The role of CD21 in mediating Ag presentation of soluble immune complexes by resting B cells was studied. Complement-coated immune complexes were formed by the incubation of influenza virus with serum from immune donors. These complexes bound to peripheral blood B cells in a complement-dependent manner. The binding required CD21 or, to a lesser extent, complement receptor 1 (CR1, CD35). B cells pulsed with immune complexes containing complement elicited a response from a panel of influenza-specific T cell clones, while those pulsed with immune complexes formed in the absence of complement did not. The expression of the early activation marker CD69 and the costimulatory molecule CD86 were not induced by CD21 ligation alone, suggesting that CD21-mediated Ag presentation occurs independently of B cell activation. Up-regulation of these markers required exposure to T cell factors elicited by the recognition of Ag derived from complement-containing immune complexes. These findings suggest that binding of Ag to CD21 enables Ag-nonspecific B cells to participate in the activation of Ag-specific T cells in a process that occurs independently of well-characterized B cell activation events.


In vitro repair synthesis of BCNU-induced DNA damage.
The nitrosoureas including BCNU are potent chemotherapeutic drugs and have been used extensively for treatment of brain tumors and other neoplasias but the mechanisms of action for the DNA lesions created and their repair are still unclear. We have recently determined the in vitro repair of BCNU-treated DNA with cellular extracts and with DNA modifying enzymes. BCNU not only caused an increase in breaks in plasmid DNA, but an increase in cross-linked DNA was also observed after restriction enzyme digestion followed by gel electrophoresis. When HeLa cell-extracts were incubated with BCNU-treated DNA, 5-10 fold increases in DNA repair synthesis were observed as compared with untreated control. Substantial increases in 5'OH and 3'OH sites of the breaks were also found in BCNU-treated DNA as determined by the 10-20 fold increases in labeling with T4-DNA kinase and by endogenous polymerases, while the amount of ligatable sites were at a minimal. When the repair capacity of two glioma cell lines (UWR1 and UWR3) with differential BCNU sensitivity, and cells from a chromosomal breakage disease, Bloom's syndrome (BS), were assessed, the activities of the two glioma cells were about 20-30% of the normal lymphoblastoid cells and HeLa cells, whereas no difference was observed in BS cells. However, differential patterns of DNA bands were observed in the glioma samples suggesting cell-type specific capacities of repair synthesis. These data are in accordance with the concept that BCNU creates multiple DNA lesions and suggests different cell types may develop a variety of repair capabilities.


Structural, spectroscopic, and multiconfigurational quantum chemical investigations of the electron-rich metal-metal triple-bonded Tc(2)X(4)(PMe(3))(4) (X = Cl, Br) complexes.
The compounds Tc(2)Cl(4)(PMe(3))(4) and Tc(2)Br(4)(PMe(3))(4) were formed from the reaction between (n-Bu(4)N)(2)Tc(2)X(8) (X = Cl, Br) and trimethylphosphine. The Tc(II) dinuclear species were characterized by single-crystal XRD, UV-visible spectroscopy, and cyclic voltammetry techniques, and the results are compared to those obtained from density functional theory and multiconfigurational (CASSCF/CASPT2) quantum chemical studies. The compound Tc(2)Cl(4)(PMe(3))(4) crystallizes in the monoclinic space group C2/c [a = 17.9995(9) A, b = 9.1821(5) A, c = 17.0090(9) A, beta = 115.4530(10) degrees ] and is isostructural to M(2)Cl(4)(PMe(3))(4) (M = Re, Mo, W) and to Tc(2)Br(4)(PMe(3))(4). The metal-metal distance (2.1318(2) A) is similar to the one found in Tc(2)Br(4)(PMe(3))(4) (2.1316(5) A). The calculated molecular structures of the ground states are in excellent agreement with the structures determined experimentally. Calculations of effective bond orders for Tc(2)X(8)(2-) and Tc(2)X(4)(PMe(3))(4) (X = Cl, Br) indicate stronger pi bonds in the Tc(2)(4+) core than in Tc(2)(6+) core. The electronic spectra were recorded in benzene and show a series of low intensity bands in the range 10 000-26 000 cm(-1). Assignment of the bands as well as computing their excitation energies and intensities were performed at both TD-DFT and CASSCF/CASPT2 levels of theory. Calculations predict that the lowest energy band corresponds to the delta* --> sigma* transition, the difference between calculated and experimental values being 228 cm(-1) for X = Cl and 866 cm(-1) for X = Br. The next bands are attributed to delta* --> pi*, delta --> sigma*, and delta --> pi* transitions. The cyclic voltammograms exhibit two reversible waves and indicate that Tc(2)Br(4)(PMe(3))(4) exhibits more positive oxidation potentials than Tc(2)Cl(4)(PMe(3))(4.) This phenomenon is discussed and ascribed to stronger metal (d) to halide (d) back bonding in the bromo complex. Further analysis indicates that Tc(II) dinuclear species containing pi-acidic phosphines are more difficult to oxidize, and a correlation between oxidation potential and phosphine acidity was established.


