"Health Psychology adopts Transparency and Openness Promotion (TOP) Guidelines": Correction to Freedland (2021).
Reports an error in "Health Psychology adopts Transparency and Openness Promotion (TOP) Guidelines" by Kenneth E. Freedland (Health Psychology, 2021[Apr], Vol 40[4], 227-229). In the article, the TOP levels were mislabeled throughout. Level 2 should have been Level 1, and Level 1 should have been Level 2. The online version of this article has been corrected. (The following abstract of the original article appeared in record 2021-35537-001.) The Editors are pleased to announce that Health Psychology has adopted the Transparency and Openness Promotion (TOP) Guidelines (Center for Open Science, 2021). We and the other core American Psychological Association (APA) journals are implementing these guidelines at the direction of the APA Publications and Communications Board. Their decision was made with the support of the APA Council of Editors and the APA Open Science and Methodology Committee. The TOP Guidelines were originally published in Science (Nosek et al. 2015) to encourage journals to incentivize open research practices. They are being implemented by a wide range of scientific publications, including some of the leading behavioral and medical research journals. The TOP guidelines for Health Psychology are outlined in our recently revised Instructions to Authors. We are implementing most of the standards at TOP Level 1, which means that adherence is required. We are implementing other standards at Level 2, which means that authors are encouraged to adhere to them and required to disclose whether and how they have done so. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Identification of novel inhibitors of dietary lipid absorption using zebrafish.
Pharmacological inhibition of dietary lipid absorption induces favorable changes in serum lipoprotein levels in patients that are at risk for cardiovascular disease and is considered an adjuvant or alternative treatment with HMG-CoA reductase inhibitors (statins). Here we demonstrate the feasibility of identifying novel inhibitors of intestinal lipid absorption using the zebrafish system. A pilot screen of an unbiased chemical library identified novel compounds that inhibited processing of fluorescent lipid analogues in live zebrafish larvae. Secondary assays identified those compounds suitable for testing in mammals and provided insight into mechanism of action, which for several compounds could be distinguished from ezetimibe, a drug used to inhibit cholesterol absorption in humans that broadly inhibited lipid absorption in zebrafish larvae. These findings support the utility of zebrafish screening assays to identify novel compounds that target complex physiological processes.


Late mortality in survivors of autologous hematopoietic-cell transplantation: report from the Bone Marrow Transplant Survivor Study.
We assessed late mortality in 854 individuals who had survived 2 or more years after autologous hematopoietic cell transplantation (HCT) for hematologic malignancies. Median age at HCT was 36.5 years, and median length of follow-up was 7.6 years. Overall survival was 68.8% +/- 1.8% at 10 years, and the cohort was at a 13-fold increased risk for late death (standardized mortality ratio [SMR] = 13.0) when compared with the general population. Mortality rates approached those of the general population after 10 years among patients at standard risk for relapse at HCT (SMR = 1.1) and in patients undergoing transplantation for acute myeloid leukemia (AML; SMR = 0.9). Relapse of primary disease (56%) and subsequent malignancies (25%) were leading causes of late death. Relapse-related mortality was increased among patients with Hodgkin disease (HD; relative risk [RR] = 3.6), non-Hodgkin lymphoma (NHL; RR = 2.1), and acute lymphoblastic leukemia (ALL; RR = 6.5). Total body irradiation (RR = 0.6) provided a protective effect. Nonrelapse-related mortality was increased after carmustine (RR = 2.3) and with use of peripheral blood stem cells (RR = 2.4). Survivors were more likely to report difficulty in holding jobs (RR = 9.4) and in obtaining health (RR = 7.7) or life insurance (RR = 8.4) when compared with siblings. Although mortality rates approach that of the general population after 10 years in certain subgroups, long-term survivors of autologous HCT continue to face challenges affecting their health and well-being.


Positional therapy for obstructive sleep apnoea.
The modalities of therapy for obstructive sleep apnoea (OSA) include behavioural and lifestyle modifications, positional therapy, oral appliances, surgery and continuous positive airway pressure therapy (CPAP). Though CPAP has proven efficacy in treating OSA, adherence with CPAP therapy is suboptimal. Positional therapy (to keep people sleeping on their side) is less invasive and therefore expected to have better adherence. This review considered the efficacy of positional therapy compared to CPAP as well as positional therapy against no positional therapy. Devices designed for positional therapy include lumbar or abdominal binders, semi-rigid backpacks, full-length pillows, a tennis ball attached to the back of nightwear, and electrical sensors with alarms that indicate change in position. To compare the efficacy of positional therapy versus CPAP and positional therapy versus inactive control (sham intervention or no positional therapy intervention) in people with OSA. We identified studies from the Cochrane Airways' Specialised Register (including CENTRAL, MEDLINE, Embase, CINAHL, AHMED and PsycINFO), ClinicalTrials.gov, and the World Health Organization trials portal (ICTRP). It also contains results derived from handsearching of respiratory journals and abstract books of major annual meetings. We searched all databases from their inception to September 2018, with no restrictions on language of publication or publication type. We included randomised controlled trials comparing positional therapy with CPAP and positional therapy with inactive control. Two review authors independently selected studies and extracted the data. We used a random-effects model in the meta-analysis to estimate mean differences and confidence intervals. We assessed certainty of evidence using the GRADE approach. We included eight studies. The studies randomised 323 participants into two types of interventions. The comparison between positional therapy and CPAP included 72 participants, while the comparison between positional therapy and inactive control included 251 participants. Three studies used supine vibration alarm devices, while five studies used physical positioning like specially designed pillows or semirigid backpacks.Positional therapy versus CPAPThe three studies included for this comparison were randomised cross-over trials. Two studies found that there was no difference in Epworth Sleepiness Scale (ESS) scores between CPAP and positional therapy. Two studies showed that CPAP produced a greater reduction in Apnoea-Hypopnoea Index (AHI) with a mean difference (MD) of 6.4 events per hour (95% CI 3.00 to 9.79; low-certainty evidence) compared to positional therapy. Subjective adherence, evaluated in one study, was found to be significantly greater with positional therapy (MD 2.5 hours per night, 95% CI 1.41 to 3.59; moderate-certainty evidence).In terms of secondary outcomes, one study each reported quality-of-life indices and quality-of-sleep indices with no significant difference between the two groups. One study reported cognitive outcomes using multiple parameters and found no difference between the groups. There were insufficient data to comment on other secondary outcomes like respiratory disturbance index (RDI), and frequency and duration of nocturnal desaturation. None of the studies clearly reported adverse effects.Positional therapy versus inactive controlThree studies of positional therapy versus no intervention were randomised cross-over trials, while two studies were parallel-arm studies. Data from two studies showed that positional therapy significantly improved ESS scores (MD -1.58, 95% CI -2.89 to -0.29; moderate-certainty evidence). Positional therapy showed a reduction in AHI compared with control (MD -7.38 events per hour, 95% CI -10.06 to -4.7; low-certainty evidence). One study reported adherence. The number of participants who continued to use the device at two months was no different between the two groups (odds ratio (OR) 0.80, 95% CI 0.33 to 1.94; low-certainty evidence). The same study reported adverse effects, the most common being pain in the back and chest, and sleep disturbance but there was no significant difference between the two groups in terms of device discontinuation (OR 1.25, 95% CI 0.5 to 3.03; low-certainty evidence). One study each reported quality-of-life indices and quality-of-sleep indices, with no significant difference between the two groups. One study reported cognitive outcome, and found no difference between the groups. There was insufficient evidence to comment on other secondary outcomes (RDI, frequency and duration of nocturnal desaturation). The review found that CPAP has a greater effect on improving AHI compared with positional therapy in positional OSA, while positional therapy was better than inactive control for improving ESS and AHI. Positional therapy may have better adherence than CPAP. There were no significant differences for other clinically relevant outcomes such as quality of life or cognitive function. All the studies were of short duration. We are unable to comment on the long-term effects of the therapies. This is important, as most of the quality-of-life outcomes will be evident only when the therapies are given over a longer period of time. The certainty of evidence was low to moderate.


Inter- and intra-observer variability in contouring of the prostate gland on planning computed tomography and cone beam computed tomography.
To investigate inter-/intra-observer variability in defining the prostate by use of planning computed tomography (PCT) and cone beam CT (CBCT) with magnetic resonance image (MRI) as guidance prior to the introduction of an adaptive radiotherapy for prostate cancer. We reviewed PCT and firstly acquired CBCT datasets of each ten patients with prostate cancer. Three physicians independently delineated the prostate based on PCT and CBCT with MRI as guidance, allowing determination of inter-physician variability. Two physicians repeated prostate contouring three times in total to investigate intra-physician variability. We compared delineated prostate volumes in terms of the generalized conformity index (CI(gen)), maximum variation ratio (MVR), and center of mass (COM). There were no significant inter-/intra-observer differences in the estimation of prostate volume on both PCT and CBCT. For both inter- and intra-observer variability in contouring the prostate gland, there were no significant differences in MVR between PCT and CBCT. The CI(gen) for inter-observer variability was 0.74 by PCT and 0.69 by CBCT. The CI(gen) for intra-observer variability on PCT and CBCT was 0.84 and 0.81 for observer 2 and 0.76 and 0.73 for observer 3. COM analyses showed that the greatest inter-/intra-observer variability was in the measurement of the prostate apex and base. With respect to CI(gen) and COM analysis for the inter-observer variability, more precise delineation of the prostate was possible on PCT than CBCT. More precise contouring in terms of both CI(gen) and COM was demonstrated by observer 2 than observer 3. Despite some ambiguity in apex and base level, there was a good consistency in delineating the gland on CBCT plus MRI-guided modification both among/within observer(s), without any significant difference from the consistency in defining the prostate on PCT. This study provides a framework for future studies of CBCT imaging of the prostate.


