Putative adaptive inter-slope divergence of transposon frequency in fruit flies (Drosophila melanogaster) at "Evolution Canyon", Mount Carmel, Israel.
The current analysis of transposon elements (TE) in Drosophila melanogaster at Evolution Canyon, (EC), Israel, is based on data and analysis done by our collaborators (Drs. J. Gonzalez, J. Martinez and W. Makalowski, this issue). They estimated the frequencies of 28 TEs (transposon elements) in fruit flies (D. melanogaster) from the ecologically tropic, hot, and dry south-facing slope (SFS) or "African" slope (AS) of EC and compared it with the TE frequencies on the temperate-cool and humid north-facing slope (NFS) or "European" slope (ES), separated, on average, by 250 m. The flies were sampled from two stations on each slope. We received their results, including the frequencies of each TE on each slope, and the probabilities of the statistical analyses (G-tests) of each TE separately. We continued the analysis of the inter-slope differences of the frequencies of the TEs, and based our different conclusions on that analysis and on the difference between micro (=EC) and macro (2000 km.) comparisons [Gonzalez et al. 2015 doi: 10.1186/s13062-015-0075-4 ]. Our collaborators based all their conclusions on the non-significant results of each of the individual tests of the 28 TEs. We analysed also the distribution of the TE differences between the slopes, based on their results. Thirteen TEs were more frequent on the SFS, 11 were more frequent on the NFS, and four had equal frequencies. Because of the equalizing effect of the ongoing migration, only small and temporary differences between the slopes (0 - 0.06) were regarded by us as random fluctuations (drift). Three TEs were intermediate (0.08-0.09) and await additional research. The 11 TEs with large frequency differences (0.12 - 0.22) were regarded by us as putative adaptive TEs, because the equalizing power of ongoing migration will eliminate random large differences. Five of them were higher on the SFS and six were higher on the NFS. Gaps in the distribution of the differences distinguished between the large and small differences. The large gap among the 11 TEs favored on the NFS was significant and supports our rejection of drift as the only explanation of the distribution of the slope differences. The gaps in the distribution of the differences separated the putative TEs with strong enough selection from those TEs that couldn't overrule the migration. The results are compared and contrasted with the directional effect of the frequencies of the same TEs in the study of global climatic comparisons across thousands of kilometers. From the 11 putative adaptive TEs in the local "Evolution Canyon," six differentiate in the same direction as in the continental comparisons and four in the opposite direction. One TE, FBti0019144, differentiated in EC in the same direction as in Australia and in the opposite direction to that of North America. We presume that the major divergent evolutionary driving force at the local EC microsite is natural selection overruling gene flow. Therefore, after we rejected drift as an explanation of all the large slope differences, we regarded them as putatively adaptive. In order to substantiate the individual TE adaptation, we need to increase the sample sizes and reveal the significant adaptive TEs. The comparison of local and global studies show only partial similarity in the adaptation of the TEs, because of the dryness of the ecologically tropical climate in EC, in contrast to the wet tropical climate in the global compared climates. Moreover, adaptation of a TE may be expressed only in part of the time and specific localities.


Oral cholecystography after alcoholic pancreatitis.
Retrospective and prospective studies were done to evaluate the efficacy of oral cholecystography (OCG) performed before hospital discharge on alcoholic patients with acute pancreatitis. In the retrospective study, OCG adequately opacified the gallbladder in 21 of 26 patients (81%). Of the 5 patients with inadequate opacification, 1 was jaundiced at the time of OCG; the other 4 had OCG before resumption of solid food. In the prospective study, OCG done in nonjaundiced patients shortly after resumption of food yielded adequate opacification in 19 of 21 patients (90%) without gallstones. We conclude that in nonjaundiced alcoholic patients with acute pancreatitis not caused by gallstones, OCG performed after resumption of a solid diet and before hospital discharge is usually successful in opacifying the gallbladder.


Aneurysm of aberrant subclavian artery with a review of the literature.
Aneurysms arising in an aberrant subclavian artery are rare but constitute a potentially lethal condition that can be treated successfully when appropriately identified. Virtually all patients have a superior mediastinal mass that may be asymptomatic, but usually patients have symptoms of dysphagia, chest pain, or shortness of breath. An accurate diagnosis can now be made noninvasively with computerized tomography. The presence of an aneurysm of an anomalous subclavian artery is an indication for surgical resection. Resection of the aneurysm may be approached through either a right or left thoracotomy. Reestablishment of continuity of flow to the right subclavian artery decreases the risk of ischemia of the extremities and prevents development of the subclavian steal syndrome. Reestablishment of flow to the right subclavian artery is more easily performed through a right thoracotomy incision but this approach limits control of the aorta at a possibly treacherous connection between aorta and aneurysm. In such circumstances a preliminary extra-anatomic reconstitution of flow to the right subclavian artery followed by a left thoracotomy may be preferable. A 67-year-old woman is described who had resection and grafting of an aneurysm in an aberrant right subclavian artery together with a review of the literature and a discussion of problems in the management of patients with this condition.


The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype.
Heterozygous COL2A1 variants cause a wide spectrum of skeletal dysplasia termed type II collagenopathies. We assessed the impact of this gene in our French series. A decision tree was applied to select 136 probands (71 Stickler cases, 21 Spondyloepiphyseal dysplasia congenita cases, 11 Kniest dysplasia cases, and 34 other dysplasia cases) before molecular diagnosis by Sanger sequencing. We identified 66 different variants among the 71 positive patients. Among those patients, 18 belonged to multiplex families and 53 were sporadic. Most variants (38/44, 86%) were located in the triple helical domain of the collagen chain and glycine substitutions were mainly observed in severe phenotypes, whereas arginine to cysteine changes were more often encountered in moderate phenotypes. This series of skeletal dysplasia is one of the largest reported so far, adding 44 novel variants (15%) to published data. We have confirmed that about half of our Stickler patients (46%) carried a COL2A1 variant, and that the molecular spectrum was different across the phenotypes. To further address the question of genotype-phenotype correlation, we plan to screen our patients for other candidate genes using a targeted next-generation sequencing approach.


Cervical hemangioma: a case report and review of the literature.
A case of cervical hemangioma is reported. This is a rare lesion of the uterine cervix, is not usually large and characteristically has a deep wine-red color. A review of the world literature indicates that all such hemangiomas that have been reported are benign. It is thought from this information that they may be treated conservatively.


The effects of prostacyclin (PGI2) on haematological and haemodynamic parameters, and lung histology in puppies undergoing cardiopulmonary bypass surgery with profound hypothermia.
Puppies 6-12 kg underwent cardiopulmonary bypass with profound hypothermia. Thirteen animals received 200 ng kg-1 min-1 of PGI2 during bypass whilst 11 control animals received equivalent volumes of glycine buffer (placebo) over a similar period. Results indicated preservation of platelets, leukocytes and fibrinogen levels, together with shortened activated partial thromboplastin times and fewer fibrinogen degradation products post-bypass in PGI2-treated animals. There was an initial fall in blood pressure and systemic vascular resistance in PGI2 treated animals, but pulmonary pressures and resistances, cardiac outputs, and heart rates showed no significant differences from controls. Higher and more satisfactory end of bypass and post-bypass blood pressure levels, together with a lesser fall-off in mean total pulmonary compliance, and shortened bypass times were achieved in treated animals. PGI2 appeared to afford some protection against lung damage as observed by histological studies. All beneficial effects appeared to be significantly greater amongst smaller animals. The results indicate possible benefits from the use of PGI2 in infant open heart surgery.


Mycobacterium tuberculosis concealed by enterococcal sacroiliitis.
A 77-year-old African American female with rheumatoid arthritis presented with fever and unsteady gait. She was started on broad-spectrum antimicrobials due to CT evidence for sacroiliitis and psoas abscess and underwent partial excision of her sacroiliac bone and drainage of the abscess. One of four blood cultures grew Enterococcus faecalis and the patient was sent home with intravenous ampicillin for 6 weeks. Two days after antimicrobial completion, the patient presented with night sweats and weakness. Chest x-ray revealed new right upper lobe pulmonary infiltrates, and the AFB culture sent during her prior admission returned positive for TB. RIPE therapy with moxifloxacin was initiated. Although she responded well to treatment, she retained functional immobility. We report a case of musculoskeletal TB initially misdiagnosed as enterococcus sacroiliitis, resulting in a delayed initiation of anti-tuberculous therapy. A high index of suspicion and rapid detection with TB-PCR testing should be considered to avoid delayed diagnosis.


Bamboozled! Resolving deep evolutionary nodes within the phylogeny of bamboo corals (Octocorallia: Scleralcyonacea: Keratoisididae).
Keratoisididae is a globally distributed, and exclusively deep-sea, family of octocorals that contains species and genera that are polyphyletic. An alphanumeric system, based on a three-gene-region phylogeny, is widely used to describe the biodiversity within this family. That phylogeny identified 12 major groups although it did not have enough signal to explore the relationships among groups. Using increased phylogenomic resolution generated from Ultraconserved Elements and exons (i.e. conserved elements), we aim to resolve deeper nodes within the family and investigate the relationships among those predefined groups. In total, 109 libraries of conserved elements were generated from individuals representing both the genetic and morphological diversity of our keratoisidids. In addition, the conserved element data of 12 individuals from previous studies were included. Our taxon sampling included 11 of the 12 keratoisidid groups. We present two phylogenies, constructed from a 75% (231 loci) and 50% (1729 loci) taxon occupancy matrix respectively, using both Maximum Likelihood and Multiple Species Coalescence methods. These trees were congruent at deep nodes. As expected, S1 keratoisidids were recovered as a well-supported sister clade to the rest of the bamboo corals. S1 corals do not share the same mitochondrial gene arrangement found in other members of Keratoisididae. All other bamboo corals were recovered within two major clades. Clade I comprises individuals assigned to alphanumeric groups B1, C1, D1&D2, F1, H1, I4, and J3 while Clade II contains representatives from A1, I1, and M1. By combining genomics with already published morphological data, we provide evidence that group H1 is not monophyletic, and that the division between other groups - D1 and D2, and A1 and M1 - needs to be reconsidered. Overall, there is a lack of robust morphological markers within Keratoisididae, but subtle characters such as sclerite microstructure and ornamentation seem to be shared within groups and warrant further investigation as taxonomically diagnostic characters.