Measuring the impact of health research.
Measuring the decision-making impact of applied health research should constitute a core function for many research funders and research organizations. Different target audiences warrant different measures of impact. The target audiences for applied health research include the general public, patients (and their families), clinicians, managers (in hospitals, regional health authorities and health plans), research and development officers (in biotechnology firms) and public policy-makers (i.e. elected officials, political staff and civil servants). Making meaningful assessments within peer groups that fund or produce similar types of research knowledge for similar types of target audiences makes more sense than a one-size-fits-all approach to impact assessment. User-pull and interactive measures of impact (i.e. measures of cultural shifts that would facilitate the on-going use of research knowledge to inform decision-making) can supplement more traditional producer-push measures that assess researchers' active efforts to inform decision-making and the outcome of these efforts. Cultural shifts may include the creation of a research-attuned culture among decision-makers and a decision-relevant culture among researchers. Moving beyond whether research was used to examine how it was used is also important. Research knowledge may be used in instrumental, conceptual or symbolic ways. These actions, coupled with on-going refinements to the proposed assessment tool as research evidence evolves, would take us a long way towards assessment and accountability in the health sector.


Qualitative Assessment of a Smartphone-Based Mobile Health Tool to Guide Diarrhea Management in Bangladesh.
Diarrheal diseases are a major cause of morbidity and mortality in children worldwide and a significant contributor to antimicrobial resistance. In the absence of laboratory diagnostics to establish diarrhea etiology, electronic clinical decision support tools can help physicians make informed treatment decisions for children with diarrhea. In Bangladesh, we assessed the feasibility and acceptability of an electronic Diarrhea Etiology Prediction algorithm (DEP tool) embedded into a rehydration calculator, which was designed to help physicians manage children with diarrhea, including decisions on antibiotic use. A team of Bangladeshi anthropologists conducted in-depth interviews with physicians (N = 13) in three public hospitals in Bangladesh about their experience using the tool in the context of a pilot trial. Physicians expressed positive opinions of the DEP tool. Participants perceived the tool to be simple and easy to use, with structured guidance on collecting and entering clinical data from patients. Significant strengths of the tool were as follows: standardization of protocol, efficiency of clinical decision-making, and improved clinical practice. Participants also noted barriers that might restrict the widespread impact of the tool, including physicians' reluctance to use an electronic tool for clinical decision-making, increasing work in overburdened healthcare settings, unavailability of a smartphone, and patients' preferences for antibiotics. We conclude that an electronic clinical decision support tool is a promising method for improving diarrheal management and antibiotic stewardship. Future directions include developing and implementing such a tool for informal healthcare physicians in low-resource settings, where families may first seek care for pediatric diarrhea.