HIV prevalence, testing and treatment among men who have sex with men through engagement in virtual sexual networks in Kenya: a cross-sectional bio-behavioural study.
In Kenya, men who have sex with men (MSM) are increasingly using virtual sites, including web-based apps, to meet sex partners. We examined HIV testing, HIV prevalence, awareness of HIV-positive status and linkage to antiretroviral therapy (ART), for HIV-positive MSM who solely met partners via physical sites (PMSM), compared with those who did so in virtual sites (either solely via virtual sites (VMSM), or via both virtual and physical sites (DMSM)). We conducted a cross-sectional bio-behavioural survey of 1200 MSM, 15 years and above, in three counties in Kenya between May and July 2019, using random sampling of physical and virtual sites. We classified participants as PMSM, DMSM and VMSM, based on where they met sex partners, and compared the following between groups using chi-square tests: (i) proportion tested; (ii) HIV prevalence and (iii) HIV care continuum among MSM living with HIV. We then performed multivariable logistic regression to measure independent associations between network engagement and HIV status. 177 (14.7%), 768 (64.0%) and 255 (21.2%), of participants were classified as PMSM, DMSM and VMSM respectively. 68.4%, 70.4% and 78.5% of PMSM, DMSM and VMSM, respectively, reported an HIV test in the previous six months. HIV prevalence was 8.5% (PMSM), 15.4% (DMSM) and 26.7% (VMSM), p < 0.001. Among those living with HIV, 46.7% (PMSM), 41.5% (DMSM) and 29.4% (VMSM) were diagnosed and aware of their status; and 40.0%, 35.6% and 26.5% were on antiretroviral treatment. After adjustment for other predictors, MSM engaged in virtual networks remained at a two to threefold higher risk of prevalent HIV: VMSM versus PMSM (adjusted odds ratio 3.88 (95% confidence interval (CI) 1.84 to 8.17) p < 0.001); DMSM versus PMSM (2.00 (95% CI 1.03 to 3.87), p = 0.040). Engagement in virtual networks is associated with elevated HIV risk, irrespective of individual-level risk factors. Understanding the difference in characteristics among MSM-seeking partners in different sites will help HIV programmes to develop subpopulation-specific interventions.


Revisions to the TNM Staging of Lung Cancer: Rationale, Significance, and Clinical Application.
Lung cancer remains the leading cause of cancer-related mortality worldwide. To formulate effective treatment strategies and optimize patient outcomes, accurate staging is essential. Lung cancer staging has traditionally relied on a TNM staging system, for which the International Association for the Study of Lung Cancer (IASLC) has recently proposed changes. The revised classification for this eighth edition of the TNM staging system (TNM-8) is based on detailed analysis of a new large international database of lung cancer cases assembled by the IASLC for the purposes of this project. Fundamental changes incorporated into TNM-8 include (a) modifications to the T classification on the basis of 1-cm increments in tumor size; (b) grouping of lung cancers that result in partial or complete lung atelectasis or pneumonitis; (c) grouping of tumors with involvement of a main bronchus irrespective of distance from the carina; (d) reassignment of diaphragmatic invasion in terms of T classification; (e) elimination of mediastinal pleural invasion from the T classification; and (f) subdivision of the M classification into different descriptors on the basis of the number and site of extrathoracic metastases. In response to these revisions, established stage groups have been modified, and others have been created. In addition, recommendations for classifying patterns of disease that result in multiple sites of pulmonary involvement, including multiple primary lung cancers, lung cancers with separate tumor nodules, multiple ground-glass/lepidic lesions, and consolidation, as well as recommendations for lesion measurement, are addressed. Understanding the key revisions introduced in TNM-8 allows radiologists to accurately stage patients with lung cancer and optimize therapy. ©RSNA, 2018.


Systematic prospective electrophysiological studies of the median nerve after simple distal radius fracture.
To assess whether there is a measurable impairment of median nerve conduction study parameters with uncomplicated distal radius fracture. Patients were assessed prospectively at the time of cast removal (visit 1) after a standard 6-8 week immobilization for uncomplicated distal radius fracture. Patients with prior entrapment neuropathy or polyneuropathy were excluded. Patients were asked to report sensory symptoms. Median and ulnar motor and sensory conduction studies were performed bilaterally, as well as transcarpal stimulation. All electrophysiologic studies were repeated at a follow-up visit 2, on average 7.8 weeks later. 39 patients were assessed at visit 1 and 30 (77%) were available for follow-up visit 2. Paresthesia in the median territory on the fractured side were reported in 20% at visit 1 and 26% at visit 2. Electrophysiological evidence of only mild carpal tunnel syndrome was found on the fractured side in 4/39 at visit 1 and 6/30 at visit 2. There were only 2 cases of moderate-marked median neuropathy, both asymptomatic and on the unfractured side. Median motor and sensory latencies and amplitudes did not show statistically significant differences between fractured and unfractured sides with the single exception of median distal motor latency at visit 1. Median territory paresthesia at the time of cast removal following distal radius fracture are often not associated with electrophysiologic evidence of median neuropathy. Most median nerve electrophysiologic parameters do not significantly differ between the fractured and uninjured sides. Significant traumatic median neuropathy is not likely to be a frequent manifestation of uncomplicated distal radius fracture. Diagnostic analysis, Level III.


Increased detection rate of glaucomatous visual field damage with locally condensed grids: a comparison between fundus-oriented perimetry and conventional visual field examination.
To compare detection rates of glaucomatous visual field defects (VFDs) between the conventional 6 degrees x 6 degrees stimulus grid and locally condensed target arrangements in morphologically suspicious regions. A total of 66 eyes of 66 patients with glaucoma or patients suspected of having glaucoma (34 females and 32 males; age range, 14-85 years) were enrolled in this study. Individual, local target condensation was realized by fundus-oriented perimetry (FOP) using a campimeter and compared with the results of conventional automated perimetry (CAP), obtained with the Humphrey Field Analyzer (30-2 grid). Twenty-three of the 66 patients showed normal findings with both methods; 27 had concordantly pathological results. In 15 patients we obtained normal findings with CAP, whereas FOP revealed early glaucomatous VFDs. Only one patient showed VFDs with CAP, whereas FOP results were normal. Scotoma detection rates significantly differed between the 2 methods (P<.001, sign test). Test duration with FOP was more than doubled compared with CAP. When considering only FOP points coinciding with the 6 degrees spacing of the 30-2 grid, there was no longer a significant difference between FOP and CAP (P>.25, sign test). This indicated that the target pattern, rather than the perimetric device, was most relevant for detecting glaucomatous VFDs. Follow-up throughout a series of 3 subsequent sessions at 6-month intervals revealed repeatable results in more than two thirds of all eyes for both FOP and CAP. Fundus-oriented perimetry that uses individually condensed test grids significantly increases the detection rate of glaucomatous VFDs in morphologically conspicuous areas compared with CAP using equidistant (6 degrees x 6 degrees) target arrangements. Repeatability is comparable between both methods.


Epidemiological evidence on the carcinogenic risk of air pollution.
In summary, higher lung cancer morbidity and mortality in urban than in rural areas and the presence of carcinogens in polluted air suggest that smoking habits and specific occupational exposures cannot account for all the urban air pollution may play a role in this disease. Surveys of lung cancer have shown that differences in excess. Positive correlations between lung cancer death rates and indices of pollution in different places, the experience of migrants and a possibile decline in lung cancer mortality with decline in pollution provide support for the view that air pollution is a factor in this disease. But the effect of pollution cannot be large. It is likely to be a small fraction (possibly a tenth) of the effect of cigarette smoking.


Utility of the Paris System in Reporting Urine Cytology.
To find out the utility of The Paris System (TPS) in reporting urine cytology and to compare it with the reporting system currently used in our laboratory. This retrospective study was undertaken over a period of 1 year during which slides of all the urine specimens sent for cytological examination were retrieved from our laboratory filling system. They were blindly reviewed and reclassified according to TPS. Surgical follow-up was obtained from the uropathology services of our department. A total of 176 cases were meticulously reviewed. The mean age of the patients was 52 years, and 71% of cases presented with hematuria. Histopathological follow-up was available in 34 cases. Reporting by TPS detected 13.0% high-grade urothelial carcinoma (HGUC) and 5.1% atypical urothelial cells versus 7.3 and 11.9% by the current reporting system, respectively. The sensitivity and diagnostic accuracy for detecting HGUC of TPS were higher than those of our reporting system. TPS has increased the rate of detection of HGUC and reduced the rate of reporting "atypical" urothelial cells. TPS has also standardized the diagnostic criteria, thereby bringing uniformity and reproducibility into the system of reporting for urine cytology.