Using the Primary Care Behavioral Health Provider Adherence Questionnaire (PPAQ) to identify practice patterns.
Primary care-mental health integration (PC-MHI) is growing in popularity. To determine program success, it is essential to know if PC-MHI services are being delivered as intended. The investigation examines responses to the Primary Care Behavioral Health Provider Adherence Questionnaire (PPAQ) to explore PC-MHI provider practice patterns. Latent class analysis was used to identify clusters of PC-MHI providers based on their self-report of adherence on the PPAQ. Analysis revealed five provider clusters with varying levels of adherence to PC-MHI model components. Across clusters, adherence was typically lowest in relation to collaboration with other primary care staff. Clusters also differed significantly in regard to provider educational background and psychotherapy approach, level of clinic integration, and previous PC-MHI training. The PPAQ can be used to identify PC-MHI provider practice patterns that have relevance for future clinical effectiveness studies, development of provider training, and quality improvement initiatives.


Differential effect of Huntington's and Parkinson's diseases in programming motor sequences of varied lengths.
Parkinson's disease (PD) and Huntington's disease (HD) patients have difficulties executing sequential movements. Attention control and short-term memory probably play an important role in programming sequential movements. To investigate the contribution of these cognitive factors to programming and executing visuomotor sequences in HD and PD patients a computerized version of the Corsi Block Tapping-Test was employed. the performance of 11 patients with early stage PD, 11 HD patients with borderline to mild caudate atrophy and 20 healthy subjects was compared. The task was a reaction time task where targets were illuminated in groups of sequences increasing from 2 items to 5 items. Subjects reproduced the sequence (pressing the illuminated target) in the same order of appearance. Reaction Times and movement times were recorded. PD patients had increasing difficulties in programming and executing series greater than three components. HD patients did not differ significantly from the controls, although they showed a tendency to lose accuracy in the longer series. Both patient groups did not differ in their attention span. In PD although the spatial information may be well stored, they have difficulty accessing it when their attention is overloaded, leading to poor encoding and slow information processing. This process interferes with programming and execution of movement sequences. HD patients in the early stages of the illness seem to have more attention resources than PD patients, so that they start to show more problems in executing visuomotor sequences with longer movement sequences than PD patients.


Protective effect of heat shock pretreatment with heat shock protein induction before hepatic warm ischemic injury caused by Pringle's maneuver.
Induction of heat shock proteins is thought to have a > cytoprotective effect against environmental stress and to result in a better ischemic tolerance. The protective ability of heat exposure and heat shock protein 72 (HSP 72) induction before warm ischemia caused by Pringle's maneuver was evaluated in rats. Heat exposed rats (HS) were compared with control animals (C). The gene expression (messenger RNA) of HSP 72 and HSP 72 were detected by Northern and Western blot analyses. During 40 minutes of in situ reperfusion, liver energy metabolism and levels of standard liver enzymes were evaluated. The survival rate was determined after postoperative day 7. After heat exposure and recovery, messenger RNA of HSP 72 and HSP 72 can be detected strongly in HS group but not in C group. During reperfusion HS group exhibited a significantly (p < 0.01) improved energy metabolism, and the release of liver enzymes was significantly (p < 0.001) reduced compared with C group. Seven-day survival rate was 100% in HS group but at 50% was significantly impaired (p < 0.05) in C group. Heat exposure associated with HSP induction has a significant protective effect against warm ischemic liver injury, which results in a relevant improvement of survival rate.


Population genetics of 29 autosomal STRs and 17 Y-chromosomal STRs in a population sample from Afghanistan.
In this study, allele frequencies for 29 autosomal short tandem repeats (STRs) and haplotype frequencies for 17 Y-chromosomal STRs of an Afghan population have been generated. Samples from 348 men and women originating from Afghanistan were analysed for the autosomal STRs, and the combined match probability was estimated to be 7.5 × 10(-37). One hundred and sixty-nine men were analysed for the Y-chromosomal STRs, which resulted in 132 different haplotypes and a haplotype diversity of 0.995.


The effect of incentive spirometer training on oromotor and pulmonary functions in children with Down's syndrome.
This study investigated the effect of incentive spirometry training on oromotor and pulmonary functions in children with Down's syndrome. Thirty-four children with Down's syndrome were randomly divided into two groups; the children were of both sexes and aged between 6 and 12 years. Group A received only oromotor exercises, while Group B received oromotor exercises and incentive spirometry training. The pulmonary function test was performed using computerized spirometry model master screen that assessed pulmonary functions (peak expiratory flow, forced vital capacity, and forced expiratory volume in 1s), while the orofacial myofunctional evaluation with score (OMES) was used to evaluate oromotor function before and after treatment. The post treatment results showed significant difference in oromotor and pulmonary functions within both groups, but no significant differences were found between the two groups. Oromotor exercises are more effective than incentive spirometry training in improving both pulmonary and oromotor functions in children with Down's syndrome.


Effect of cyclic third components on non-deoxygenated RTP and their potential in developing optical thermometer.
Effect of five cyclic third components, cyclohexane, methylcyclohexane, perfluorocyclohexane, perfluoromethylcyclohexane and adamantane, on cyclodextrin-induced room-temperature phosphorescence (CD-RTP) of 1-bromonaphthalene is studied. It is found that these five compounds can induce intensive RTP, and the enhancement order is as follows: cyclohexane>adamantane>methylcyclohexane>perfluorocyclohexane>perfluoromethylcyclohexane. Dependence of RTP intensity on temperature of these systems shows the potential application in developing optical thermometer.


Parental [correction of Perinatal] consanguinity: a risk factor for developmental delay in Pakistani children.
To investigate the association of parental consanguinity and delayed development in terms of gross motor, fine motor, speech and social aspects in their children. One hundred and seventy seven children (age 15 days--72 months) were evaluated for their developmental status utilizing the Denver Developmental Screening Test (DDST). An unmatched case-control study design was used. Case group consisted of 94 children and control group 83 children. Odds ratios were calculated for parental consanguinity and delay in gross and fine motor, speech and social development in their children, for cases and controls, utilizing Binary Multiple Logistic Regression Analysis. Acquired delay was excluded through detailed birth history in both cases and control group respectively. Univariate analysis showed high significant Odds ratios for all areas of developmental delay (viz. gross and fine motor, speech and social development), between cases and controls (p < .001). At the multivariate analysis level however, our results showed no increased risk of parental consanguinity on delayed gross and fine motor, speech and social development in their children. Our results show no increased risk of parental consanguinity on delayed gross and fine motor, speech or social development (as measured by the DDST), in their children.


Comparison of autoradiography and DNA histograms in assessing S-phase cells from patients with myeloid leukemias.
The studies reported here were designed to determine whether DNA histogram analysis provided the same estimate for the percentage of cells in S-phase as does 3H-TdR labeling index (LI). For DNA histogram analysis high resolution flow cytometry was employed together with 3 different computer based methods for histogram analysis. When tissue culture cells were employed there was a good correlation (r = 0.89) between the estimates for the percentage of cells in S-phase by the LI and DNA histogram techniques. In contrast, when 1138 bone marrow or peripheral blood specimens obtained from leukemic patients were studied the correlation was poor. For example when 243 pretherapy bone marrow aspirate cells were studied by both methods the correlation was only 0.46. A direct comparison of the clinical relevance of the two methods for measuring S-phase cells when high dose cytosine arabinoside therapy was used to treat patients demonstrated that only LI measurements provided clinically useful information. In conclusion, DNA histogram analysis provides an inaccurate estimate of the percentage of cells in S-phase.


Impact of transitioning from long-term to intermittent opioid therapy on the development of opioid-related adverse outcomes: A retrospective cohort study.
Increasing pressures exist to reduce or discontinue opioid use among patients currently on long-term opioid therapy (LTOT). It is essential to understand the potential effects of opioid reduction. This retrospective cohort study was conducted among veterans with chronic pain and on LTOT. Using 1:1 propensity score-matched samples of veterans switching to intermittent opioid therapy and those continuing LTOT, we examined the development of subsequent substance use disorders (SUD composite; individual SUD types: opioid, non-opioid drug, and alcohol use disorders) and opioid-related adverse outcomes (ORAO composite; individual ORAO types: accidents resulting in wounds/injuries, opioid-related and alcohol/non-opioid medication-related accidents and overdoses, self-inflicted and violence-related injuries). Sensitivity analyses were conducted using logistic regression with stabilized inverse probability of treatment weighting (SIPTW) and instrumental variable (IV) models. A total of 29,293 veterans switching to intermittent therapy were matched to veterans continuing LTOT. With matched samples, no differences were found in composite SUDs and ORAOs between the groups. With SIPTW, veterans switching to intermittent opioid therapy had higher odds of composite SUDs and ORAOs (SUDs aOR=1.12, 95%CI: 1.07,1.17; ORAOs aOR=1.05, 95%CI:1.00,1.09). IV models found lower risks for composite SUDs and ORAOs among veterans switching to intermittent opioid therapy (SUDs: β = -0.38, 95%CI:-0.63,-0.13; ORAOs: β = -0.27, 95%CI:-0.50,-0.04). There were no consistent associations between transitioning patients from LTOT to intermittent opioid therapy and the risk of SUDs and ORAOs.


The Parkland Burn Center experience with 297 cases of child abuse from 1974 to 2010.
Pediatric burns due to abuse are unfortunately relatively common, accounting for 5.8-8.8% of all cases of abuse annually. Our goal was to evaluate our 36-year experience in the evaluation and management of the victims of abuse in the North Texas area. A prospectively maintained database containing records on all admissions from 1974 through 2010 was queried for all patients aged less than 18 years. Patients admitted for management of a non-burn injury were excluded from the analysis. Of 5,553 pediatric burn admissions, 297 (5.3%) were due to abuse. Children with non-accidental injuries tended to be younger (2.1 vs. 5.0 years, p<0.0001) and male (66.0 vs. 56.5%, p=0.0008). Scald was the most common mechanism of injury overall (44.8%), and was also the predominant cause of inflicted burns (89.6 vs. 42.3%, p<0.0001). Multivariate logistic regression identified age, gender, presence of a scald, contact, or chemical burn, and injury to the hands, bilateral feet, buttocks, back, and perineum to be significant predictors of abuse. Victims of abuse were also found to have worse outcomes, including mortality (5.4 vs. 2.3%, p=0.0005). After adjusting for age, mechanism of injury, and burn size, abuse remained a significant predictor of mortality (OR 3.3, 95% CI 1.5-7.2) CONCLUSIONS: Clinicians should approach all burn injuries in young children with a high index of suspicion, but in particular those with scalds, or injuries to the buttocks, perineum, or bilateral feet should provoke suspicion. Burns due to abuse are associated with worse outcomes, including length of stay and mortality.