Experimental brain infarcts in cats. II. Ischemic brain edema.
In cats, the early development of ischemic brain edema was studied 1 to 4 hours after transorbital occlusion of the left middle cerebral artery (MCA). Two groups of animals were compared: those in which blood flow in the territory of the MCA decreased below the threshold of 10--15 ml/100 g/min (critical ischemia) and those in which it remained above this level (non-critical ischemia). In animals with critical ischemia, water content in the cortex of the MCA territory increased from 80.7 +/- 0.4 to 83.0 +/- 0.3 vol. % (means +/- SE) within 4 h. Edema was associated with an increase in tissue osmolality by 16--22 mosm/kg w.w., and a rise of sodium from 262 +/- 9 to 454 +/- 13 meq/kg d.w. and a decrease of potassium from 442 +/- 20 to 305 +/- 32 meq/kg d.w. The sodium/potassium ratio rose from 0.60 +/- 0.03 to 1.55 +/- 0.17. The water and electrolyte disturbances were accompanied by a major shift of extracellular fluid into the intracellular compartment, as evidenced by the increase in cortical impedance from 282 to 660 ohm/cm within 2 h. According to the Maxwell equation, this reflects a narrowing of the extracellular space from 19.8 to 11.4%. Brain volume was continuously monitored using an induction transducer; swelling began within a few minutes of vascular occlusion, and it continued throughout the 4 h observation period. During this time the blood-brain barrier remained intact as evidenced by the absence of Evans blue staining. Edema was associated with disturbances of the energy producing metabolism, but there was no strict correlation with either lactate or the concentration of high energy phosphates. In animals without critical ischemia, i.e. in which blood flow remained above 10--15 ml/100 g/min, edema was absent despite a distinct deterioration of the energy state of the brain. Edema was also absent in the border zone, in the territory of the posterior cerebral artery and in the contralateral hemisphere of animals with both critical and non-critical ischemia. It is concluded that the early ischemic brain edema following middle cerebral artery occlusion is of the cytotoxic type, that it develops at a flow rate below 10--15 ml/100 g/min, and that it is not strictly correlated with the energy state of the brain.


Urinary exosome miR-146a is a potential marker of albuminuria in essential hypertension.
There is increasing interest in using extracellular vesicle-derived microRNAs (miRNAs) as biomarkers in renal dysfunction and injury. Preliminary evidence indicates that miRNAs regulate the progression of glomerular disease. Indeed, exosomes from the renal system have provided novel evidence in the clinical setting of albuminuria. Thus, the aim of this study was to quantify the urinary miRNAs present in exosome and microvesicles (MVs), and to assess their association with the presence of increased urinary albumin excretion in essential hypertension. Exosomes were collected from urine specimens from a cohort of hypertensive patients with (n = 24) or without albuminuria (n = 28), and from 20 healthy volunteers as a control group. Urinary exosomes were phenotyped by Western blot, tunable resistive pulse sensing, and electronic microscopy. Expression of miR-146a and miR-335* was analysed by qRT-PCR and any associations between albuminuria and exosomal miRNAs were analysed. Urinary miRNAs are highly enriched in exosome subpopulations compared to MVs, both in patients with or without increased albuminuria (p < 0.001), but not in the control group. High albuminuria was associated with 2.5-fold less miR-146a in exosomes (p = 0.017), whereas miR-146a levels in MV did not change. In addition, exosome miR-146a levels were inversely associated with albuminuria (r = 0.65, p < 0.0001), and discriminated the presence of urinary albumin excretion presence [area under the curve = 0.80, 95% confidence interval: 0.66-0.95; p = 0.0013]. Our results indicate that miRNAs were enriched in the urinary exosome subpopulation in hypertensive patients and that low miR-146a expression in exosomes was associated with the presence of albuminuria. Thus, urinary exosome miR-146a may be a potentially useful tool for studying early renal injury in hypertension.