Signaling pathways mediating anti-apoptotic action of neurotrophins.
Neurotrophins promote survival and suppress apoptosis in many populations of neurons. Currently, phosphatidylinositol-3 kinase (PI-3K) is recognized as the main mediator of this protective effect. However, most of the data collected so far on the anti-apoptotic signaling of neurotrophins were obtained using trophic withdrawal paradigms. Recent data from our and other groups indicate that extracellular-signal-regulated kinase 1/2 (Erk 1/2) may play a critical role in suppressing neuronal apoptosis triggered by cellular damage. Thus, it appears that either Erk1/2 or PI-3K, depending on the nature of the death-inducing stimulus, can mediate anti-apoptotic signaling of neurotrophins. In this review, we discuss the contribution of Erk1/2 and PI-3K to neuroprotection by neurotrophins. We also present data suggesting possible mechanisms by which these pathways might suppress neuronal death.


Susceptibility of Helicobacter pylori to metronidazole.
The reliability of the Epsilometer-test (E-Test) and the disk diffusion (DD) method in the assessment of susceptibility of Helicobacter pylori (H. pylori) to metronidazole has recently been questioned, with possible clinical implications for the management of patients undergoing H. pylori eradication. The aims of this study were: 1) to compare the E-Test and disk diffusion methods to the agar dilution method for determining the susceptibility of H. pylori to metronidazole; and 2) to investigate whether potential discrepancies could be caused by the simultaneous presence of metronidazole susceptible and metronidazole resistant bacterial subpopulations. A total of 109 H. pylori strains from 121 consecutive patients were examined. All tests were carried out at the same time starting from primary plates. Agar dilution was performed according to National Committee for Clinical Laboratory Standard (NCCLS) standards, the E-Test according to the manufacturer's guidelines, and disk diffusion according to standard procedure using 5-mug metronidazole disks. Isolates were considered to be metronidazole resistant if the minimal inhibitory concentration was >8 mug/ml for the agar dilution and the E-Test, or if the inhibition zone around the disk was <20 mm for disk diffusion. Of 109 isolates, 43 were also investigated to detect mixed infection. Quantities of 100 mul of bacterial suspensions of each strain were seeded onto plain agar plates and plates containing 8 mug/ml of metronidazole. Cultures were considered to be mixed if the number of colonies on agar plates exceeded by at least 30% those on the metronidazole plates. According to agar dilution, 57 strains (52.3%, 95% CI = 43-61.4) were metronidazole resistant. E-Test misdiagnosed two strains that were considered sensitive to metronidazole, but according to the agar dilution test they were resistant. Disk diffusion misdiagnosed three strains. Two of these strains (the same as the E-Test) were sensitive, but according to agar dilution they were metronidazole resistant; the third strain was resistant, but according to agar dilution it was sensitive. The percentages of discordance were 1.9 (95% CI = 0.5-6.6) and 2.8 (95% CI = 0.9-7.8), respectively, when the E-Test and disk diffusion were compared to agar dilution. Intertest variability among agar dilution and the E-Test showed that 39.4% (95% CI = 30.8-48.8) of minimal inhibitory concentrations were equivalent (within +/-1 log(2)), 60.6% (95% CI = 51.2-69.2) were major errors (more than +/-1 log(2)), and 3% (95% CI = 0.8-10.4) were very major errors (change in susceptibility pattern). Mixed infection was found in six of the 43 cases examined (13.9%). In four cases, metronidazole resistant strains were 1 log(10) less numerous than those that were metronidazole susceptible. In the remaining two cases, the metronidazole resistant strains were 2-3 log(10) less numerous, which caused the two misdiagnoses. The E-Test and disk diffusion method are very good alternatives to agar dilution. Mixed infections are a possible cause of the discrepancies between these tests and the reference method.


Extension of useful reagent shelf life beyond manufacturers' recommendations. Cell Markers Committee of the College of American Pathologists.
The College of American Pathologists Cell Markers Committee designed a study to evaluate the use of immunohistochemistry primary antibodies beyond manufacturers' recommended dates. Pathologists were asked to save aliquots of primary antibodies during mid-1997 so that by spring 1998 the reagents would be "outdated" according to manufacturers' recommendations. Three tumors were immunostained both in mid-1997 and early 1998 (using outdated reagents in 1998). Two hundred twenty-one laboratories participated. Immunostained materials consisted of an angiomyolipoma immunostained for muscle-specific actin and HMB-45, a melanoma immunostained for S100 protein and HMB-45, and a large cell lymphoma immunostained for common leukocyte antigen and HMB-45. Blocks from the same tumor were used in each instance. We compared the immunostaining results as a percentage of laboratories indicating a positive or negative immunohistochemical result between the 1997 and 1998 time points. Only minor differences were identified for the 221 reporting laboratories in 1998 as compared with those in 1997. The data suggest review of the Health Care Financing Administration's ruling on extending the useful reagent shelf life beyond manufacturers recommendations. Similar studies using more inherently quantitative methodology are suggested.


Adiposity in relation to vitamin D status and parathyroid hormone levels: a population-based study in older men and women.
In small case-control studies, obesity was associated with worse vitamin D status. Our aim was to assess the association of adiposity (anthropometric measures as well as dual energy x-ray absorptiometry) with serum 25-hydroxyvitamin D (25-OH-D) and serum PTH levels in a large population-based study including older men and women. Subjects were participants of the Longitudinal Aging Study Amsterdam and were aged 65 yr and older. In 453 participants, serum 25-OH-D and PTH were determined, and body mass index, waist circumference, waist to hip ratio, sum of skin folds, and total body fat percentage by dual energy x-ray absorptiometry were measured. After adjustment for potential confounders, higher body mass index, waist circumference, and sum of skin folds were statistically significantly associated with lower 25-OH-D (standardized beta values were -0.136, -0.137, and -0.140, respectively; all P < 0.05) and with higher PTH (0.166, 0.113, and 0.114, respectively; all P < 0.05). Total body fat percentage was more strongly associated with 25-OH-D and PTH (-0.261 and 0.287, respectively; both P < 0.001) compared with anthropometric measures. Total body fat percentage remained associated with 25-OH-D after adjustment for PTH, and with PTH after adjustment for 25-OH-D. Precisely measured total body fat is inversely associated with 25-OH-D levels and is positively associated with PTH levels. The associations were weaker if anthropometric measures were used, indicating a specific role of adipose tissue. Regardless of the possible underlying mechanisms, it may be relevant to take adiposity into account when assessing vitamin D requirements.


Clinical drug response prediction from preclinical cancer cell lines by logistic matrix factorization approach.
Predicting tumor drug response using cancer cell line drug response values for a large number of anti-cancer drugs is a significant challenge in personalized medicine. Predicting patient response to drugs from data obtained from preclinical models is made easier by the availability of different knowledge on cell lines and drugs. This paper proposes the TCLMF method, a predictive model for predicting drug response in tumor samples that was trained on preclinical samples and is based on the logistic matrix factorization approach. The TCLMF model is designed based on gene expression profiles, tissue type information, the chemical structure of drugs and drug sensitivity (IC 50) data from cancer cell lines. We use preclinical data from the Genomics of Drug Sensitivity in Cancer dataset (GDSC) to train the proposed drug response model, which we then use to predict drug sensitivity of samples from the Cancer Genome Atlas (TCGA) dataset. The TCLMF approach focuses on identifying successful features of cell lines and drugs in order to calculate the probability of the tumor samples being sensitive to drugs. The closest cell line neighbours for each tumor sample are calculated using a description of similarity between tumor samples and cell lines in this study. The drug response for a new tumor is then calculated by averaging the low-rank features obtained from its neighboring cell lines. We compare the results of the TCLMF model with the results of the previously proposed methods using two databases and two approaches to test the model's performance. In the first approach, 12 drugs with enough known clinical drug response, considered in previous methods, are studied. For 7 drugs out of 12, the TCLMF can significantly distinguish between patients that are resistance to these drugs and the patients that are sensitive to them. These approaches are converted to classification models using a threshold in the second approach, and the results are compared. The results demonstrate that the TCLMF method provides accurate predictions across the results of the other algorithms. Finally, we accurately classify tumor tissue type using the latent vectors obtained from TCLMF's logistic matrix factorization process. These findings demonstrate that the TCLMF approach produces effective latent vectors for tumor samples. The source code of the TCLMF method is available in https://github.com/emdadi/TCLMF.


Titration of AAV-2 particles via a novel capsid ELISA: packaging of genomes can limit production of recombinant AAV-2.
We demonstrate the rapid and reliable quantification of physical AAV-2 (adeno-associated virus type 2) particles via a novel ELISA based on a monoclonal antibody which selectively recognizes assembled AAV-2 capsids. Titration of a variety of recombinant AAV-2 (rAAV) preparations revealed that at least 80+percent of all particles were empty, compared with a maximum of 50percent in wild-type AAV-2 stocks, indicating that the recombinant genomes were less efficiently encapsidated. This finding was confirmed upon titration of CsCl gradient fractions from recombinant and wild-type AAV-2 stocks. ELISA-based measurement of capsid numbers revealed a large number of physical particles with low densities corresponding to empty capsids in the recombinant, but not in the wild-type AAV-2 preparations. Moreover, additional expression of VP proteins during rAAV production was found to result in an excessive capsid formation, whilst yielding only minor increases in DNA-containing or transducing rAAV particles. We conclude that encapsidation of viral genomes rather than capsid assembly can be limiting for rAAV production, provided that a critical level of VP expression is maintained. The feasibility of quantifying AAV-2 capsid numbers via the ELISA allows determination of physical to DNA-containing or infectious particle ratios. These are important parameters which should help to optimize and standardize the production and application of recombinant AAV-2.