[RNA polymerase as a molecular machine].
Structure and function of DNA-dependent RNA polymerase is considered in terms of a conveying molecular machine. The use of mechanical energy and mechanical devices, such as "power-stroke motor", is supposed unlikely in the conveying function of RNA polymerase, as well as other molecular machines. Brownian motion and thermal mobility of macromolecules and their parts are postulated as the only motive impulse at the molecular level. Binding of substrates and subsequent chemical reaction as the energy input may provide successive selection and fixation of alternative conformational states of the enzyme complex thus providing the directionality of the conveyance ("Brownian ratchet mechanism"). The following sequence of events "substrate binding--fixation of a certain conformational state--chemical reaction--fixation of an alternative conformational state--translocation (dissociation and downstream reassociation) of product-template duplex" is proposed as the principal scheme of the forward movement of RNA polymerase along DNA template.


Facilitating emotional processing in depression: the application of exposure principles.
Even with the best psychosocial and pharmacological treatments for unipolar depression, relapse is a serious problem. One path to improve treatments for depression is to target fundamental processes that go awry in depression and to enhance new learning by adapting principles and strategies from exposure-based treatments for anxiety and fear-related disorders. I describe basic principles of exposure and emotional processing and illustrate with Exposure-Based Cognitive Therapy (EBCT) for depression, how these principles can be applied, with some adaptation, to address the therapeutic targets of depression. Clinical trial data of EBCT suggest that this application might be fruitful and that the process of change might be similar to that in exposure-based treatments for anxiety and trauma-related disorders.


Improvement with ongoing Enzyme Replacement Therapy in advanced late-onset Pompe disease: a case study.
Benefits of enzyme replacement therapy with Myozyme (alglucosidase alfa), anecdotally reported in late-onset Pompe disease, range from motor and pulmonary improvement in less severely affected patients, to stabilization with minimal improvement in those with advanced disease. We report a case of a 63-year-old patient with significant morbidity who made notable motor and pulmonary function gains after two years on therapy. Thus, improvements in those with advanced disease may be possible after long-term treatment.


L-type lectin receptor-like kinase OsCORK1 as an important negative regulator confers copper stress tolerance in rice.
Copper (Cu) is vital for plant growth but becomes toxic in excess, posing potential threats to human health. Although receptor-like kinases (RLKs) have been studied in plant response to abiotic stresses, their roles in Cu stress response remain poorly understood. Therefore, we aimed to evaluate Cu toxicity effects on rice and elucidate its potential molecular mechanisms. Specifically, rice lectin-type RLK OsCORK1 (Copper-response receptor-like kinase 1) function in Cu stress response was investigated. RNA sequencing and expression assays revealed that OsCORK1 is mainly expressed in roots and leaves, and its expression was significantly induced by Cu stress time- and dose-dependently. Kinase activity assays demonstrated OsCORK1 as a Mn2+-preferred functional kinase. Genetically, OsCORK1 gene-edited mutants exhibited increased tolerance to Cu stress and reduced Cu accumulation compared to the wild type (WT). Conversely, OsCORK1 overexpression compromised the Cu stress tolerance observed in OsCORK1 gene-edited mutants. OsCORK1 gene-edited mutants slightly damaged the root tips compared to the WT under Cu stress. Furthermore, OsCORK1 was demonstrated to modulate Cu stress tolerance by mainly altering cell wall components, particularly lignin, in rice. Overall, OsCORK1 is an important negative regulator of Cu stress tolerance, providing a potential gene target to reduce Cu pollution in rice production.


Stable inhibition of human thymidylate synthase expression following retroviral introduction of an siRNA gene.
Thymidylate synthase (TS) is an essential enzyme that synthesizes thymidylic acid in the de novo biosynthetic pathway. Inhibiting TS enzyme activity with substrate or cofactor analogs leads to inhibition of DNA replication and cell death. For this reason, TS is an important target enzyme for cancer chemotherapeutic drugs. We describe an alternative approach to reducing cellular TS enzyme activity using short interfering RNA (siRNA) technology to lower TS mRNA levels. Plasmids that direct the synthesis of siRNAs that target nucleotides 898-916 and 965-983 (relative to the A of the translational start codon) of human TS mRNA were highly effective at reducing TS enzyme levels in transient transfection assays. Infection of HeLa cells with retroviruses that contain the effective siRNA genes led to a stable 80-95% reduction of TS enzyme and mRNA. A similar percent reduction in TS expression was observed in a cell line that overproduces TS enzyme 100-fold due to TS gene amplification. Cells that exhibited the greatest reduction in TS enzyme level grew poorly in medium that lacked thymidine. These observations suggest that siRNA approaches may provide an alternative therapeutic strategy to reduce TS enzyme levels.


Increased mRNA Expression of CTRP3 and CTRP9 in Adipose Tissue from Obese Women: Is it Linked to Obesity-Related Parameters and mRNA Expression of Inflammatory Cytokines?
Obesity, a medical condition with impaired adipokine secretion and function, has a detrimental effect on insulin and glucose metabolism. CTRP3 and CTRP9 are adipokines with possible roles in energy homeostasis regulation. We sought to compare CTRP3, CTRP9, and inflammatory gene expression in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) from obese women who underwent bariatric surgery and non-obese women as controls. For this study, the investigators recruited 20 morbidly obese women (BMI> 35) who qualified for bariatric surgery and 20 normal-weight women (BMI< 25) who underwent elective surgeries. Real-time PCR was performed to investigate mRNA expression of CTRP3, CTRP9, and the inflammatory genes IL1-β, IL-6, MCP-1, and TNF-α in SAT and VAT from both obese patients and controls. We observed that CTRP3 mRNA levels were significantly greater in VAT from obese patients than from controls (P< 0.0003). Also, patient group had higher levels of CTRP9 that control group (P< 0.0026). Inflammatory cytokines were markedly increased in SAT of obese patients compared to controls (P< 0.05). In addition, our results revealed a positive correlation of CTRP9 with HOMA-IR and waist circumference in VAT and CTRP3 with IL-1β, MCP-1, and TNF-α in SAT. Both CTRP3 and CTRP9 expression were significantly higher in VAT from obese patients than from controls, and CTRP3 expression positively correlated with inflammatory parameters. Our findings indicate that CTRP3 and CTRP9 might be important in regulating glucose metabolism and obesity-related conditions such as inflammation.


Beta 2-microglobulin, HIV-1 p24 antibody and acid-dissociated HIV-1 p24 antigen levels: predictive markers for vertical transmission of HIV-1 in pregnant Ugandan women.
To evaluate the clinical utility of plasma beta 2-microglobulin (beta 2M) levels, acid-dissociated HIV-1 p24 antigen, and HIV-1 p24-antibody titers in predicting HIV-1 vertical transmission in 227 HIV-1-infected Ugandan pregnant women. Plasma beta 2M levels, acid-dissociated HIV-1 p24-antigen positivity, and HIV-1 p24-antibody titers were determined using commercial enzyme immunoassays (EIA) in a Ugandan cohort of 52 HIV-1-seropositive transmitting mothers, 175 HIV-1-seropositive non-transmitting mothers, and 52 seronegative mothers within 6 weeks prior to delivery. Transmitter mothers had significantly higher plasma concentrations of beta 2M (1.80 +/- 1.13 mg/l) than non-transmitter seropositive mothers (1.32 +/- 0.81 mg/l; P = 0.0013). Similarly, a significantly higher proportion of transmitter mothers had detectable p24 antigen than non-transmitter mothers [six out of 51 (11.8%) versus six out of 173 (3.5%); P = 0.03]. Compared with the vertical transmission rate of 23% in the seropositive group, the positive predictive values of a beta 2M level > 1.5 mg/l or detectable HIV-1 p24 antigen for vertical transmission were 34 and 50%, respectively. Five of six (83.3%) seropositive mothers with both a beta 2M level > 1.5 mg/l and detectable p24 antigenemia transmitted HIV-1 infection to their infants compared with 25 of 124 (20.2%) seropositive mothers with values below the cut-off values for both tests (P = 0.00249). However, beta 2M was not found to be a significant independent predictor of vertical transmission when analyzed in a multivariate model with p24 antigenemia. There was no significant difference in HIV-1 p24-antibody titers in transmitter mothers versus non-transmitter mothers (P = 0.299). beta 2M levels and acid-dissociated HIV-1 p24-antigen assays may be used to predict which HIV-1-infected pregnant women are at greatest risk for vertical transmission. However, only the p24-antigen test was independently predictive of vertical transmission and its clinical utility is limited.


Co-expression of CD44+/RANKL+ tumor cells in the carcinogenesis of oral squamous cell carcinoma.
Receptor activator of nuclear factor-kappa (RANK)/receptor activator of nuclear factor-kappa B ligand (RANKL) signaling helps putative cancer stem cells (CSC) to maintain their stemness. Expression of CD44 and RANKL was analyzed in oral squamous cell carcinoma specimen (n = 191). Moreover, RANKL expression was measured in cancer cell lines (BICR3, BICR56) by immunohistochemistry and western blot analysis. Scanned images were digitally analyzed using ImageJ and the immunomembrane plug-in. CD44 and RANKL expression on protein level was correlated with clinical characteristics and impact on survival. RANKL was co-labeled with CD44 in immunohistochemical and immunofluorescence double labeling experiments. Although high CD44+/RANKL+ co-expression was significantly associated with clinicopathological factors and worse survival, multivariate analysis did not demonstrate high CD44+/RANKL+ co-expression as independent prognostic factor. Immunohistochemical and immunofluorescence double labeling experiments revealed RANKL expression by CD44+ cancer cells. RANKL specificity was confirmed by western blot analysis. For the first time, this study provides evidence that RANKL expression in OSCC might be associated with disease recurrence and a cell compartment measured by CD44+/RANKL+ co-expression within the mucosal epithelial basal layer cells.


Long-term efficacy and safety of a new botulinum toxin type A preparation in mouse gastrocnemius muscle.
A new type A botulinum toxin (BoNT/A) preparation, JTM201 (NCBI chromosomal DNA ID: CP046450), has been developed, which comprises 900-kDa complexed toxin purified from Clostridium botulinum (strain: NCTC13319), but its safety and efficacy have not yet been evaluated. The purpose of this study was to evaluate the long-term efficacy and safety of JTM201 at different concentrations in comparison to another commercially available BoNT/A product, Botox® (onabotulinumtoxin A, ONA), using a mouse model. The LD50 of JTM201 was similar to that of ONA, but the intrinsic activity of JTM201 was higher than that of ONA. Functional recovery of the nerves and muscles in SKH-1 mice after administration of the two BoNT/A preparations (JTM201 and ONA) to the right gastrocnemius muscle was observed over 24 weeks. In addition, JTM201 did not induce any skin or muscle inflammatory response in 24 weeks. Paralysis induced by neurotransmitter blockade after JTM201 administration was comparable to that of ONA treatment. Both muscle weight and volume decreased in a concentration-dependent manner following JTM201 or ONA toxin injection until week 4. Reduced muscle fiber size due to atrophy and consequent fibrosis were detected following injection of JTM201 or ONA. Moreover, we assessed the extent of diffusion of JTM201 or ONA to the tibialis anterior and quadriceps femoris muscles, demonstrating limited diffusion to off-target muscles. In conclusion, JTM201 demonstrated long-term efficacy and safety equivalent to those of ONA based on compound muscle action potential, muscle volume, and histology analyses. These data suggest that JTM201 is a new BoNT/A formulation with safety and efficacy comparable to those of ONA.