Usefulness of the Direct and/or Total Bilirubin to Predict Adverse Outcomes in Patients With Acute Decompensated Heart Failure.
Abnormal liver function test results are often observed in acute decompensated heart failure (ADHF). However, the prognostic value of bilirubin fractionation has not been elucidated. The prognostic value of direct bilirubin (DB), in comparison with total bilirubin (TB), was examined in 556 consecutive patients with ADHF. Patients with elevated DB showed mostly similar patient characteristics including signs of elevated right-sided pressure (frequent hepatomegaly, jugular venous distention, dilated inferior vena cava, and elevated gamma-glutamyltransferase) and decreased cardiac output (cold extremities, decreased pulse pressure, and lower blood pressure) and other parameters of heart failure (HF) severity (increased plasma renin activity, decreased sodium, total cholesterol, and ejection fraction) to elevated TB; however, only patients with elevated DB showed a significant difference in the frequency of HF history and alkaline phosphatase value. Kaplan-Meier analysis showed that patients with elevated DB had a significantly higher rate of the composite end point of all-cause mortality or HF readmission (p = 0.021) compared with those with normal DB, whereas patients with elevated TB did not show a statistically significant difference compared with those with normal TB (NS). A multivariate Cox hazards model showed that DB was an independent predictor of adverse events (adjusted hazard ratio 1.052, 95% confidence interval 1.001 to 1.099, p = 0.034), whereas TB was not (adjusted hazard ratio 1.017, 95% confidence interval 0.985 to 1.046, p = 0.27). Adding DB to existing prognostic variables resulted in higher C-statistics than adding TB (C-statistics: 0.670 to 0.675, 0.670 to 0.674, respectively). In conclusion, elevated DB in ADHF was an independent prognostic predictor that was superior to TB. DB may be useful for further risk stratification in ADHF.


A Flexible Framework for Nonparametric Graphical Modeling that Accommodates Machine Learning.
Graphical modeling has been broadly useful for exploring the dependence structure among features in a dataset. However, the strength of graphical modeling hinges on our ability to encode and estimate conditional dependencies. In particular, commonly used measures such as partial correlation are only meaningful under strongly parametric (in this case, multivariate Gaussian) assumptions. These assumptions are unverifiable, and there is often little reason to believe they hold in practice. In this paper, we instead consider 3 nonparametric measures of conditional dependence. These measures are meaningful without structural assumptions on the multivariate distribution of the data. In addition, we show that for 2 of these measures there are simple, strong plug-in estimators that require only the estimation of a conditional mean. These plug-in estimators (1) are asymptotically linear and non-parametrically efficient, (2) allow incorporation of flexible machine learning techniques for conditional mean estimation, and (3) enable the construction of valid Wald-type confidence intervals. In addition, by leveraging the influence function of these estimators, one can obtain intervals with simultaneous coverage guarantees for all pairs of features.


Construction of a new binding manner in carboxylic acid-functionalized phosphomolybdates.
Carboxylic acid-functionalized polyoxomolybdates have been widely reported. In this study, we tried to establish a new connection pattern between an organic carboxylic acid ligand and inorganic phosphomolybdates by employing N-containing pyridine dicarboxylic acids and two other benzene dicarboxylic acids. Herein, four kinds of organic-inorganic hybrids have been synthesized. Studies reveal that these compounds are dimers, trimer or hexamer, displaying the templating effect of different carboxylic acids. In compound 2, besides the normal C-O-Mo bonds, a new binding manner of C-N-Mo bonds was presented as a linker to connect the organic and inorganic portions, and the polyanion demonstrated the conformation of a hexamer. Moreover, the photochromic properties of these compounds were studied, and the kinetics of the coloration process was analyzed and compared. It seems that based on the aromaticity of their organic ligands, the t1/2 values of the four compounds are much less than those of the compounds functionalized by aliphatic acids.


Areca nut: a review.
Areca cattechu Linn is commonly known as areca nut or betel nut. It is a very widely cultivated plant in eastern countries like India, Bangladesh, Ceylon, Malaya, the Philippines and Japan. The importance of this nut is due to its use for chewing purposes. It had an important place as a pharmaceutical in Ayurveda--the ancient Indian system of medicine--also in the Chinese medicinal practices. The pharmaceutical importance of areca nut is due to the presence of an alkaloid, arecoline. Synthetic arecoline hydrobromide is also shown to possess numerous pharmacological properties. Chewing of "betel quid" or areca nut is a typical oriental habit. Betel quid comprises betel leaf, areca nut, catechu, lime and sometimes also tobacco. It is shown that there exists a correlationship between betel quid or areca nut chewing habit and oral cancer. A number of investigators have been able to produce cellular changes such as leukoplakia by application of betel quid or areca nut extract to the buccal mucosa of different animal.