Production of prostaglandins E2 and F2 alpha in the freshwater mussel Ligumia subrostrata: relation to sodium transport.
Pharmacological experiments indicate that prostaglandins (PGs) have a role in the control of sodium regulation in freshwater mussels and the mechanism may be linked to cyclic AMP and serotonin. To test this hypothesis we used radioimmunoassay to investigate the ability of freshwater mussels to synthesize PGs. The levels of precursor fatty acids were determined in a gas-liquid chromatograph. Arachidonic acid (precursor to the diene PGs) was the major fatty acid component of total lipids in the gill and accounted for 14% of the total. In addition, gill homogenates synthesize PG-like material from [3H]arachidonic acid. Material corresponding to PGE2 and PGF2 alpha were identified on thin-layer radiochromatograms. These data indicate that gills (the primary site of Na transport) can produce PGs. The presence of PGs in freshwater mussels was verified by radioimmunoassay of blood. Both PGE2 and PGF2 alpha were identified using highly specific antisera. The concentrations of both PGs was significantly reduced when the mussels were injected with inhibitors of phospholipase A2 or cyclooxygenase before sampling blood. Stimulation of Na transport by serotonin and cyclic AMP results in a depression of blood PGE2 with no effect on circulating PGF2 alpha. PGE2 levels are inversely correlated with net Na flux. These data indicate endogenous PGE2 negatively modulated Na transport and PGE2 levels are regulated by a serotonin-cyclic AMP mediated system.


Nrf1-mediated transcriptional regulation of the proteasome requires a functional TIP60 complex.
Inhibition of the proteasome leads to proteotoxic stress, which is characterized by the buildup of ubiquitinated proteins that cannot be degraded properly. The transcription factor Nrf1 (also called NFE2L1) counteracts proteotoxic stress by inducing transcription of proteasome subunit genes, resulting in the restoration of proteasome activity. Further understanding of the Nrf1 pathway is therefore of interest in both neurodegeneration, where proteasome activity could be enhanced, and cancer, where suppression of this pathway could potentiate the cell-killing effect mediated by proteasome inhibitor drugs. Here, to identify novel regulators of Nrf1, we performed an RNAi screen in an engineered cell line, reporting on Nrf1 transcriptional activity. In addition to validating known regulators, we discovered that the AAA+ ATPase RUVBL1 is necessary for Nrf1's transcriptional activity. Given that RUVBL1 is part of different multisubunit complexes that play key roles in transcription, we dissected this phenomenon further and found that the TIP60 chromatin-regulatory complex is essential for Nrf1-dependent transcription of proteasome genes. Consistent with these observations, Nrf1, RUVBL1, and TIP60 proteins were co-recruited to the promoter regions of proteasome genes after proteasome inhibitor treatments. More importantly, depletion of RUVBL1 or TIP60 in various cancer cells sensitized them to cell death induced by proteasome inhibition. Overall, our study provides a framework for manipulating the TIP60-Nrf1 axis to alter proteasome function in various human diseases, including cancer.


Who responds to prophylactic lithium?
Response to prophylactic lithium was studied in relation to clinical and psychological characteristics in a large series of patients with recurrent affective disorders. The findings were that bipolar patients with a family history of mania or depression had more favourable responses than those with no family history of affective disorders. Unipolar patients with more endogenous illnesses and those with pure familial depressive disease had more favourable responses than those with less endogenous illnesses and those with sporadic and depression spectrum diseases. Good responders showed generally less personality disturbance on a variety of measures than fair-to-poor responders. Response to lithium over 6 months in unipolar illness and over the first year in bipolar illness was strongly associated with long-term response.


Severe ischemic bowel necrosis caused by terlipressin during treatment of hepatorenal syndrome.
Terlipressin is a vasopressin analogue that is widely used in the treatment of hepatorenal syndrome or variceal bleeding. Because it acts mainly on splanchnic vessels, terlipressin has a lower incidence of severe ischemic complications than does vasopressin. However, it can still lead to serious complications such as myocardial infarction, skin necrosis, or bowel ischemia. Herein we report a case of severe ischemic bowel necrosis in a 46-year-old cirrhotic patient treated with terlipressin. Although the patient received bowel resection, death occurred due to ongoing hypotension and metabolic acidosis. Attention should be paid to patients complaining of abdominal pain during treatment with terlipressin.


Development of a thermostable SARS-CoV-2 variant-based bivalent protein vaccine with cross-neutralizing potency against Omicron subvariants.
SARS-CoV-2 variants have posed significant challenges to the hopes of using ancestral strain-based vaccines to address the risk of breakthrough infection by variants. We designed and developed a bivalent vaccine based on SARS-CoV-2 Alpha and Beta variants (named SCTV01C). SCTV01C antigens were stable at 25 oC for at least 6 months. In the presence of a squalene-based oil-in-water adjuvant SCT-VA02B, SCTV01C showed significant protection efficacy against antigen-matched Beta variant, with favorable safety profiles in rodents. Notably, SCTV01C exhibited cross-neutralization capacity against Omicron subvariants (BA.1, BA.1.1, BA.2, BA.3, and BA.4/5) in mice, superior to a WT (D614G)-based vaccine, which reinforced our previously published findings that SCTV01C exhibited broad-spectrum neutralizing potencies against over a dozen pre-Omicron variants and the Omicron BA.1 variant. In summary, variant-based multivalent protein vaccine could be a platform approach to address the challenging issues of emerging variants, vaccine hesitancy and the needs of affordable and thermal stable vaccines.


Phytochemical compounds with promising biological activities from Ascophyllum nodosum extracts using microwave-assisted extraction.
Phytochemical-rich antioxidant extracts were obtained from Ascophyllum nodosum (AN) using microwave-assisted extraction (MAE). Critical extraction factors such as time, pressure, and ethanol concentration were optimized by response surface methodology with a circumscribed central composite design. Under the optimal MAE conditions (3 min, 10.4 bar, 46.8 % ethanol), the maximum recovery of phytochemical compounds (polyphenols and fucoxanthin) with improved antioxidant activity from AN was obtained. In addition, the optimized AN extract showed significant biological activities as it was able to scavenge reactive oxygen and nitrogen species, inhibit central nervous system-related enzymes, and exhibit cytotoxic activity against different cancer cell lines. In addition, the optimized AN extract showed antimicrobial, and anti-quorum sensing activities, indicating that this extract could offer direct and indirect protection against infection by pathogenic microorganisms. This work demonstrated that the sustainably obtained AN extract could be an emerging, non-toxic, and natural ingredient with potential to be included in different applications.


Jejunal cancer in patients with familial adenomatous polyposis.
Familial adenomatous polyposis (FAP) is an inherited disease affecting approximately 1:10,000 newborns, characterized by the formation of numerous adenomas in the digestive tract. Surveillance and prophylactic treatment of colonic and duodenal manifestations of this disease have much influenced disease course and survival. In more recent years, it has become clear that adenoma formation in FAP patients is not restricted to the colon and duodenum. Accordingly, these adenomas might have malignant potential, although the actual risk is unknown. We report 3 cases of jejunal carcinoma in FAP patients and review data on incidence, prognosis, and risk factors of jejunoileal adenoma and carcinoma development in FAP. Three patients with FAP aged 71, 57, and 59 years developed advanced duodenal adenomatosis and a jejunal carcinoma, which was associated with poor prognosis in 2 patients. Jejunal adenomas in FAP patients are reported occasionally and can progress into adenocarcinoma with a poor prognosis. In the future a subset of FAP patients benefitting from jejunal surveillance should be identified.


Interactions between the S-domain receptor kinases and AtPUB-ARM E3 ubiquitin ligases suggest a conserved signaling pathway in Arabidopsis.
The Arabidopsis (Arabidopsis thaliana) genome encompasses multiple receptor kinase families with highly variable extracellular domains. Despite their large numbers, the various ligands and the downstream interacting partners for these kinases have been deciphered only for a few members. One such member, the S-receptor kinase, is known to mediate the self-incompatibility (SI) response in Brassica. S-receptor kinase has been shown to interact and phosphorylate a U-box/ARM-repeat-containing E3 ligase, ARC1, which, in turn, acts as a positive regulator of the SI response. In an effort to identify conserved signaling pathways in Arabidopsis, we performed yeast two-hybrid analyses of various S-domain receptor kinase family members with representative Arabidopsis plant U-box/ARM-repeat (AtPUB-ARM) E3 ligases. The kinase domains from S-domain receptor kinases were found to interact with ARM-repeat domains from AtPUB-ARM proteins. These kinase domains, along with M-locus protein kinase, a positive regulator of SI response, were also able to phosphorylate the ARM-repeat domains in in vitro phosphorylation assays. Subcellular localization patterns were investigated using transient expression assays in tobacco (Nicotiana tabacum) BY-2 cells and changes were detected in the presence of interacting kinases. Finally, potential links to the involvement of these interacting modules to the hormone abscisic acid (ABA) were investigated. Interestingly, AtPUB9 displayed redistribution to the plasma membrane of BY-2 cells when either treated with ABA or coexpressed with the active kinase domain of ARK1. As well, T-DNA insertion mutants for ARK1 and AtPUB9 lines were altered in their ABA sensitivity during germination and acted at or upstream of ABI3, indicating potential involvement of these proteins in ABA responses.