Ultrafine particles cause cytoskeletal dysfunctions in macrophages: role of intracellular calcium.
Particulate air pollution is reported to cause adverse health effects in susceptible individuals. Since most of these particles are derived form combustion processes, the primary composition product is carbon with a very small diameter (ultrafine, less than 100 nm in diameter). Besides the induction of reactive oxygen species and inflammation, ultrafine particles (UFP) can cause intracellular calcium transients and suppression of defense mechanisms of alveolar macrophages, such as impaired migration or phagocytosis. In this study the role of intracellular calcium transients caused by UFP was studied on cytoskeleton related functions in J774A.1 macrophages. Different types of fine and ultrafine carbon black particles (CB and ufCB, respectively), such as elemental carbon (EC90), commercial carbon (Printex 90), diesel particulate matter (DEP) and urban dust (UD), were investigated. Phagosome transport mechanisms and mechanical cytoskeletal integrity were studied by cytomagnetometry and cell viability was studied by fluorescence microscopy. Macrophages were exposed in vitro with 100 and 320 microg UFP/ml/million cells for 4 hours in serum free medium. Calcium antagonists Verapamil, BAPTA-AM and W-7 were used to block calcium channels in the membrane, to chelate intracellular calcium or to inhibit the calmodulin signaling pathways, respectively. Impaired phagosome transport and increased cytoskeletal stiffness occurred at EC90 and P90 concentrations of 100 microg/ml/million cells and above, but not with DEP or UD. Verapamil and W-7, but not BAPTA-AM inhibited the cytoskeletal dysfunctions caused by EC90 or P90. Additionally the presence of 5% serum or 1% bovine serum albumin (BSA) suppressed the cytoskeletal dysfunctions. Cell viability showed similar results, where co-culture of ufCB together with Verapamil, W-7, FCS or BSA produced less cell dead compared to the particles only.


Hunter-Gatherer Color Naming Provides New Insight into the Evolution of Color Terms.
Most people name the myriad colors in the environment using between two and about a dozen color terms, with great variation within and between languages. Investigators generally agree that color lexicons evolve from fewer terms to more terms, as technology advances and color communication becomes increasingly important. However, little is understood about the color naming systems at the least technologically advanced end of the continuum. The Hadza people of Tanzania are nomadic hunter-gatherers who live a subsistence lifestyle that was common before the advent of agriculture (see Supplemental Experimental Procedures, section I;), suggesting that the Hadzane language should be at an early stage of color lexicon evolution. When Hadza, Somali, and US informants named 23 color samples, Hadza informants named only the black, white, and red samples with perfect consensus. Otherwise, they used low-consensus terms or responded "don't know." However, even low-consensus color terms grouped test colors into lexical categories that aligned with those found in other world languages. Furthermore, information-theoretic analysis showed that color communication efficiency within the Hadza, Somali, and US language communities falls on the same continuum as other world languages. Thus, the structure of color categories is in place in Hadzane, even though words for many of the categories are not in general use. These results suggest that even very simple color lexicons include precursors of many color categories but that these categories are initially represented in a diverse and distributed fashion.


Medium-term Oncological Efficacy and Patient-reported Outcomes After Focal High-intensity Focused Ultrasound: The FOXPRO Trial.
Multiparametric magnetic resonance imaging (mpMRI)/transrectal ultrasound (TRUS) fusion-guided high-intensity focused ultrasound (HIFU) is a focal treatment option for MRI-visible localized prostate cancer (PCa). High-quality evidence regarding the clinical efficacy remains limited. To assess medium-term oncological efficacy along with patient-reported outcome measures (PROMs). This prospective single-center cohort study was performed from 2014 to 2020. Patients with primary International Society of Urological Pathologists (ISUP) grade group (GG) ≤2 by combined MRI/TRUS fusion and systematic prostate biopsy and prostate-specific antigen (PSA) <10 ng/ml were included. MRI/TRUS fusion-guided focal HIFU therapy. The primary outcome was the cancer-free rate of the HIFU-treated lesion by biopsy after 1 yr. Secondary endpoints included salvage treatment-free survival (STFS), metastasis-free survival (MFS), overall survival (OS), and PROMs according to International Consortium for Health Outcomes Measurement recommendations. Fifty patients were included (median [range] age 68 [48-80] yr; median PSA 6.5 [1.2-9.9] ng/ml; GG 1 54% [n = 27], and GG 2 46% [n = 23]). The median (range) PSA decrease from baseline to 12 mo was 51% (35.9-72.7%). In total, 37/50 patients (74%) underwent a 1-yr biopsy. PCa was detected in 23 patients (46%; GG 1 20% [n = 10]; GG >1 26% [n = 13]; infield 40% [n = 20]). At a median follow-up of 42 (13-73) mo, PCa was detected in 30 men (60%). Among all patients, 19 (38%) underwent salvage treatments (median [95% confidence interval] STFS 53 [44.3-61.7] mo). MFS and OS were 100% and 98%, respectively. The Expanded Prostate Cancer Index Composite-26 sexual domain decreased by 20.8 points (p = 0.372). MRI/TRUS-guided focal HIFU therapy results in complete cancer ablation in only half of the treated patients after 1 yr, with further recurrences at medium-term follow-up. A decline of potency occurs in a subset of patients. Focal image-guided high-intensity focused ultrasound therapy controls cancer in one of two patients. Its impact on urinary continence and erectile function is low.


Photoinduction of arginine decarboxylase activity in leaves of Pharbitis nil.
The activity of arginine decarboxylase (ADC) in leaves of Pharbitis nil was induced by light. The ADC activity increased to a maximum 1 h after illumination, followed by a gradual decrease. This suggested light either induced synthesis of ADC protein de novo or was involved in its activation. Cycloheximide inhibited the photoinduction of ADC activity, and the half life of ADC in leaves was 30-40 min. The temperature and relative humidity in darkness before illumination had no effect on the photoinduction of ADC activity, contrary to the photoresponse of S-adenosylmethionine decarboxylase (SAMDC) activity where the conditions of darkness before lights-on have a marked effect. The light response of the polyamine (PA)-biosynthetic enzyme activity produced transient accumulation of PA. The level of spermidine increased in leaves in which activities of both SAMDC and ADC increased after illumination, while the level of putrescine increased in leaves in which the activity of ADC increased but that of SAMDC did not.


The isc gene cluster expression ethanol tolerance associated improves its ethanol production by organic acids flux redirection in the ethanologenic Escherichia coli KO11 strain.
Fossil fuels consumption impacts the greenhouse gas emissions. Biofuels are considered as alternative renewable energy sources to reduce the fossil fuels dependency. Bioethanol produced by recombinant microorganisms is a widely suggested alternative to increase the yield in fermentation processes. However, ethanol and acetate accumulation under the fermentation process had been described as important stressors for the metabolic capabilities of the microorganisms, stopping the fermentation process and affecting the ethanol yield. Ethanol tolerance is a determining factor in the improvement of fermentative properties of microorganisms; however understanding of ethanol tolerance is limited. The engineered Escherichia coli KO11 strain has been studied in detail and used as an ethanologenic bacteria model. The strain is capable of using glucose and xylose for an efficient ethanol yield. In the current work, the effect of the iron-sulfur cluster (ISC) over-expression in the KO11 strain, on its tolerance and ethanol yield, was evaluated. Fatty acids profiles of membrane phospholipids in the E. coli KO11 were modified under ethanol addition, but not due to the hscA mutation. The hscA mutation provoked a decrease in ethanol tolerance in the Kmp strain when was grown with 2% ethanol, in comparison to KO11 parent strain. Ethanol tolerance was improved in the mutant Kmp complemented with the recombinant isc gene cluster (pJC10 plasmid) from LD50 2.16% to LD50 3.8% ethanol. In batch fermentation on 1 L bioreactor using mineral medium with glucose (120 g/L), the KO11 strain showed ethanol production efficiencies of ~ 76.9%, while the hscA mutant (Kmp) ~ 75.4% and the transformed strain Kmp(pJC10) showed ~ 92.4% efficiency. Ethanol amount increase in the engineered Kmp(pJC10) strain was correlated with less organic acids (such as acetate and lactate) production in the fermentation medium (2.3 g/L), compared to that in the KO11 (17.05 g/L) and the Kmp (16.62 g/L). Alcohol dehydrogenase (ADH) activity was increased ~ 350% in the transformed Kmp(pJC10) strain, whereas in the Kmp mutant, the phosphoglycerate kinase (PGK), pyruvate kinase (PYK), and ADH activities were diminished, comparing to KO11. The results suggest that the isc system over-expression in the ethanologenic E. coli KO11 strain, increases ethanol yield mainly by improving ethanol tolerance and ADH activity, and by redirecting the metabolic flux from acetate synthesis to ethanol.


Update in Advancing the Gastrointestinal Frontier in Cystic Fibrosis.
Clinical complications of cystic fibrosis (CF) include a variety of gastrointestinal (GI) and hepatobiliary manifestations. Recent years have witnessed several advances in the understanding and management of these complications, in addition to opportunities for therapeutic innovations. Herein we review the current understanding of these disorders and also discuss the management of the GI and hepatobiliary complications experienced by persons with CF.


Detection of a heat- and acid-stable 'progesterone'-binding protein in the rat lung.
Using a modified charcoal method, we could detect a steroid-binding component in rat lung cytosol which specifically binds R5020, progesterone, and some of its natural derivatives. The concentration of binding sites is high (30-40 pmol/mg protein), the affinity is moderate, the Kd of the R5020 complex being approximately 10(-7) M. Proteolytic enzymes and sulfhydryl reagents destroyed the binding sites indicating the protein nature and the requirement for disulfide bonds. The protein sedimented in the 2 S range thus had an Mr of 10,000-15,000. Further characteristics are the extreme heat (30 min at 100 degrees C) and acid (pH 1) stability. These properties and the fact that it was not detected in serum, distinguish this binding protein from receptors and specific serum steroid binders.