Pharmacokinetic Study of Biotransformation Products from an Anxiolytic Fraction of Tilia americana.
An anxiolytic fraction of Tilia americana standardized in tiliroside, rutin, quercitrin, quercetin glucoside, and kaempferol was obtained. After oral administration of the fraction, the above-mentioned flavonoids were not detected in plasma over 24 h. However, meta and para hydroxyphenylacetic acid and dihydroxyphenylacetic acid (m-HPAA, p-HPAA and DOPAC) were monitored. These are the biotransformation compounds of the aglycones of kaempferol and quercetin; these aglycones are products of the other flavonoids present in the anxiolytic fraction. The analytical methods (HPLC) for flavonoids and the related compounds (m-HPAA, p-HPAA and DOPAC) were validated, determining the parameters of accuracy, precision, specificity or selectivity, limit of detection, quantification range, and robustness. The pharmacokinetic assay was performed with ICR mice strains, which were given 200 mg/kg of the standardized active fraction. The results of validation of the analytical methods were obtained, allowing it to be established in a validated way that no flavonoids present in the anxiolytic fraction of T. americana were detected in plasma. However, detection and follow up was possible for the serum levels of m-HPAA, p-HPAA, and DOPAC. The three compounds follow a two-compartment model with very similar parameters between m-HPAA and p-HPAA, some being different from the ones characterized in the pharmacokinetics of DOPAC.


A United States survey on diagnosis, treatment, and outcome of primary hyperoxaluria.
Primary hyperoxaluria (PH) is a heterogeneous disease with a variable age of onset and a variable progression into kidney failure. Early diagnosis is mandatory to avoid the damaging effects of systemic calcium oxalate deposition. In 1997, we initiated a nationwide survey of American nephrologists to ascertain epidemiological data and current practices. PH was reported in only 102 patients, with PH I in 79 and PH II in 9; 14 patients were not classified. Most patients were Caucasian (84%). Main symptoms at diagnosis were urolithiasis (54.4%) and nephrocalcinosis (30%). A significant delay of diagnosis was seen in 42% of patients and 30% of patients were diagnosed only at end-stage renal disease (ESRD). Diagnosis was usually based on history and urinary oxalate excretion. Glycolate and l-glyceric acid excretion were rarely determined. To determine the enzyme defect, a liver biopsy was performed in 40%. Even at ESRD, only 56% of patients received an adequate diagnostic work-up. Half of the patients showed 'good' or 'fair' pyridoxine sensitivity. In addition to B(6), most patients received either citrate or orthophosphate. Kidney transplantation (KTx) failed in 19 of 32 transplants ( n=27 patients) and was due to recurrent oxalosis in 8 transplants. Liver Tx was performed after KTx in 5 patients (1 patient died). Combined liver-kidney Tx in 21 patients (in 9 patients after failure of KTx) achieved good organ function in 13 patients; 7 patients, however, died shortly after transplantation. In conclusion, the time between first symptom and diagnosis of PH must be minimized, and the diagnostic procedures have to be improved. The cases of unclassified hyperoxaluria suggest the possibility of additional type(s) of PH. As isolated KTx failed in 59% of patients, combined liver-kidney Tx seems to be the better choice in place of isolated KTx as the primary transplant procedure.


Adult forebrain NMDA receptors gate social motivation and social memory.
Motivation to engage in social interaction is critical to ensure normal social behaviors, whereas dysregulation in social motivation can contribute to psychiatric diseases such as schizophrenia, autism, social anxiety disorders and post-traumatic stress disorder (PTSD). While dopamine is well known to regulate motivation, its downstream targets are poorly understood. Given the fact that the dopamine 1 (D1) receptors are often physically coupled with the NMDA receptors, we hypothesize that the NMDA receptor activity in the adult forebrain principal neurons are crucial not only for learning and memory, but also for the proper gating of social motivation. Here, we tested this hypothesis by examining sociability and social memory in inducible forebrain-specific NR1 knockout mice. These mice are ideal for exploring the role of the NR1 subunit in social behavior because the NR1 subunit can be selectively knocked out after the critical developmental period, in which NR1 is required for normal development. We found that the inducible deletion of the NMDA receptors prior to behavioral assays impaired, not only object and social recognition memory tests, but also resulted in profound deficits in social motivation. Mice with ablated NR1 subunits in the forebrain demonstrated significant decreases in sociability compared to their wild type counterparts. These results suggest that in addition to its crucial role in learning and memory, the NMDA receptors in the adult forebrain principal neurons gate social motivation, independent of neuronal development.