Decreased photosynthesis and growth with reduced respiration in the model diatom Phaeodactylum tricornutum grown under elevated CO2 over 1800 generations.
Studies on the long-term responses of marine phytoplankton to ongoing ocean acidification (OA) are appearing rapidly in the literature. However, only a few of these have investigated diatoms, which is disproportionate to their contribution to global primary production. Here we show that a population of the model diatom Phaeodactylum tricornutum, after growing under elevated CO2 (1000 μatm, HCL, pHT : 7.70) for 1860 generations, showed significant differences in photosynthesis and growth from a population maintained in ambient CO2 and then transferred to elevated CO2 for 20 generations (HC). The HCL population had lower mitochondrial respiration, than did the control population maintained in ambient CO2 (400 μatm, LCL, pHT : 8.02) for 1860 generations. Although the cells had higher respiratory carbon loss within 20 generations under the elevated CO2 , being consistent to previous findings, they downregulated their respiration to sustain their growth in longer duration under the OA condition. Responses of phytoplankton to OA may depend on the timescale for which they are exposed due to fluctuations in physiological traits over time. This study provides the first evidence that populations of the model species, P. tricornutum, differ phenotypically from each other after having been grown for differing spans of time under OA conditions, suggesting that long-term changes should be measured to understand responses of primary producers to OA, especially in waters with diatom-dominated phytoplankton assemblages.


Localized flexible integration of high-efficiency surface enhanced Raman scattering (SERS) monitors into microfluidic channels.
We report here a facile approach for flexible integration of high efficiency surface enhanced Raman scattering (SERS) monitors in a continuous microfluidic channel. In our work, femtosecond laser direct writing was adopted for highly localizable and controllable fabrication of the SERS monitor through a multi-photon absorption (MPA) induced photoreduction of silver salt solution. The silver substrate could be shaped into designed patterns, and could be precisely located at the desired position of the microchannel bed, giving the feasibility for real-time detection during reactions. SEM and TEM images show that the silver substrates were composed of crystallized silver nanoplates with an average thickness of 50 nm. AFM results reveal that the substrates were about 600 nm in height and the surface was very rough. As representative tests for SERS detection, p-aminothiophenol (p-ATP) and flavin adenine dinucleotide (FAD) were chosen as probing molecules for microfluidic analysis at visible light (514.5 nm) excitation, exhibiting an enhancement factor of ~10(8). In addition, the combination of the SERS substrate with the microfluidic channel allows detection of inactive analytes through in situ microfluidic reactions.


Dacryocystorhinostomy with nasolacrimal duct prostesis.
For many years the standard surgical treatment for chronic dacryocystitis has been the anastomosis of the lacrimal sac mucosa to nasal mucosa over the margins of an ostium through the lacrimal bone. Failures of this standard procedure have been attributed to many factors and complications frequently require reoperation. The procedure described in this paper was developed as one means of overcoming some of these difficulties. It consists of the implantation of a specially shaped nasolacrimal duct prosthesis from the base of the sac through the interosseous canal into the inferior nasal meatus. This procedure gives reasonable assurance of permanent drainage and is recommended as a primary procedure of choice. The operation is described.


Analysis of temporal transcription expression profiles reveal links between protein function and developmental stages of Drosophila melanogaster.
Accurate gene or protein function prediction is a key challenge in the post-genome era. Most current methods perform well on molecular function prediction, but struggle to provide useful annotations relating to biological process functions due to the limited power of sequence-based features in that functional domain. In this work, we systematically evaluate the predictive power of temporal transcription expression profiles for protein function prediction in Drosophila melanogaster. Our results show significantly better performance on predicting protein function when transcription expression profile-based features are integrated with sequence-derived features, compared with the sequence-derived features alone. We also observe that the combination of expression-based and sequence-based features leads to further improvement of accuracy on predicting all three domains of gene function. Based on the optimal feature combinations, we then propose a novel multi-classifier-based function prediction method for Drosophila melanogaster proteins, FFPred-fly+. Interpreting our machine learning models also allows us to identify some of the underlying links between biological processes and developmental stages of Drosophila melanogaster.


Shiga-like toxin-1 receptor on human breast cancer, lymphoma, and myeloma and absence from CD34(+) hematopoietic stem cells: implications for ex vivo tumor purging and autologous stem cell transplantation.
The ribosome-inactivating protein, Shiga-like toxin-1 (SLT-1), targets cells that express the glycolipid globotriaosylceramide (CD77) on their surface. CD77 and/or SLT-1 binding was detected by flow cytometry and immunocytochemistry on lymphoma and breast cancer cells recovered from biopsies of primary human cancers as well as on B cells or plasma cells present in blood/bone marrow samples of multiple myeloma patients. Breast cancer cell lines also expressed receptors for the toxin and were sensitive to SLT-1. Treatment of primary B lymphoma, B-cell chronic lymphocytic leukemia, and myeloma B or plasma cells with SLT-1-depleted malignant B cells by 3- to 28-fold, as measured by flow cytometry. Depletion of myeloma plasma cells was confirmed using a cellular limiting dilution assay followed by reverse transcriptase-polymerase chain reaction analysis of clonotypic IgH transcripts, which showed a greater than 3 log reduction in clonotypic myeloma cells after SLT-1 treatment. Receptors for the toxin were not detected on human CD34(+) hematopoietic progenitor cells (HPC). HPC were pretreated with a concentration of SLT-1 known to purge primary malignant B cells and cultured for 6 days. The number of HPC was comparable in toxin-treated and untreated cultures. HPC were functionally intact as well. Colony-forming units (CFU) were present at an identical frequency in untreated and SLT-1 pretreated cultures, confirming that CFU escape SLT-1 toxicity. The results suggest the ex vivo use of SLT-1 in purging SLT-1 receptor-expressing malignant cells from autologous stem cell grafts of breast cancer, lymphoma, and myeloma patients.


Sonographic appearances and percutaneous management of primary tuberculous liver abscess.
Primary tuberculous liver abscesses are rare. We report on 3 patients who presented with a nonresolving abscess in the liver. Clinical presentation and sonographic findings in each case were nonspecific. A diagnosis of tuberculosis was established with microbiologic examination of pus in 2 cases and examination of an excised abscess wall in 1 case. Needle aspiration (1 patient) and short-term (72 hours) catheter drainage (1 patient) were unsuccessful, and surgical excision was required in these patients. In the third patient, continuous catheter drainage over 18 days resulted in cure, indicating that long-term catheter drainage with antituberculous chemotherapy may be a viable alternative to surgery in the management of primary tuberculous liver abscess.


Effect of drilling technique on the early integration of plateau root form endosteal implants: an experimental study in dogs.
This study tested the hypothesis that early integration of plateau root form endosseous implants is significantly affected by surgical drilling technique. Sixty-four implants were bilaterally placed in the diaphysial radius of 8 beagles and remained 2 and 4 weeks in vivo. Half the implants had an alumina-blasted/acid-etched surface and the other half a surface coated with calcium phosphate. Half the implants with the 2 surface types were drilled at 50 rpm without saline irrigation and the other half were drilled at 900 rpm under abundant irrigation. After euthanasia, the implants in bone were nondecalcified and referred for histologic analysis. Bone-to-implant contact, bone area fraction occupancy, and the distance from the tip of the plateau to pristine cortical bone were measured. Statistical analyses were performed by analysis of variance at a 95% level of significance considering implant surface, time in vivo, and drilling speed as independent variables and bone-to-implant contact, bone area fraction occupancy, and distance from the tip of the plateau to pristine cortical bone as dependent variables. The results showed that both techniques led to implant integration and intimate contact between bone and the 2 implant surfaces. A significant increase in bone-to-implant contact and bone area fraction occupancy was observed as time elapsed at 2 and 4 weeks and for the calcium phosphate-coated implant surface compared with the alumina-blasted/acid-etched surface. Because the surgical drilling technique did not affect the early integration of plateau root form implants, the hypothesis was refuted.


12-O-tetradecanoyl-phorbol-13-acetate induction of the human collagenase gene is mediated by an inducible enhancer element located in the 5'-flanking region.
Genomic clones coding for human fibroblast collagenase were isolated. By constructing and transfecting mutants with 5' and 3' deletion mutations of the 5' control region of the gene into human or murine cells, we delimited a 32-base-pair sequence at positions -73 to -42 which is required for the induction of transcription by the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate. The DNA element behaves as a 12-O-tetradecanoyl-phorbol-13-acetate-inducible enhancer: it mediates the stimulation of transcription to the heterologous herpes simplex virus thymidine kinase promoter and acts in a position- and orientation-independent manner. Differences in enhancer efficiency in different cell lines are interpreted to indicate differences in the activity of a trans-acting factor.


Rapid induction of microsomal delta 12(omega 6)-desaturase activity in chilled Acanthamoeba castellanii.
The activity of microsomal delta 12-desaturase in Acanthamoeba castellanii was increased after growing cultures were chilled from the optimal growth temperature (30 degrees C) to 15 degrees C. This increase was detectable in microsomes isolated from organisms subjected to only 10 min chilling. The mechanism of induction was investigated. The increase in activity on chilling was greatly reduced when protein synthesis was blocked before the temperature shift. Thus the major mechanism for the induction of delta 12-desaturase is increased protein synthesis. delta 12-Desaturase activity was higher when assayed at 20 degrees C than when assayed at 30 degrees C, but these changes were not due to the increased solubility of O2 at 20 degrees C. The major substrate of delta 12-desaturase was found to be 1-acyl-2-oleoyl phosphatidylcholine.