Carvedilol inhibits vascular smooth muscle cell proliferation.
The antiproliferative properties of carvedilol, a newly developed multiple-action antihypertensive agent, were evaluated in early passage cultured rat aortic vascular smooth muscle cells. Carvedilol (10(-7)-10(-5) M) produced concentration-dependent decreases in basal and endothelin-1-stimulated mitogenesis of rat aortic vascular smooth muscle cells. The IC50 for inhibition of [3H]thymidine incorporation by carvedilol in both basal and endothelin-1-stimulated rat aortic vascular smooth muscle cells was approximately 1 microM. Carvedilol (10 microM) inhibited basal mitogenesis by approximately 65%, and endothelin-1-stimulated mitogenesis by approximately 95%. Carvedilol (1-10 microM) also produced significant concentration-dependent inhibition of the mitogenic response mediated by thrombin (0.5 U/ml), epidermal growth factor (1 nM), platelet-derived growth factor (1 nM), and angiotensin II (5 nM). Endothelin-1- or PDGF A/B-induced increases in cell number were also significantly inhibited by carvedilol (10 microM). The antimitogenic effect of carvedilol on cell growth was reversible. The inhibitory effect of carvedilol was not shared by other beta-adrenoceptor antagonists such as labetalol (10 microM), celiprolol (10 microM), or sotalol (10 microM), which did not significantly affect [3H]thymidine incorporation in rat vascular smooth muscle cells. Propranolol (10 microM) was the only beta-adrenoceptor antagonist tested that inhibited [3H]thymidine incorporation, with effects of approximately 50 and 75% on basal and endothelin-1-mediated stimulation, respectively. In contrast, celiprolol (10 microM) produced significant stimulation of DNA synthesis (125% over basal). The calcium channel antagonist nifedipine (10 microM) inhibited basal and endothelin-1-mediated mitogenesis by 58 and 72%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Oscillation control of carbon nanotube mechanical resonator by electrostatic interaction induced retardation.
Despite the superb intrinsic properties of carbon nanotube mechanical resonators, the quality factors at room temperature are 1,000 or less, even in vacuum, which is much lower than that of mechanical resonators fabricated using a top-down approach. This study demonstrates the improvement of the quality factor and the control of nonlinearity of the mechanical resonance of the cantilevered nanotube by electrostatic interaction. The apparent quality factor of the nanotube supported by insulator is improved drastically from approximately 630 to 3200 at room temperature. Results show that retardation of the electrostatic force induced by the contact resistance between the nanotube and the insulator support improves the quality factor. Finite element method calculation reveals that the nonuniform pileup charge on the insulator support strongly influences the nonlinearity of the resonance.


Development of HANABI, an ultrasonication-forced amyloid fibril inducer.
Amyloid fibrils involved in amyloidoses are crystal-like aggregates, which are formed by breaking supersaturation of denatured proteins. Ultrasonication is an efficient method of agitation for breaking supersaturation and thus inducing amyloid fibrils. By combining an ultrasonicator and a microplate reader, we developed the HANABI (HANdai Amyloid Burst Inducer) system that enables high-throughput analysis of amyloid fibril formation. Among high-throughput approaches of amyloid fibril assays, the HANABI system has advantages in accelerating and detecting spontaneous amyloid fibril formation. HANABI is also powerful for amplifying a tiny amount of preformed amyloid fibrils by seeding. Thus, HANABI will contribute to creating therapeutic strategies against amyloidoses by identifying their biomarkers.


A new recombinant thrombolytic and antithrombotic agent with higher fibrin affinity--a staphylokinase variant. I. In vitro study.
We attempted to construct a new recombinant protein characterized by fibrin-specific properties of plasminogen activation combined with antithrombin and antiplatelet activities. To the C-terminal part of recombinant staphylokinase (r-SAK), which is a promising profibrinolytic agent, we assembled: (i) the Kringle 2 domain (K2) of tissue-type plasminogen activator (t-PA), containing a fibrin-specific binding site, (ii) the RGD sequence (Arg-Gly-Asp) for the prevention of platelet aggregation and (iii) the antithrombotic agent - hirudin. The cDNA for hybrid protein SAK-RGD-K2-Hir was cloned into pESP-3 yeast protein expression vector. The introduction of K2 t-PA, RGD sequence and hirudin into r-SAK molecule did not alter the SAK activity. The plasminogen activation rate (determined by K(M) and K(cat)) of SAK-RGD-K2-Hir was not significantly different from that of r-SAK. Affinity and binding strength of the recombinant protein to fibrin immobilized on the biosensor were higher than to r-SAK. We observed a higher clot lysis potency of SAK-RGD-K2-Hir as evidenced by a faster and more profound lysis of 125I-labeled human fibrin clots. The potency of thrombin inhibition by the hirudin part of the recombinant fusion protein SAK-RGD-K2-Hir was the same as that of r-Hir alone. In conclusion, the results of the in vitro study suggest that the SAK-RGD-K2-Hir construct can be a more potent and faster-acting thrombolytic agent with antithrombin and antiplatelet properties compared with standard r-SAK.


Whole-body vibration and resistance exercise prevent long-term hindlimb unloading-induced bone loss: independent and interactive effects.
Skeletal unloading induced by disuse or immobilization causes a decrease in bone mass and strength. We investigated the relationship between whole-body vibration (WBV) and resistance exercise (RE) in preventing bone loss induced by 8-week hindlimb unloading in young male rats. Sixty male Wistar rats were assigned randomly to 6 groups: age-matched control group (CON, n = 10), hindlimb unloading group (HU, n = 10), hindlimb unloading + standing group (HU + ST, n = 10), hindlimb unloading + WBV group (HU + WBV, n = 10), hindlimb unloading + RE group (HU + RE, n = 10) and hindlimb unloading + WBV + RE group (HU + WBV + RE, n = 10). After 8-week hindlimb unloading, micro-CT scanning and three-point bending test were performed in the femur. Sera were collected for analysis of bone formation and resorption markers. Compared with HU group, WBV, RE and the combination of WBV and RE (WBV + RE) significantly improved (P < 0.01) one repetition maximum (1RM) (expressed as the percentage change from baseline, HU: -23%, HU + WBV: 21%, HU + RE: 48%, HU + WBV + RE: 51%), and maintained (P < 0.05) cancellous volumetric bone mineral density (vBMD) and trabecular structure. No difference of cortical vBMD was found among all groups (P > 0.05). WBV had no effects on biomechanical properties of the femur diaphysis (P > 0.05). RE and WBV + RE significantly increased maximum load and cross-sectional moment of inertia of the femur diaphysis in hindlimb unloading rats (P < 0.05). There was an interaction between WBV and RE in improving cancellous bone. These results demonstrate that WBV and RE interactively maintain cancellous structure and vBMD, and independently partially mitigate the reduction of bone strength in long-term hindlimb unloading rats.


[Temporary henna tattoos: Sometimes serious side effects].
Temporary henna tattoos are becoming increasingly popular among Western tourists during summer holidays, especially children, teenagers and young adults. Natural henna takes several hours to be absorbed into the skin, imparts a brownish-orange color, and causes very few allergic reactions. Para-phenylenediamine (PPD), a powerful allergen, is added to henna tattoo mixtures (black henna tattoo) to decrease application time and intensify the color. It is responsible for most of the complications reported after henna tattoos: localized or generalized contact dermatitis, hypertrophic or keloid scars, and temporary or permanent hyper- or hypopigmentation. More rarely, type I hypersensitivity reactions (urticaria, angioedema, or anaphylaxis) with potentially lethal outcomes have been reported. PPD allergy can induce cross-reactivity with other substances, such as hair dyes and textile azo dyes. Patch testing for PPD must be performed at a very diluted concentration (0.01% in vaseline) to avoid unnecessarily strong reactions and sensitization to PPD. In the absence of any legal control of henna tattooing practices, prevention requires the annual provision of information to Western consumers, especially young people and their parents.


A cortical filter that learns to suppress the acoustic consequences of movement.
Sounds can arise from the environment and also predictably from many of our own movements, such as vocalizing, walking, or playing music. The capacity to anticipate these movement-related (reafferent) sounds and distinguish them from environmental sounds is essential for normal hearing1,2, but the neural circuits that learn to anticipate the often arbitrary and changeable sounds that result from our movements remain largely unknown. Here we developed an acoustic virtual reality (aVR) system in which a mouse learned to associate a novel sound with its locomotor movements, allowing us to identify the neural circuit mechanisms that learn to suppress reafferent sounds and to probe the behavioural consequences of this predictable sensorimotor experience. We found that aVR experience gradually and selectively suppressed auditory cortical responses to the reafferent frequency, in part by strengthening motor cortical activation of auditory cortical inhibitory neurons that respond to the reafferent tone. This plasticity is behaviourally adaptive, as aVR-experienced mice showed an enhanced ability to detect non-reafferent tones during movement. Together, these findings describe a dynamic sensory filter that involves motor cortical inputs to the auditory cortex that can be shaped by experience to selectively suppress the predictable acoustic consequences of movement.


Description of a "phoenix" phenomenon in the growth of Campylobacter jejuni at temperatures close to the minimum for growth.
When Campylobacter jejuni cultures that had been grown in broth at 39 degrees C were subcultured into fresh medium at 30 degrees C, there was a transient period of growth followed by a decline in viable-cell numbers before growth resumed once more. We propose that this complex behavior is the net effect of the growth of inoculum cells followed by a loss of viability due to oxidative stress and the subsequent emergence of a spontaneously arising mutant population that takes over the culture.


[Burkitt-like lymphoma: diagnosis, clinical features, and response to chemotherapy (author's transl)].
The Burkitt-like lymphoma is extremely rare. It shows a predominance of presentation in abdominal and pelvic sites and an older median age as compared to the endemic Burkitt's lymphoma. Both are independent prognostic determinants and reflect a poor prognosis. This might be the reason for the low response rate to cytotoxic treatment. Cyclophosphamide is a substantial part of any chemotherapeutic regimen used. Serum lactic dehydrogenase (LDH) levels are closely correlated with the extent of tumor mass and the response to therapy. Chemotherapy might be associated with serious metabolic complications including hyperkalemia, lactic acidosis, anuria, and sudden death from lethal embolization of the lung. In contrast to Burkitt's lymphoma, the Burkitt-like tumor has no association with the Epstein-Barr-virus. In both lymphomas a translocation from the 8q onto 14q chromosome occurs being a characteristic marker for these malignancies.