Sexual selection and the risk of extinction in mammals.
Sexual selection is commonly envisaged as a force working in opposition to natural selection, because extravagant or exaggerated traits could apparently have never evolved via natural selection alone. There is good evidence that a selection load imposed by sexual selection may be eased experimentally by restricting the opportunity for it to operate. Sexual selection could therefore potentially play an important role in influencing the risk of extinction that a population faces, thereby contributing to the apparent selectivity of extinctions. Conversely, recent theory predicts that the likelihood of extinction may decrease when sexual selection is operating because it could accelerate the rate of adaptation in concert with natural selection. So far, comparative evidence (coming mostly from birds) has generally indicated support for the former scenario, but the question remains open. The aim of this study was therefore to examine whether the level of sexual selection (measured as residual testes mass and sexual size dimorphism) was related to the risk of extinction that mammals are currently experiencing. We found no evidence for a relationship between these factors, although our analyses may have been confounded by the possible dominating effect of contemporary anthropogenic factors.


Feasibility of a pilot study on point-of-care biomarkers in spontaneous intracerebral hemorrhage in an emergency setting.
Stroke is a worldwide leading cause of death and disability and spontaneous intracerebral hemorrhage (sICH) has significant economic and social impact, regardless of recent efforts towards outcome-bettering acute interventions. The aim of the study was to assess the feasibility of a prospective observational research regarding point-of-care (POC) biomarkers in sICH, conducted in a level one emergency department (ED). Patients with acute (<8 hours) sICH were enrolled in this study. Patients presenting a Glasgow Coma Scale score <8, secondary causes of intracerebral hemorrhage, seizures, recent ischemic events, known thromboembolic disease, anticoagulant treatment, severe pre-stroke disability, terminal disease, scheduled neurosurgery/hemostatic treatment were excluded. Feasibility was defined as ED inclusion and follow-up rates, time-to-inclusion, and frequency of missing data. Baseline demographic, imaging and POC biochemical status of the study group were documented, including inflammatory (complete blood count, C-reactive protein), metabolic (glucose, hepatic, and renal function) and cardiovascular markers (cardiac troponin I, D-dimer). The inclusion rate was 2.16 patients/month with a final sample of 35 patients out of 239 potentially eligible patients. The median time from symptom onset to ED presentation was 128 minutes (IQR 96-239), with 21/35 patients having presented within the first 3 hours from ictus. Median times between symptoms' onset to Computer Tomography (CT) scan and ED presentation to CT scan were 170 minutes (IQR 126-317) and 25 minutes (IQR 17-62), respectively. The median time from patient's presentation to CBC result was 12 minutes (IQR 6.5-20), with 21/35 study participants having the results available within 15 minutes from ED arrival. The median cohort age was 72-years, with a 19/16 male/female ratio. Hypertension was the most frequent risk factor (77%), along with ischemic heart disease (31%) and diabetes (29%). One-third of the hypertensive patients did not undergo blood pressure lowering treatment. Median values of POC biomarkers on ED admission were within normal range. It was feasible to determine point-of-care biomarkers in spontaneous intracerebral hemorrhage on admission in ED, despite the urgency of the medical condition.


Prefrontal alterations in Parkinson's disease with levodopa-induced dyskinesia during fMRI motor task.
Levodopa-induced dyskinesia represents disabling complication of long-term therapy with dopaminergic drugs in treating Parkinson's disease (PD). Recently, our group demonstrated that PD patients with levodopa-induced dyskinesia were characterized by abnormal volumetric changes in the inferior prefrontal gyrus. In this study, the functional relevance of this structural abnormality was explored using functional magnetic resonance imaging. Ten dyskinetic PD patients and 10 nondyskinetic PD patients were studied in the OFF phase with functional magnetic resonance imaging while performing externally and internally triggered visuomotor tasks. Although neither group demonstrated behavioral differences during execution of motor tasks, magnetic resonance imaging analysis detected significant changes in target cortical regions. In particular, PD patients with levodopa-induced dyskinesia showed significant overactivity in the supplementary motor area and underactivity in the right inferior prefrontal gyrus during execution of both tasks when compared with PD patients without levodopa-induced dyskinesia. Moreover, these prefrontal functional alterations were significantly correlated with Abnormal Involuntary Movement Scale scores. This functional magnetic resonance imaging study together with our previous volumetric findings highlights the role of the prefrontal cortex in the neuronal mechanisms of dyskinesia.