Positional plagiocephaly: an analysis of the literature on the effectiveness of current guidelines.
Positional plagiocephaly (PP) has been on the rise in recent years. In this review, the authors' aim was to assess the effectiveness of current recommendations to parents on this exceedingly common problem through a comprehensive literature search. Additionally, the current treatment options and the most recent studies on PP are reviewed. A search of the existing literature was conducted to obtain all relevant studies on guidelines, recommendations, parental and clinician practices, and epidemiological aspects. Although the incidence and risk factors for PP have been well delineated, there continues to be debates on its management and association with developmental delays. Current guidelines and recommendations on prevention set by the American Association of Pediatrics may not be easily followed by both parents and clinicians. There is also evidence that certain populations, including those with lower education, socioeconomic status, and in particular geographic regions may be more affected by the condition. Additionally, the marketing and financial aspects of PP treatments exist and should be addressed. Better awareness and education are necessary to inform the population as a whole, although certain populations should be given special attention. Additionally, current guidelines and recommendations can be modified to foster a better grasp of the condition by both parents and clinicians. Adjusting current recommendations, introducing initiatives, and offering elaborate educational campaigns would help deliver these aims. Educating parents on PP as early as possible through clearer guidelines and close monitoring is central to preventing and managing this common condition.


Methylation of the MGMT and p16 genes in sporadic colorectal carcinoma and corresponding normal colonic mucosa.
Colorectal cancer, one of the most aggressive cancers, occurs with a high incidence in most countries. The usual treatment is surgery and subsequent chemotherapy and radiotherapy. Cancer development and progression is dictated by series of alterations in genes such as tumor suppressor genes, DNA repair genes, oncogenes and others. In colorectal carcinogenesis disturbances different from mutations called an epigenetic regulation are also taken into consideration. Epigenetics is defined as a modifications of the genome, heritable during cell division, which do not involve a change in the DNA sequence. In our study we analyzed methylation of CpG islands in the MGMT and p16 genes in sporadic colorectal cancers and normal corresponding colonic mucosa. Fresh tissue samples were obtained from 68 patients (age of 23 to 81 years) with primary colorectal adenocarcinoma and corresponding normal tissues. We used methylation-specific polymerase chain reaction (MSP) for analysis of the methylation status of MGMT and p16. Methylation of MGMT and p16 was detected in 59% and 53% of tumors, respectively. In corresponding normal colonic mucosa methylation of MGMT was detected in 20% and p16 in 18%. The normal colon mucosa obtained from younger patients (age of <65 years) showed less methylation frequency as compared with the normal mucosa from the older ones (age of >65 years). The older age and female gender are generally associated with higher methylation levels for most CpG islands in normal colonic mucosa. These results indicate that MGMT and/or p16 aberrant methylation may play an important role in colorectal cancer.


A commentary: the impact of the IEEE TRANSACTIONS ON REHABILITATION ENGINEERING on the field of rehabilitation engineering and science.
The IEEE TRANSACTIONS ON REHABILITATION ENGINEERING, founded 8.5 years ago, has survived, thrived, been of high quality, attracted the best authors in its field and related fields, been the publication of choice for manuscript submission in the rehabilitation engineering and related science area, possessed a wide and international distribution and loyal readership, been oft-cited, been financially sound, and made a marked impact on the field of Rehabilitation Engineering.


An Undergraduate Laboratory Exercise to Study Weber's Law.
Weber's Law describes the relationship between actual and perceived differences in stimulus intensity. To observe the relationship described in this law, we developed an exercise for undergraduate students, as experiential learning is an integral part of scientific education. We describe the experimental methods used for determining the subject's discriminative capacity at multiple vibrotactile amplitudes. A novel four-point stimulator (designed and fabricated at the University of North Carolina) was used for the study. Features of the device, such as automated skin detection, make it feasible to perform this laboratory exercise in a reasonable lab period. At the conclusion of the lab exercise, students will thoroughly understand the principle of Weber's Law as well as fundamental quantitative sensory testing concepts. This introduction to sensory testing will provide a suitable foundation for the undergraduate neuroscience student to investigate other aspects of sensory information processing in subsequent lab exercises.


[Usefulness of chromogranin A determination in the diagnosis of neuroendocrine neoplasia].
Neuroendocrine gastroenteropancreatic tumor diagnosis is a very difficult and expensive procedure. This study compared Chromogranin A (CgA) to Neuron-specific enolase (NSE) in 55 patients affected by neuroendocrine tumors. Advanced local or metastatic neoplasia was found in 43 patients. Radical operation was performed in 12 patients. Seventeen cases of lung microcystoma, 23 cases of other intestinal tumors and 19 patients affected by irritable bowel syndrome were used as controls. CgA sampling demonstrated sensitivity of 73% and specificity of 66%, a positive predictive value of 77% and a negative predictive value of 61% while NSE sampling showed sensitivity of 100%, specificity of 36%, a positive predictive value of 15% and a negative predictive value of 100%. CgA values demonstrated a statistically significant difference between patients with neuroendocrine tumors and tumor-free resected patients (p = 0.0015), microcystoma patients (p = 0.0087), other types of neoplasia (p = 0.01) and irritable bowel syndrome patients (p = 0.0004). No significant difference was found among the same groups when NSE values were analyzed. The high diagnostic accuracy of CgA sampling renders it very useful in early neoplastic detection, even in cases of nonfunctioning neoplasms or absence of liver metastases. In addition, CgA sampling may be an effective screening test in patients with irritable bowel syndrome or with liver or lung metastases when there is no evidence of the primitive tumor.


A common methylenetetrahydrofolate reductase (C677T) polymorphism is associated with low bone mineral density and increased fracture incidence after menopause: longitudinal data from the Danish osteoporosis prevention study.
A polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) has recently been associated with bone mineral density (BMD) in postmenopausal Japanese women. It is not known whether this effect is also present in European populations and whether it is caused by lower peak bone mass or accelerated postmenopausal bone loss. MTHFR genotyping was done in 1748 healthy postmenopausal Danish women participating in a prospective study of risk factors for osteoporosis. At the time of enrollment, 3-24 months after last menstrual period, the less prevalent genotype (TT, 8.7% of the population) was associated with significantly lower BMD at the femoral neck (ANOVA, p < 0.05), total hip (p < 0.01), and spine (p < 0.05 adjusted for lifestyle covariates, p = 0.06 without adjustment). The mean difference was between 0.1 and 0.3 SD, depending on measurement site. MTHFR genotype added significantly to prediction of BMD by weight and age. Fracture incidence was increased more than 2-fold in subjects with the TT genotype (risk ratio [RR], 2.6; 95% CI 1.2-5.6). This remained significant when the Cox analysis was controlled for BMD (RR, 2.4; 95% CI 1.1-5.2). No differences in serum osteocalcin, bone-specific alkaline phosphatase, and 25-OH-vitamin D were found between genotypes. The response to hormone replacement therapy (HRT) did not differ, but the association of the TT genotype with reduced BMD was maintained at the total hip after 5 years of HRT. The MTHFR TT genotype is associated with low BMD and increased fracture incidence in early postmenopausal women.


Whole-community genome amplification (WCGA) leads to compositional bias in methane-oxidizing communities as assessed by pmoA-based microarray analyses and QPCR.
Whole-genome amplification (WGA) using multiple displacement amplification (MDA) has recently been introduced to the field of environmental microbiology. The amplification of single-cell genomes or whole-community metagenomes decreases the minimum amount of DNA needed for subsequent molecular community analyses. The resolution of profiling methods of environmental microbial communities will increase substantially by the use of the whole-community genome amplification (WCGA) procedure, assuming that the original community composition is not affected qualitatively as well as quantitatively. The present study aims to test if WCGA introduces a bias when applied to aerobic proteobacterial methanotrophic communities. For this, first, we subjected samples from freshwater lake sediment to WCGA, and amplified using primers targeting the pmoA gene coding for the α-subunit of the methane monooxygenase enzyme. Second, we analysed community composition using a diagnostic microarray and quantitative PCR (QPCR) assays. These methods clearly demonstrated that the WCGA amplification introduced a bias. Thus, numbers of γ-proteobacterial methanotrophs ('type Ia') increased significantly while the α-proteobacterial methanotrophs ('type II') were not amplified by the WCGA procedure. It is hypothesized that this bias is caused by the differences in GC content, which may compromise the efficiency of the MDA reaction.


Pontibacter lucknowensis sp. nov., isolated from a hexachlorocyclohexane dump site.
A Gram-negative, orange-pigmented, rod-shaped, motile and aerobic bacterial strain designated DM9(T) was isolated from hexachlorocyclohexane (HCH)-contaminated soil (Lucknow, India) and its taxonomic position was determined using a polyphasic approach. 16S rRNA gene sequence analysis showed that the isolate belonged to the phylum Bacteroidetes and confirmed its placement in the genus Pontibacter, with sequence similarity ranging from 93.92 to 96.21 % with other members of the genus Pontibacter. The major cellular fatty acids of the novel strain were iso-C(17 : 0) 3-OH (6.00 %), iso-C(15 : 0) (21.54 %) and summed feature 4 (comprising C(17 : 1) iso I/anteiso B; 32.3 %). The polar lipid profile of strain DM9(T) showed the presence of phosphatidylethanolamine, an unidentified aminophospholipid, two unknown aminolipids and four unknown polar lipids. Strain DM9(T) contained MK-7 as the predominant menaquinone and its DNA G+C content was 49.2 mol%. sym-Homospermidine was the major polyamine observed in the cell. The results obtained on the basis of phenotypic characteristics, phylogenetic analysis, biochemical and physiological tests clearly distinguished DM9(T) from closely related members of the genus Pontibacter. It is proposed that DM9(T) represents a novel species, Pontibacter lucknowensis sp. nov.; the type strain is DM9(T) (= CCM 7955(T) = MTCC 11079(T)).