Nonparametric quantile estimation with correlated failure time data.
In biomedical studies, correlated failure time data arise often. Although point and confidence interval estimation for quantiles with independent censored failure time data have been extensively studied, estimation for quantiles with correlated failure time data has not been developed. In this article, we propose a nonparametric estimation method for quantiles with correlated failure time data. We derive the asymptotic properties of the quantile estimator and propose confidence interval estimators based on the bootstrap and kernel smoothing methods. Simulation studies are carried out to investigate the finite sample properties of the proposed estimators. Finally, we illustrate the proposed method with a data set from a study of patients with otitis media.


Development of local immunity: role in mechanisms of protection against or pathogenesis of respiratory syncytial viral infections.
The bronchus associated lymphoid tissue (BALT) and the precursor immunocompetent lymphoid cells in the nasopharynx, tonsils, and salivary glands represent the basic source of specific secretory IgA, other immunoglobulin, and T cell mediated specific immunity in the respiratory tract. The bulk of this immunologic reactivity is derived largely from BALT, and via the migration of antigen-sensitized immunocompetent cells, from the gut associated lymphoid tissues (GALT). Recent investigations have suggested that mechanisms underlying the development of virus-induced bronchopulmonary diseases, notably bronchospasm, include host factors such as altered immune response with persistent virus-specific IgE and IgG4 antibody responses in the respiratory tract, the appearance of specific immune complexes, and development of exaggerated immune response to other environmental agents and dietary proteins. In addition, pathogen related factors responsible for direct tissue damage during infection also play an important role.


Roles of Arenavirus Z Protein in Mediating Virion Budding, Viral Transcription-Inhibition and Interferon-Beta Suppression.
The smallest arenaviral protein is the zinc-finger protein (Z) that belongs to the RING finger protein family. Z serves as a main component required for virus budding from the membrane of the infected cells through self-oligomerization, a process that can be aided by the viral nucleoprotein (NP) to form the viral matrix of progeny virus particles. Z has also been shown to be essential for mediating viral transcriptional repression activity by locking the L polymerase onto the viral promoter in a catalytically inactive state, thus limiting viral replication. The Z protein has also recently been shown to inhibit the type I interferon-induction pathway by directly binding to the intracellular pathogen-sensor proteins RIG-I and MDA5, and thus inhibiting their normal functions. This chapter describes several assays used to examine the important roles of the arenaviral Z protein in mediating virus budding (i.e., either Z self-budding or NP-Z budding activities), viral transcriptional inhibition in a viral minigenome (MG) assay, and type I IFN suppression in an IFN-β promoter-mediated luciferase reporter assay.


Endomyocardial biopsy in the clinical context: current indications and challenging scenarios.
Endomyocardial biopsy (EMB) is an invasive procedure originally developed for the monitoring of heart transplant rejection. Over the year, this procedure has gained a fundamental complementary role in the diagnostic work-up of several cardiac disorders, including cardiomyopathies, myocarditis, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumours. Major advances in EMB equipment and techniques for histological analysis have significantly improved diagnostic accuracy of EMB. In recent years, advanced imaging modalities such as echocardiography with three-dimensional and myocardial strain analysis, cardiac magnetic resonance and bone scintigraphy have transformed the non-invasive approach to diagnosis and prognostic stratification of several cardiac diseases. Therefore, it emerges the need to re-define the current role of EMB for diagnostic work-up and management of cardiovascular diseases. The aim of this review is to summarize current knowledge on EMB in light of the most recent evidences and to discuss current indications, including challenging scenarios encountered in clinical practice.


The extended understanding of chronic granulomatous disease.
We briefly address the advances in genetics, pathophysiology, and phenotypes of chronic granulomatous disease (CGD). This is one of the most studied primary immunodeficiencies, which comprise mutations in genes encoding the different subunits of the NADPH oxidase system. Those mutations lead to defective reactive oxygen species production, and consequently a failure to eliminate pathogens. Patients with CGD are susceptible to fungal, bacterial, and parasitic infections. Other symptoms, as systemic adverse effects to BCG vaccine and hyperinflammation, are also important clinical conditions in this disease. This wide-ranging clinical spectrum of CGD comes from heterogeneity of mutations, X-linked-CGD or autosomal recessive inheritance, and diverse environmental pressure factors. Early accurate diagnosis and prompt treatment are necessary to diminish the consequences of the disease. The most used diagnostic tests are dihydrorhodamine, cytochrome c reduction, and luminol-enhanced chemiluminescence assay. The determination of mutations is essential for diagnosis confirmation and genetic counseling. CGD treatment usually includes prophylactic antibiotics and antifungals. Prophylactic recombinant human interferon-γ, immunosuppressors or immune modulators may be, respectively, indicated for preventing infections or inflammatory manifestations. Hematopoietic stem cell transplantation and gene therapy are currently the available options for curative treatment of CGD.


Ablation of ORMDL3 impairs adipose tissue thermogenesis and insulin sensitivity by increasing ceramide generation.
Genome-wide association studies identified ORMDL3 as an obesity-related gene, and its expression was negatively correlated with body mass index. However, the precise biological roles of ORMDL3 in obesity and lipid metabolism remain uncharacterized. Here, we investigate the function of ORMDL3 in adipose tissue thermogenesis and high fat diet (HFD)-induced insulin resistance. Ormdl3-deficient (Ormdl3-/-) mice were employed to delineate the function of ORMDL3 in brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. Glucose and lipid homeostasis in Ormdl3-/- mice fed a HFD were assessed. The lipid composition in adipose tissue was evaluated by mass spectrometry. Primary adipocytes in culture were used to determine the mechanism by which ORMDL3 regulates white adipose browning. BAT thermogenesis and WAT browning were significantly impaired in Ormdl3-/- mice upon cold exposure or administration with the β3 adrenergic agonist. In addition, compared to WT mice, Ormdl3-/- mice displayed increased weight gain and insulin resistance in response to HFD. The induction of uncoupling protein 1 (UCP1), a marker of thermogenesis, was attenuated in primary adipocytes derived from Ormdl3-/- mice. Importantly, ceramide levels were elevated in the adipose tissue of Ormdl3-/- mice. In addition, the reduction in thermogenesis and increase in body weight caused by Ormdl3 deficiency could be rescued by inhibiting the production of ceramides. Our findings suggest that ORMDL3 contributes to the regulation of BAT thermogenesis, WAT browning, and insulin resistance.


Effects of n-hexadecane and PM-100 clay on trichloroethylene degradation by Burkholderia cepacia.
Trichloroethylene (TCE) is a non-flammable, volatile organochlorine compound which was a widely used degreasing agent, anesthetic, and coolant prior to 1960, but has since been placed on the Environmental Protection Agency's (EPA) list of priority pollutants. The inadequate disposal practices for TCE have created numerous TCE-contaminated superfund sites. The most commonly employed practice for remediating TCE-contaminated sites is to purge the contaminant from the source and trap it onto an adsorbent which is disposed of in a landfill or by incineration. This investigation was undertaken to evaluate the effectiveness of Burkholderia cepacia strain G4 (G4) to regenerate used sorbents by degrading TCE from the sorbent directly or indirectly. The results of this investigation showed that G4 was capable of reducing TCE attached to PM-100 clay but at significantly reduced rate due to the slow desorption rate. Conversely, it was shown that G4 was capable of degrading TCE dissolved in n-hexadecane at the same rate as systems without n-hexadecane present. The reduction in TCE degradation when the TCE is attached to the PM-100 clay could be overcome by solvent rinsing the TCE from the clay with subsequent removal of the TCE from the n-hexadecane by G4.


Career prospects and professional landscape after advanced endoscopy fellowship training: a survey assessing graduates from 2009 to 2013.
The advanced endoscopy (AE) fellowship is a popular career track for graduating gastroenterology fellows. The number of fellows completing AE fellowships and the number of programs offering this training have increased in the past 5 years. Despite this, we suspect that the number of AE attending (staff physician) positions have decreased (relative to the number of fellows graduating), raising concerns regarding AE job market saturation. Our aim was to survey practicing gastroenterology physicians who completed an AE fellowship within the past 5 years regarding their current professional status. A 16-question survey was distributed using Research Electronic Data Capture by e-mail to practicing gastroenterologists who completed an AE fellowship between 2009 and 2013. The survey questions elicited information regarding demographics, professional status, and additional information. A total of 96 invitations were distributed via e-mail. Forty-one of 96 respondents (43%) replied to the survey. Approximately half of the respondents were employed in an academic practice, with the remainder in private practice (56% and 44%, respectively). Nearly half (46%) of the respondents found it "difficult" to find an AE position after training. Thirty-nine percent of private-practice endoscopists were performing > 200 ERCPs/year, whereas 65% were doing so in academic settings (P = .09). Fifty-six percent of respondents were in small practices (0 to 1 partner), with a significantly smaller group size in private versus academic practice (72% versus 43%, P = .021). Seventy-eight percent of respondents believed the AE job market was saturated; most responded that the AE job market was saturated in both academic and private practice (44%), whereas 34% believed the job market was saturated in academics only. Most respondents (73%) who were training AE fellows found it difficult to place them in AE attending positions. Respondents from academic practice found it significantly more difficult to balance work and personal life compared with those in private practice (87% versus 33%, respectively; P = .0004). This index survey highlights the trends related to the current state of the post-AE fellowship professional landscape. Further evaluation and discussion are needed to address these evolving issues in professional practice in the field of gastroenterology.


Streptococci from root canals in teeth with apical periodontitis receiving endodontic treatment.
The object of this study was to investigate the diversity among streptococcal species isolated from root canals in conjunction with endodontic therapy and to characterize their production of extracellular proteins. Consecutive root canal samples (RCS) taken as bacteriological controls during root canal treatment of teeth with apical periodontitis were analyzed in a total of 100 clinical cases. Bacteria were isolated and classified by selective media and gas liquid chromatography. Streptococcal strains were identified by carbohydrate fermentation, hydrolysis of aesculin/arginine, and production of enzymes. Releases of extracellular proteins by streptococci and Enterococcus spp in fluid culture media were examined with SDS-PAGE and 2-dimension gel electrophoresis (2 DE). Extracellular proteins produced were quantified and qualitatively analyzed. Specific proteins were targeted with Western immunoblot assays. Comparisons were made with type strains. Of a total of 241 bacterial strains recovered in the first samples submitted, Streptococcus gordonii, S anginosus, and S oralis were the most frequently isolated streptococci. In 49 of 89 resubmitted samples showing bacterial growth, S gordonii and S oralis still predominated among streptococci. Other common bacterial isolates were Enterococcus spp, Lactobacillus paracasei, and Olsenella uli. Quantitative and qualitative differences in extracellular protein production were observed among clinical isolates and laboratory streptococcal strains. In similar conditions for growth, S intermedius, S anginosus, S oralis, and S gordonii were strong producers of extracellular proteins (>3.0 microg/mL), while Enterococcus spp and S mutans were weak. Whole cell protein extracts showed a different profile from that of extracellular proteins. The chaperone protein DnaK was recognized to be produced extracellularly by S gordonii, S oralis, S anginosus, and S parasanguis. Being strong producers of extracellular proteins and by virtue of common presence in teeth undergoing endodontic therapy, S gordonii, S anginosus, and S oralis may be of pathogenic significance in posttreatment apical periodontitis.