A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry.
Approximately 5% of lung adenocarcinomas harbor an EML4-ALK gene fusion and define a unique tumor group that may be responsive to targeted therapy. However ALK-rearranged lung adenocarcinomas are difficult to detect by either standard fluorescence in situ hybridization or immunohistochemistry (IHC) assays. In the present study, we used novel antibodies to compare ALK protein expression in genetically defined lung cancers and anaplastic large cell lymphomas. We analyzed 174 tumors with one standard and two novel monoclonal antibodies recognizing the ALK protein. Immunostained tissue sections were assessed for the level of tumor-specific ALK expression by objective quantitative image analysis and independently by three pathologists. ALK protein is invariably and exclusively expressed in ALK-rearranged lung adenocarcinomas but at much lower levels than in the prototypic ALK-rearranged tumor, anaplastic large cell lymphoma, and as a result, is often not detected by conventional IHC. We further validate a novel IHC that shows excellent sensitivity and specificity (100% and 99%, respectively) for the detection of ALK-rearranged lung adenocarcinomas in biopsy specimens, with excellent interobserver agreement between pathologists (kappa statistic, 0.94). Low levels of ALK protein expression is a characteristic feature of ALK-rearranged lung adenocarcinomas. However, a novel, highly sensitive IHC assay reliably detects lung adenocarcinomas with ALK rearrangements and obviates the need for fluorescence in situ hybridization analysis for the majority of cases, and therefore could be routinely applicable in clinical practice to detect lung cancers that may be responsive to ALK inhibitors.


Occupational therapy with Nordic walking and therapeutic touch: A pilot study for multidisciplinary rehabilitation in Parkinson's disease.
Physical exercise combined with occupational therapy (OT) can lead to a global improvement in personal well-being. To assess in PD patients: 1) if a rehabilitation program involving OT, Nordic walking (NW) and therapeutic touch (TT) yields motor/non-motor benefits; 2) if the time collocation of OT within the program influences results. This is a pilot study on 17 PD patients undergoing a 10-week rehabilitation program consisting of OT, NW and TT. Patients were randomized to receive OT in the first [Group 1, n = 8] vs. last five weeks [Group 2, n = 9] of the program. Scales (MMSE, FAB, BDI, UPDRS II and III, PDQ39 and AES-S) and 6MWT, Gait speed and length were assessed at three time-points. Thirteen out of 17 patients were analyzed. 6MWT, Gait speed and length improved in time without between-group differences (p < 0.05) as did UPDRII, UPDRSIII, FAB and PDQ39 (p < 0.05). Baseline UPDRS II and III significantly determined Δ6MWT (adjusted R2 = 0.6738) and ΔGAIT speed (R2 = 0.6746) at multiple regression, while ΔGAIT length showed the best regression (adjusted R2 = 0.8247) with impact of age, gender and baseline PDQ39 (ADL and cognition dimensions). Multidisciplinary rehabilitation including OT can improve motor and non-motor conditions in PD patients. The OT time-collocation at beginning or end of the rehabilitation program does not significantly affect results.