Coronary heart disease and risk factors in latin america.
Cardiovascular diseases are the leading cause of death in Latin America, with ischemic heart disease as the principal cause in most countries. Risk factors for cardiovascular disease are highly prevalent in the region, but there are international variations in the pattern and level of risk factors. Overweight and obesity are increasing. In the 2012 Mexican National Survey, overweight or obesity was found in 64.9% of men and 73% of women, and they were strongly associated with sedentarism. The most characteristic dyslipidemia abnormality in the region is low high-density lipoprotein cholesterol, followed by elevated low-density lipoprotein cholesterol and increased levels of triglycerides. National diabetes mellitus prevalence ranges from 2.8% to 9.4% and tobacco smoking from 12.8% to 42%. According to the INTERHEART (A Study of Risk Factors for First Myocardial Infarction in 52 Countries and Over 27,000 Subjects) data for Latin America, the highest attributable risks for myocardial infarction were related to abdominal obesity, dyslipidemia, and smoking.


High BMI Predicts Attention to Less Healthy Product Sets: Can a Prompt Lead to Consideration of Healthier Sets of Products?
While the food environment has been implicated in diet-related health disparities, individuals' ability to shape the food environment by limiting attention to a subset of products has not been studied. We examine the relationship between BMI category and consideration set-the products the individual considers before making a final choice-in an online hypothetical shopping experiment. Specifically, we focus on the healthiness of the consideration set the individual selected. Secondly, we examined the interaction of a health prompt (versus a no-prompt control) with BMI category on the healthiness of the consideration set. We used linear probability models to document the relationship between weight status and consideration set, between prompt and consideration set, and the effect of the interaction between prompt and weight status on consideration set. We found that (1) obese individuals are 10% less likely to shop from a consideration set that includes the healthy options, (2) viewing the prompt increased the probability of choosing a healthy consideration set by 9%, and (3) exposure to the prompt affected individuals in different BMI categories equally. While obese individuals are more likely to ignore healthier product options, a health-focused prompt increases consideration of healthy options across all BMI categories.


Dental Arch Dimensions of Nigerian Children with Hypertrophied Adenoids.
The study objective was to assess the effect of adenoid hypertrophy on the dental arch dimensions of children in Ile-Ife, Nigeria. Ninety patients aged 3-12 years attending the Otorhinolaryngology Clinic at Obafemi Awolowo University Teaching Hospital Ile-Ife diagnosed as having hypertrophied adenoids and 90 children from the Child Dental Health Clinic were recruited as adenoid and control subjects respectively. Arch and palatal vault dimensions, including total arch length; inter-canine, inter-premolar, and inter-molar widths; palatal length; and palatal heights measured at three levels and palatal volume were determined for both groups from dental casts. Maxillary arch dimensions were shorter in the adenoid group than the control group; however, only total maxillary arch length was significantly shorter (p=0.049). Mandibular arch dimensions with the exception of inter-molar width were significantly shorter in the adenoid group (p<0.05). Adenoid subjects had significantly increased palatal heights at canine, premolar, and molar levels and reduced palatal volume compared to the control subjects (p<0.05). Adenoid subjects demonstrated shorter maxillary and mandibular arch dimensions compared with control subjects, with the differences being more evident in the lower arch. They also exhibited increased palatal heights at all levels and reduced palatal volume compared with control subjects.


Future trends in spinal cord stimulation.
Spinal cord stimulation (SCS) has been available for about 30 years, but only in the past five years has it met with widespread acceptance and recognition by the medical community. Traditionally performed by neurosurgeons, SCS is being increasingly utilized by anesthesiologists, orthopedic surgeons and physiatrists. Pain management continues to be the most widespread application of SCS. More sophisticated technology has allowed the implanters to successfully address more complex pain syndromes such as widespread reflex sympathetic dystrophy and the failed back syndrome. Other applications are being developed, combining the ability to stimulate the spinal cord, the nerve roots and the peripheral nerves. Examples include angina pectoris, urinary incontinence and occipital neuralgia. Computer-interactive programming is gaining popularity, especially due to the extreme complexity of the implanted stimulation devices. The ability to stimulate independently multiple channels as well as multiple arrays of electrodes is today a reality. This has increased greatly the efficacy, safety and reliability of the modality. In the future, SCS will undoubtedly move several steps up in the treatment ladder of chronic pain conditions, while new applications will be discovered. The future of neural implantable technologies is bright, with an increasingly important role in the medical management of chronic conditions affecting the nervous system.


Control of the Nucleotide Cycle in Photoreceptor Cell Extracts by Retinal Degeneration Protein 3.
Retinal degeneration protein 3 (RD3) is crucial for photoreceptor cell survival and linked to Leber Congenital Amaurosis type 12 (LCA12), a hereditary retinal disease in humans. RD3 inhibits photoreceptor guanylate cyclases GC-E and GC-F and is involved in transport of GCs from the inner to the outer segments. Otherwise, its role in photoreceptor physiology is poorly understood. Here, we describe a new function of RD3. Purified RD3 evoked an increase in guanylate kinase activity, an enzyme that is involved in the nucleotide cycle in photoreceptors. We demonstrate a direct interaction between guanylate kinase and RD3 using back-scattering interferometry and show by immunohistochemistry of mouse retina sections that RD3 and guanylate kinase co-localize in photoreceptor inner segments and to a lesser extent in the outer plexiform layer. Our findings point toward a more complex function of RD3 in photoreceptors. The RD3 - guanylate kinase interaction may also play a role in other cellular systems, while the GC - RD3 interaction is exclusive to photoreceptors.


Current characteristics, challenges and coping strategies of young people with cystic fibrosis as they transition to adulthood.
This study provides detailed data on the current characteristics, perceptions and outcomes of 45 young people with cystic fibrosis (CF) as they transition into adulthood. Although many had severe disease, they generally coped well, found attendance at a transition clinic helpful and welcomed the increased independence of an adult healthcare environment. Levels of psychological distress were low with only 15.6% having anxiety and 6.7% depression. The main psychological coping strategy used was optimistic acceptance. Overall, most remained stable after transfer but 33% had some decline in lung function and 9% in nutritional status, requiring intensification of treatment. They had high levels of satisfaction with their relationships and life situations and 76% were in employment or education. These results are encouraging and as life expectancy improves, young adults with CF are coping well with transition into adulthood.


Effects of Trio and Pair Breeding of Mice on Environmental Parameters and Nasal Pathology and Their Implications for Cage Change Frequency.
According to the Guide, cage change frequencies must be considered when cage density requirements are exceeded. We monitored ammonia, carbon dioxide, cage wetness, health status, and breeding parameters of trio and pair breeding cages containing CD1 mice in ventilated and static microisolation caging (4 cages per condition) daily for approximately 6 wk. Minimum cage change frequencies for each condition were determined on the basis of performance data. At 3 d after cage change, static trio and pair cages had average ammonia levels of 74 and 38 ppm. Ventilated cages remained below the 25ppm threshold reported to be potentially deleterious for mice until at least day 7 after cage change. By 7 d after cage change, ammonia levels had risen to an average of 100 ppm and 64 ppm in static trio and pair cages and to 34 ppm and 20 ppm in ventilated trio and pair cages, respectively. Ammonia levels in ventilated cages continued to rise slowly through day 14 after cage change. CO₂ levels exceeded 5000 ppm in all groups at 2 d after cage change. Pair breeders in ventilated cages took the longest-10 to 14 d-to reach cage wetness threshold scores. On day 7, pups in trio static cages were noted to have decreased and squinted eyes, whereas in ventilated cages containing trios and pairs, these clinical signs were rare to absent. Histologically, there was an increasing incidence and severity of nasal lesions in weanlings with increasing housing density and decreasing ventilation, consistent with nasal epithelial toxicity. Given these parameters, we concluded that under the current husbandry conditions, it may be necessary to change breeders in static cages more frequently than every 7 d. Additional studies are necessary to evaluate the effects of more frequent cage changes on reproductive parameters, given that cage changing is stressful for mice and affects breeding results.


New electroantennography method on a marine shrimp in water.
Antennular chemoreception in aquatic decapods is well studied via the recording of single chemoreceptor neuron activity in the antennule, but global responses of the antennule (or antennae in insects) by electroantennography (EAG) has so far been mainly restricted to aerial conditions. We present here a well-established underwater EAG method to record the global antennule activity in the marine shrimp Palaemon elegans in natural (aqueous) conditions. EAG responses to food extracts, recorded as net positive deviations of the baseline, are reproducible, dose-dependent and exhibit sensory adaptation. This new EAG method opens a large field of possibilities for studying in vivo antennular chemoreception in aquatic decapods, in a global approach to supplement current, more specific techniques.