Steroid enhancement of Mullerian duct regression.
The biologic activity of the glycoprotein, Mullerian Inhibiting Substance (MIS), was enhanced by added testosterone, medroxyprogesterone acetate, and progesterone, although these steroids did not cause Mullerian duct regression when added alone. Statistically significant augmentation by testosterone and medroxyprogesterone was observed at concentrations of 10(-7) and 10(-8) M. Progesterone enhanced MIS activity at a concentration of 10(-6) M. By contrast, dihydrotestosterone, estradiol, and corticosterone at concentrations of 10(-9) to 10(-5) M produced no significant effect on MIS activity. Since MIS does not bind directly to the steroids studied, we suspect that the enhancement effect occurs at the receptor level, probably at the mesenchyme as observed in other developmental systems.


The directional absorption properties of rhodopsin and its photoproducts.
The experimental data on the absorption of a plane polarised light by a solution of cattle rhodopsin at -196 degrees C have been theoretically analysed to model the directional absorption properties of rhodopsin and its photoproducts. It is seen that these molecules behave like planar absorbers having a ratio of about 100 : 7 between the extinction coefficients along the long axis and perpendicular to it. Using this result and the experimental observations on absorption and dichroism in the retina in situ, a model for the configuration of chromophores in the disc membranes has been derived. In this model the plane of the chromophore is perpendicular to that of the disc and the long axis of the chromophore makes an angle of 6.6 degrees with the plane of the disc. The solution of the problem depends on the assumption that the absorption axes are the same for the rhodopsin, prelumirhodopsin and isorhodopsin.


Diagnosis and staging of pancreatic neoplasms.
The relative value of current approaches to the diagnosis and staging of pancreatic cancer is discussed. A rational sequence of testing is recommended based on the clinical presentation of the patient and the local institutional expertise and facilities that are available.


Design and evaluation of a null lens for testing the optical performance of silicone intraocular lenses.
A two-element null lens, optimized for a 20-diopter silicone intraocular lens (IOL), was designed and tested. The performance of the null lens was examined for silicone IOL's with in situ powers from 16 to 24 diopters. Improvements in resolution, resolution efficiency, and modulation transfer function were obtained over the tested power range.


Insertable inductively coupled volumetric coils for MR microscopy in a human 7T MR system.
To demonstrate the capability of insertable inductively coupled volumetric coils for MR microscopy in a human 7T MR system. Insertable inductively coupled volume coils with diameters of 26 and 64 mm (D26 and D64 coils) targeted for monkey and mouse brain specimen sizes were designed and fabricated. These coils were placed inside the imaging volume of a transmit/receive knee coil without wired connections to the main system. Signal-to-noise ratio (SNR) evaluations were conducted with and without the insertable coils, and the g-factor maps of parallel imaging (PI) were also calculated for the D64 coil. Brain specimens were imaged using 3D T2∗ -weighted images with spatial resolution of isotropic 50 and 160 μm using D26 and D64 coils, respectively. Relative average (SD) SNRs compared with knee coil alone were 12.54 (0.30) and 2.37 (0.05) at the center for the D26 and D64 coils, respectively. The mean g-factors of PI with the D64 coil for the factor of 2 were less than 1.1 in the left-right and anterior-posterior directions, and around 1.5 in the superior-inferior direction or when the PI factor of 3 was used. Acceleration in two directions showed lower g-factors but suffered from intrinsic low SNR. Representative T2∗ -weighted images of the specimen showed structural details. Inductively coupled small diameter coils insertable to the knee coil demonstrated high SNR and modest PI capability. The concept was successfully used to visualize fine structures of the brain specimen. The insertable coils are easy to handle and enable MR microscopy in a human whole-body 7T MRI system.


On the in vitro fatigue behavior of human dentin: effect of mean stress.
Human dentin is susceptible to failure under repetitive cyclic-fatigue loading. This investigation seeks to address the paucity of data that reliably quantify this phenomenon. Specifically, the effect of alternating vs. mean stresses, characterized by the stress- or load-ratio R (ratio of minimum-to-maximum stress), was investigated for three R values (-1, 0.1, and 0.5). Dentin was observed to be prone to fatigue failure under cyclic stresses, with susceptibility varying, depending upon the stress level. The "stress-life" (S/N) data obtained are discussed in the context of constant-life diagrams for fatigue failure. The results provide the first fatigue data for human dentin under tension-compression loading and serve to map out safe and unsafe regimes for failure over a wide range of in vitro fatigue lives (< 10(3) to > 10(6) cycles).


Preclinical safety and efficacy of human CD34(+) cells transduced with lentiviral vector for the treatment of Wiskott-Aldrich syndrome.
Gene therapy with ex vivo-transduced hematopoietic stem/progenitor cells may represent a valid therapeutic option for monogenic immunohematological disorders such as Wiskott-Aldrich syndrome (WAS), a primary immunodeficiency associated with thrombocytopenia. We evaluated the preclinical safety and efficacy of human CD34(+) cells transduced with lentiviral vectors (LV) encoding WAS protein (WASp). We first set up and validated a transduction protocol for CD34(+) cells derived from bone marrow (BM) or mobilized peripheral blood (MPB) using a clinical grade, highly purified LV. Robust transduction of progenitor cells was obtained in normal donors and WAS patients' cells, without evidence of toxicity. To study biodistribution of human cells and exclude vector release in vivo, LV-transduced CD34(+) cells were transplanted in immunodeficient mice, showing a normal engraftment and differentiation ability towards transduced lymphoid and myeloid cells in hematopoietic tissues. Vector mobilization to host cells and transmission to germline cells of the LV were excluded by different molecular assays. Analysis of vector integrations showed polyclonal integration patterns in vitro and in human engrafted cells in vivo. In summary, this work establishes the preclinical safety and efficacy of human CD34(+) cells gene therapy for the treatment of WAS.


The SMILe integrated care model in allogeneic SteM cell TransplantatIon faciLitated by eHealth: a protocol for a hybrid effectiveness-implementation randomised controlled trial.
While effectiveness outcomes of eHealth-facilitated integrated care models (eICMs) in transplant and oncological populations are promising, implementing and sustaining them in real-world settings remain challenging. Allogeneic stem cell transplant (alloSCT) patients could benefit from an eICM to enhance health outcomes. To combat health deterioration, integrating chronic illness management, including continuous symptom and health behaviour monitoring, can shorten reaction times. We will test the 1st-year post-alloSCT effectiveness and evaluate bundled implementation strategies to support the implementation of a newly developed and adapted eICM in allogeneic stem cell transplantation facilitated by eHealth (SMILe-ICM). SMILe-ICM has been designed by combining implementation, behavioural, and computer science methods. Adaptions were guided by FRAME and FRAME-IS. It consists of four modules: 1) monitoring & follow-up; 2) infection prevention; 3) physical activity; and 4) medication adherence, delivered via eHealth and a care coordinator (an Advanced Practice Nurse). The implementation was supported by contextually adapted implementation strategies (e.g., creating new clinical teams, informing local opinion leaders). Using a hybrid effectiveness-implementation randomised controlled trial, we will include a consecutive sample of 80 adult alloSCT patients who were transplanted and followed by University Hospital Basel (Switzerland). Inclusion criteria are basic German proficiency; elementary computer literacy; internet access; and written informed consent. Patients will be excluded if their condition prevents the use of technology, or if they are followed up only at external centres. Patient-level (1:1) stratified randomisation into a usual care group and a SMILe-ICM group will take place 10 days pre-transplantation. To gauge the SMILe-ICM's effectiveness primary outcome (re-hospitalisation rate), secondary outcomes (healthcare utilization costs; length of inpatient re-hospitalizations, medication adherence; treatment and self-management burden; HRQoL; Graft-versus-Host Disease rate; survival; overall survival rate) and implementation outcomes (acceptability, appropriateness, feasibility, fidelity), we will use multi-method, multi-informant assessment (via questionnaires, interviews, electronic health record data, cost capture methods). The SMILe-ICM has major innovative potential for reengineering alloSCT follow-up care, particularly regarding short- and medium-term outcomes. Our dual focus on implementation and effectiveness will both inform optimization of the SMILe-ICM and provide insights regarding implementation strategies and pathway, understudied in eHealth-facilitated ICMs in chronically ill populations. ClinicalTrials.gov. Identifier: NCT04789863 . Registered April 01, 2021.


Diagnostic significance of urinary enzymes: development of a high performance liquid chromatographic method for the measurement of urinary lysozyme.
We describe a new high pressure liquid chromatography (HPLC) method for quantitative determination of urinary lysozyme. The method is simple, reproducible and with detection limit of 0.2 microgram. Before HPLC analysis the urine was purified using a Sep-Pak C18 cartridge. Lysozyme concentration was significantly higher in patients with chronic renal failure than in a control group (p less than 0.001). The concentration of lysozyme in urine is shown to be a sensitive indicator of renal damage.


Vaginal sonography and gender preference for sonographer.
The invasive nature of vaginal sonography, recently introduced as an improved diagnostic method for imaging the contents of the pregnant uterus, has provoked discussion about patient preference for female sonographers. This study examined whether patients had a gender preference for the sonographer who would conduct such an examination. Over 3 months, a written survey was given to pregnant women to complete anonymously while waiting for their scheduled sonographic examination. The survey covered gender preference for the sonographer and education, ethnicity, and previous experience with the procedure. Surveys were turned in by 1,002 pregnant women. Of the women whose survey responses were analyzed, 62% preferred a female sonographer. The principal reason given for this preference was comfort with the same gender. The majority of respondents were 25-40 years old, married, white, and multiparous. The level of education varied widely. These findings point to a need to seek consumer input when new technology is introduced, to provide women with choices where possible, and to ensure that they have access to information about those choices.