Short peptides derived from pigment epithelium-derived factor attenuate retinal ischemia reperfusion injury through inhibition of apoptosis and inflammatory response in rats.
Pigment epithelium-derived factor (PEDF) is widely recognized as a neuroprotective factor expressed in the retina and has shown therapeutic potential in several retinal diseases. Our study aimed to identify the neuroprotective fragment in PEDF and investigate its protective activity in retinas under ischemia-reperfusion (IR) condition. We synthesized a series of shorter synthetic peptides, 6-mer (Ser93-Gln98) and its d-form variant (6 dS) derived from the 44-mer (Val78-Thr121; a PEDF neurotrophic fragment), to determine their cytoprotective activity in IR injury, which was induced in rat retinas by injection of saline into the anterior chamber to increase the intraocular pressure (IOP) followed by reperfusion. We found the cytoprotective effect of 6-mer on glutamate-treated Neuro-2a cells and tert-butyl hydroperoxide (tBHP)-treated 661W cells were 2.6-fold and 1.5-fold higher than the 44-mer, respectively. The cytoprotective effect was blocked by a chemical inhibitor atglistatin and blocking antibody targeting PEDF receptor (PEDF-R). IR induced several impairments in retina, including cell apoptosis, activation of microglia/macroglia, degeneration of retinal capillaries, reduction in electroretinography (ERG) amplitudes, and retinal atrophy. Such IR injuries were ameliorated by treatment with 6-mer and 6 dS eye drops. Also, the neuroprotective activity of 6-mer and 6 dS in ischemic retinas were dramatically reversed by atglistatin preconditioning. Taken together, our data demonstrate smallest neuroprotective fragment of PEDF has potential to treat retinal degeneration-related diseases.


The role of prourokinase gene in protecting vein grafts from intimal hyperplasia.
To study the duration of prourokinase gene expression in vein grafts and the role of the prourokinase gene in protecting vein grafts from neointimal hyperplasia. Fifty-four Wistar rats were used in this study. In each rat, the jugular vein was excised and distended for 30 minutes using a solution containing either Adv(5)-CMV (control group) or Adv(5)-CMV/Pro-UK (treatment group). Next, the jugular vein was reversed and interposed into the divided carotid artery of the same rat. On the 14th day after transfection, vein grafts of the control group were collected in order to perform a fibrinolysis test for prourokinase (Pro-UK) activity. On the 2nd, 7th, 14th, 28th, and 60th day, the vein grafts of the treatment group were likewise collected in order to detect prourokinase activity. On the 28th day, the vein grafts of both groups were explanted to evaluate the (3)H-TDR incorporation so that pathologic analysis could be performed. Pro-UK activity could not be detected in the control group, while in the treatment group, the Pro-UK activity could be detected from the 2nd day onwards, peaking on the 7th day and declining from the 14th day, but yet persisting at a low level for a further month. The amount of (3)H-TDR incorporated in the control group was higher than that in the treatment group. Pathologic analysis demonstrated that vein grafts of both groups exhibited wall thickening, but that the degree of graft neointimal hyperplasia and reduction of the graft lumen was greater in the control group than that in the treatment group. The occlusion rate of grafts in the control group was 20%. All grafts in the treatment group were patent. Pro-UK gene transfer before vein grafting in vitro results in a high level of gene expression in the vein graft from the 7th day to 14th day. And its gene expression in the vein graft could reduce neointimal hyperplasia in the vein graft.


Molecular and functional insight into focal adhesion kinases: Therapeutic implications for oral malignancies.
Oral carcinoma is the sixth most common cancer globally, with one death occurring every hour. Focal adhesion kinase (FAK) is an intercellular protein tyrosine kinase, a key indicator of the development of oral cancer. FAK overexpression leads to the initiation and significant progression of metastasis in head and neck cancers, indicating its vital role in cancer progression and potential as a biomarker for early oral malignant transformation. The present review elaborates on FAK's function in oral malignancies since it could serve as a biomarker of the initial stages of oral malignant transformation and a possible predictive factor for risk assessment.


The value of neck drain in esophageal surgery: a randomized trial.
The use of surgical drains in certain clean elective operations remains controversial. To evaluate the role of closed-suction drain for an esophageal anastomosis in the neck, we conducted a randomized, controlled study in 40 patients with esophageal carcinoma who underwent esophagectomy with an esophageal anastomosis in the neck, half of whom had a neck drain inserted at the end of operation. The median (range) duration of drainage was 46 hours (36 to 88 hours). The median (range) amount of drainage was 63 ml (15 to 210 ml). There was no incidence of haematoma or seroma formation in both the drained and non-drained groups. Anastomotic leakage did not occur in any patient. The benefits of closed suction neck drain could not be demonstrated. Routine use of neck drain for esophageal anastomosis in the neck is not necessary.