Association of Pain and Impact of Dual-Task Exercise on Function, Cognition and Quality of Life.
This study aimed to assess the factors associated with pain and evaluate the impact of dual-task exercise on pain improvement, quality of life (QOL), cognition and function in older adults. This study is a secondary data analysis of the HAPPY (Healthy Ageing Promotion Program for You) study. At risk older adults ≥ 60 years old were enrolled in a community dual-task exercise program. Assessments for frailty, sarcopenia, falls, quality of life (QOL) and perceived health, depression, cognition and physical function were performed at baseline and 3 months. Pain intensity was derived from EQ-5D and stratified into no pain, slight pain and moderate to extreme pain. Out of 296 participants, 37.2% had slight pain and 11.1% had moderate to severe pain. Both slight and moderate to extreme pain compared with no pain group were significantly associated with lower perceived health (68.2,63.6 vs 76.0) and QOL index (0.70,0.59 vs 0.93); moderate to extreme pain was also significantly associated with depression, low mental vitality, frailty, sarcopenia and poorer physical performance. After 3 months of dual-task exercise, pain improved in 70.8% of the moderate to extreme pain group and 50.8% of slight pain group. Significant improvement in perceived health, QOL, physical function and cognition were also observed. Proactive efforts are required to screen for pain and manage frailty, sarcopenia and depression. Dual-task exercise proved safe and possibly effective in reducing pain and improving QOL, physical and cognitive function in older adults. Prospective randomized studies are needed to validate the effectiveness of dual-task vs single-task exercise, including impact of reversal of frailty and sarcopenia in pain management.


The Value of the 8th Edition of American Joint Committee on Cancer Pathological Prognostic Staging on the Selection of Postmastectomy Radiotherapy for T1-2N1 Breast Cancer.
Patients diagnosed with pT1-2N1M0 breast cancer between 2008 and 2018 in West China Hospital, Sichuan University were included. Locoregional-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), breast cancer-specific survival (BCSS), and overall survival (OS) were defined as endpoints. The propensity score matching (PSM), receiver operating characteristic (ROC) curve, the Kaplan-Meier analysis, and the Cox multivariable model were used for data analysis. We identified 1,615 patients with T1-2N1M0 breast cancer, and 44.9% (n = 744) of them were treated with PMRT. With a median follow-up of 76 months, 46 (2.8%) recurrences, 96 (5.9%) deaths, and 80 (5.0%) breast cancer-related deaths occurred. The 5-year LRFS, DMFS, DFS, BCSS, and OS were 98.6%, 95.3%, 93.7%, 96.5%, and 96.0%, respectively. PMRT could not improve 5-year LRFS, DMFS, DFS, BCSS, and OS compared with non-PMRT neither before nor after PSM in the era of contemporary systemic treatment. ROC curve showed that the 8th pathological prognostic staging had better discriminative ability compared with the 7th anatomical staging [the area under the curve (AUC) 0.653 vs. 0.546, P < 0.001]. In the anatomical staging system, PMRT had comparable 5-year BCSS in comparison with non-PMRT both in stages IIA (97.4% vs. 96.8%, P = 0.799) and IIB (95.3% vs. 97.0%, P = 0.071). When stratified according to the pathological staging, PMRT was associated with better 5-year BCSS in stage IIB (97.1% vs. 90.7%, P = 0.039), while not in stages IA, IB, IIA, and IIIA. Multivariate analysis demonstrated that PMRT was a significantly protective factor for BCSS in stage IIB (HR 0.331, 95% CI: 0.100-0.967, P = 0.044). The new staging could better select high-risk patients with T1-2N1 breast cancer for radiotherapy compared with the 7th staging, and PMRT might be exempted except the 8th staging of IIB in the era of contemporary systemic therapy in this disease.


Band smearing of PCR amplified bacterial 16S rRNA genes: dependence on initial PCR target diversity.
Band smearing in agarose gels of PCR amplified bacterial 16S rRNA genes is understood to comprise amplicons of varying sizes arising from PCR errors, and requires elimination. We consider that with amplified heterogeneous DNA, delayed electro-migration is caused not by PCR errors but by dsDNA structures that arise from imperfect strand pairing. The extent of band smearing was found to be proportional to the sequence heterogeneity in 16S rRNA variable regions. Denaturing alkaline gels showed that all amplified DNA was of the correct size. A novel bioinformatic approach was used to reveal that band smearing occurred due to imperfectly paired strands of the amplified DNA. Since the smear is a structural fraction of the correct size PCR product, it carries important information on richness and diversity of the target DNA. For accurate analysis, the origin of the smear must first be identified before it is eliminated by examining the amplified DNA in denaturing alkaline gels.


Lymphangioma of the oesophagus. Diagnosis and treatment by endoscopic polypectomy.
Finding a lymphangioma in the upper digestive tract is a rather infrequent event. A case of a 64-year-old man is reported. Diagnosis was made in the course of an endoscopic oesophagogastroduodenal examination and tumor excision with a diathermy snare at the same time. Two years after resection there was no sign of recidivation of the tumor.


Interactive metagenomic visualization in a Web browser.
A critical output of metagenomic studies is the estimation of abundances of taxonomical or functional groups. The inherent uncertainty in assignments to these groups makes it important to consider both their hierarchical contexts and their prediction confidence. The current tools for visualizing metagenomic data, however, omit or distort quantitative hierarchical relationships and lack the facility for displaying secondary variables. Here we present Krona, a new visualization tool that allows intuitive exploration of relative abundances and confidences within the complex hierarchies of metagenomic classifications. Krona combines a variant of radial, space-filling displays with parametric coloring and interactive polar-coordinate zooming. The HTML5 and JavaScript implementation enables fully interactive charts that can be explored with any modern Web browser, without the need for installed software or plug-ins. This Web-based architecture also allows each chart to be an independent document, making them easy to share via e-mail or post to a standard Web server. To illustrate Krona's utility, we describe its application to various metagenomic data sets and its compatibility with popular metagenomic analysis tools. Krona is both a powerful metagenomic visualization tool and a demonstration of the potential of HTML5 for highly accessible bioinformatic visualizations. Its rich and interactive displays facilitate more informed interpretations of metagenomic analyses, while its implementation as a browser-based application makes it extremely portable and easily adopted into existing analysis packages. Both the Krona rendering code and conversion tools are freely available under a BSD open-source license, and available from: http://krona.sourceforge.net.


Positive surveillance blood culture is a predictive factor for secondary metastatic infection in patients with Staphylococcus aureus bacteraemia.
Staphylococcus aureus bacteraemia (SAB) may be complicated by secondary metastatic infection such as endocarditis, osteomyelitis or septic arthritis. This cohort study aimed to assess the prognostic value of sustained bacteraemia for outcomes related to Staphylococcus aureus bacteraemia. The study took place in three tertiary-care, university-affiliated hospitals. Patients were prospectively included if they agreed to participate and if the following data were available: (a). surveillance blood culture taken between 24 and 48 h after commencement of effective antibiotic therapy; (b). appropriate investigations (at least a TTE) performed as suggested by the infectious diseases consult service. Patients with sustained bacteraemia defined as persistent positive blood cultures more than 24 h after commencement of effective antibiotic therapy were compared to patients for whom the surveillance blood culture was negative. One hundred and four patients were enrolled, including 51 patients diagnosed with sustained bacteraemia. Sustained bacteraemia was significantly associated with a higher frequency of secondary metastatic infection (p<0.001) and with a higher frequency of CRP>100 mg/l. Frequency of acute complications due to infection, septic shock and death due to bacteraemia was higher for patients with sustained bacteraemia but this difference was not statistically significant. Using a Cox model, the risk for death associated with sustained SAB, controlling for Index of comorbidity and age (categorised as<or>or=70 years), was 1.2 (95% CI: (0.5, 3); p>0.05). In conclusion, surveillance blood cultures, especially performed on effective antibiotic therapy, may be a simple and cost-effective way to select a population at risk for secondary metastatic infection from SAB.


[Changes in the concentration of N-acetylneuraminic acid in the blood of patients with bladder cancer during radiotherapy].
The N-acetylneuraminic acid (N-ANA) concentration of serum in 24 patients with bladder carcinoma was measured with a modified Arzneibuch (D.L.) GDR-method before, during and after the postoperative radiotherapy. It was found that the N-ANA-concentrations in the patients operated resulted in a dependence from tumor staging already before the radiotherapy. The N-ANA concentration rose with increased staging. A temporary enhancement of the N-ANA-concentration with the maximum between 20. and 25 radiation fractions occurred in patients of staging T3 and relapses as well as with tumor cells being only little differentiated. The results are discussed in relation to the clinical importance.


Conserved tRNA gene cluster in starfish mitochondrial DNA.
Partial sequencing of mtDNA from four long-diverged species of starfish reveals the existence of a conserved cluster of 13 tRNA genes, organized in a manner similar to that of the tRNA cluster of sea urchin mtDNA, but located at a position distant from the presumed replication origin. These findings suggest that a clustered organization of tRNA genes may have been present in the ancestral mitochondrial genome, and raise the possibility that tRNAs may have catalyzed the dispersal rather than the accumulation of the genes which encode them.


Isolation and characterization of enterocin EJ97, a bacteriocin produced by Enterococcus faecalis EJ97.
The bacteriocinogenic strain of Enterococcus faecalis EJ97 has been isolated from municipal waste water. It produces a cationic bacteriocin (enterocin EJ97) of low molecular mass (5,340 Da) that is very stable under mild heat conditions and is sensitive to proteolytic enzymes. The amino acid sequence of the first 18 N-terminal residues of enterocin EJ97 indicates that it is different from other known protein sequences. Enterocin EJ97 is active on several gram-positive bacteria including enterococci, several species of Bacillus, Listeria, and Staphylococcus aureus. The producer strain is immune to bacteriocin. Enterocin EJ97 has a concentration-dependent bactericidal and bacteriolytic effect on E. faecalis S-47.


Long-term memory is maintained by continuous activity of Arp2/3 in lateral amygdala.
Evidence indicates that long-term memory formation involves alterations in synaptic efficacy produced by modifications in neural transmission and morphology. However, it is not clear how such changes induced by learning, that encode memory, are maintained over long period of time to preserve long-term memory. It has been shown that the actin nucleating protein Arp2/3 is essential for supporting neuronal morphology and synaptic transmission. We therefore hypothesized that continuous Arp2/3 activity is needed to maintain long-term memory over time. To test this hypothesis we microinjected into lateral amygdala (LA) of rats CK-666, a specific inhibitor of Arp2/3, two days after fear conditioning and tested the effect on long-term fear memory maintenance a day afterward. We found that injection of CK-666 two days after training abolished fear conditioning memory. Fear conditioning could be formed when a control compound CK-689 was applied two days after training. Microinjection of CK-666 a day before fear conditioning training had no effect on fear conditioning learning and long-term memory formation. We revealed that Arp2/3 is also needed to maintain long-term conditioned taste aversion (CTA) memory in LA. Microinjection of CK-666 two days after CTA training impaired long-term memory tested a day afterwards. We conclude that continuous activity of Arp2/3 in LA is essential for the maintenance of long-term memory.