Architecture of the outer membrane of Escherichia coli. III. Protein-lipopolysaccharide complexes in intramembraneous particles.
In a previous paper (A. Verkleij, L. van Alphen, J. Bijvelt, and B. Lugtenberg, Biochim. Biophys. Acta 466:269-282, 1977) we have hypothesized that particles on the outer fracture face of the outer membrane ([Formula: see text]), with corresponding pits on the inner fracture face of the outer membrane ([Formula: see text]), consist of lipopolysaccharide (LPS) aggregates stabilized by divalent cations and that they might contain protein and/or phospholipid. In the present paper the roles of LPS, cations, and proteins in these [Formula: see text] particles are described more extensively, using a strain that lacks the major outer membrane proteins, b, c, and d (b(-) c(-) d(-)), and has a reduction in the number of [Formula: see text] particles of 75%. To study the role of divalent cations in the formation of [Formula: see text] particles, these b(-) c(-) d(-) cells were grown or incubated with Ca(2+), Mg(2+), or putrescine. The presence of Ca(2+) resulted in the appearance of many [Formula: see text] particles and [Formula: see text] pits. Mg(2+) and putrescine were less effective than Ca(2+). Introduction of these particles was not accompanied by alterations in the relative amounts of LPS and cell envelope proteins. Ca(2+) treatment of a heptoseless derivative of a b(-) c(-) d(-) strain did not result in morphological changes. Incubation of Ca(2+)-treated cells with ethylenediaminetetraacetate caused the disappearance of the introduced particles as well as the release of more than 60% of the cellular LPS. These results strongly support the hypothesis that LPS is involved in the formation of [Formula: see text] particles and [Formula: see text] pits. The roles of various outer membrane proteins in the formation of [Formula: see text] particles were studied by comparing the freeze-fracture morphology of b(-) c(-) d(-) cells with that of cells which contain one of the outer membrane proteins b, c, d, and e or the receptor protein for bacteriophage lambda. The results showed that the presence of any of these five proteins in a b(-) c(-) d(-) background resulted in a large increase in the number of [Formula: see text] particles and [Formula: see text] pits, indicating that these proteins are, independent of each other, involved in the formation of [Formula: see text] particles and [Formula: see text] pits. The simplest explanation for the results is that in wild-type cells each particle consists of LPS complexed with some molecules of a single protein species, stabilized by either divalent cations or polyamines. It is hypothesized that the outer membrane of the wild-type cell contains a heterogeneous population of particles, of which 75% consists of protein b-LPS, protein c-LPS, and protein d-LPS particles. A function of these particles as aqueous pores is proposed.


'Every teacher is a researcher!': Creating indigenous epistemologies and practices for HIV prevention through values-based action research.
Since gender is an undisputed driver of HIV infection, teachers concerned with HIV prevention education should ideally encourage critical awareness of and culturally sensitive practices around gender inequalities. Many interventions and programmes have been developed for teachers to enable them to do this, however most have met with limited success. This article proceeds from the viewpoint that for HIV-prevention interventions to be sustainable and effective, teachers should be actively engaged in their design, implementation and evaluation. It outlines how teachers in an HIV prevention programme utilised an action research design to explore their own gender constructs as a necessary first step to the creation of more gender-sensitive school climates and teaching practices. This values-based self-enquiry moved the teachers to action on two levels: first, to adopt a more gender-sensitive approach in their own personal and professional lives and second, to take action to challenge gender inequalities within their particular educational contexts. Evidence is presented to justify the claim that action research of this genre helps teachers to generate indigenous epistemologies and practices that not only are effective in creating sustainable and empowering learning environments for HIV prevention education, but also for teaching and learning in general.


Motor performance, body fatness and environmental factors in preschool children.
The first aim of this study was to investigate the relationship between motor performance and body fatness among 3- to 5-year-old children. The second aim was to assess whether this relationship works similarly for boys and girls. We also investigated whether socioeconomic status (SES) and geographical area when children are aged 3 years old predicts the motor performance of 4 and 5-yr-old children. Motor performance was assessed through the Preschool Test Battery, while body fatness was estimated through body mass index (BMI). SES and geographical area were assessed via parent proxy-report questionnaires. BMI was negatively associated with standing long jump. The association of BMI and motor performance was not statistically different for boys and girls. Children from low SES performed better than high SES peers in tennis ball throw for distance. Rural children were better performers than urban peers in standing long jump. Rural area at baseline was also predictor of standing long jump and tennis ball throw for distance at time 1 and 2. In conclusion, BMI had a negative association with standing long jump and the relationship of BMI with all motor tests was similar for boys and girls. SES and rural area were predictors of motor performance.


Liposome-based vaccines for minimally or noninvasive administration: an update on current advancements.
Vaccination requires innovation to provide effective protection. Traditional vaccines have several drawbacks, which can be overcome with advanced technologies and different administration routes. Over the past 10 years, a significant amount of research has focussed on the delivery of antigens into liposomes due to their dual role as antigen-carrying systems and vaccine adjuvants able to increase the immunogenicity of the carried antigen. This review encompasses the progress made over the last 10 years with liposome-based vaccines designed for minimally or noninvasive administration, filling the gaps in previous reviews and providing insights on composition, administration routes, results achieved, and Technology Readiness Level of the most recent formulations. Liposome-based vaccines administered through minimally or noninvasive routes are expected to improve efficacy and complacency of vaccination programs. However, the translation from lab-scale production to large-scale production and collaborations with hospitals, research centers, and companies are needed to allow new products to enter the market and improve the vaccination programs in the future.


Proceedings of Consensus Conference on Simultaneous Liver Kidney Transplantation (SLK).
A consensus conference sponsored by the American Society of Transplant Surgeons (ASTS), American Society of Transplantation (AST), United Network for Organ Sharing (UNOS) and American Society of Nephrology (ASN) convened to examine simultaneous liver-kidney transplantation (SLK). Directors from the 25 largest liver transplant programs along with speakers with recognized expertise attended. The purposes of this conference were to propose indications for SLK, to establish a prospective data registry and, most importantly, to recommend standard listing criteria for these patients. Scientific registry of transplant recipients data, and single center data regarding chronic kidney disease (CKD) and acute kidney injury (AKI) in conjunction with liver failure as a basis for SLK was presented and discussed. The consensus was that Regional Review Boards (RRB) should determine listing for SLK, as with other MELD exceptions, with automatic approval for: (i) End-stage renal disease with cirrhosis and symptomatic portal hypertension or hepatic vein wedge pressure gradient >/= 10 mm Hg (ii) Liver failure and CKD with GFR </= 30 mL/min (iii) AKI or hepatorenal syndrome with creatinine >/= 2.0 mg/dL and dialysis >/= 8 weeks (iv) Liver failure and CKD and biopsy demonstrating > 30% glomerulosclerosis or 30% fibrosis. The RRB would evaluate all other requests to determine appropriateness.


The role of Bordetella infections in patients with acute exacerbation of chronic bronchitis.
Acute exacerbations of chronic bronchitis (AECB) are associated with a variety of viral and bacterial infectious agents, some of which are potentially preventable by immunization. Bordetella pertussis, which causes whooping cough, has not been studied in this context. We aimed to assess the role of Bordetella infections in patients with AECB. Patients with AECB, who presented to participating private practices in Basel, Switzerland, between October 2000 and June 2002, were evaluated by a standardized questionnaire, nasopharyngeal swabs for culture (Bordetella spp.), and PCR (Bordetella spp. and selected other respiratory pathogens) and paired blood samples for serologic diagnosis of Bordetella infection. A total of 26 patients (34-86 years of age) were recruited. All culture and PCR samples were negative. Serology revealed Bordetella infection in eight (31%) patients. Duration of cough was shorter in patients with Bordetella infection compared to those without Bordetella infection (mean 15 days vs 41 days, p = 0.04). Cough > or = 21 days duration was present in three (43%) of seven patients with evidence of Bordetella infection compared to 17 (94%) of 18 controls (p = 0.012). Progression to convalescence from initial to follow-up visit after 4-6 weeks was comparable between both groups. Bordetella infections appear to play a significant role in AECB and preventive measurements such as immunization with acellular pertussis vaccines should be considered. Extended investigations are necessary to confirm our preliminary and provocative findings.


Exploring the potential of variola virus infection of cynomolgus macaques as a model for human smallpox.
Smallpox virus (variola) poses a significant threat as an agent of bioterrorism. To mitigate this risk, antiviral drugs and an improved vaccine are urgently needed. Satisfactory demonstration of protective efficacy against authentic variola will require development of an animal model in which variola produces a disease course with features consistent with human smallpox. Toward this end, cynomolgus macaques were exposed to several variola strains through aerosol and/or i.v. routes. Two strains, Harper and India 7124, produced uniform acute lethality when inoculated i.v. in high doses (10(9) plaque-forming units). Lower doses resulted in less fulminant, systemic disease and lower mortality. Animals that died had profound leukocytosis, thrombocytopenia, and elevated serum creatinine levels. After inoculation, variola was disseminated by means of a monocytic cell-associated viremia. Distribution of viral antigens by immunohistochemistry correlated with the presence of replicating viral particles demonstrated by electron microscopy and pathology in the lymphoid tissues, skin, oral mucosa, gastrointestinal tract, reproductive system, and liver. These particles resembled those seen in human smallpox. High viral burdens in target tissues were associated with organ dysfunction and multisystem failure. Evidence of coagulation cascade activation (D dimers) corroborated histologic evidence of hemorrhagic diathesis. Depletion of T cell-dependent areas of lymphoid tissues occurred, probably as a consequence of bystander apoptotic mechanisms initiated by infected macrophages. Elaboration of cytokines, including IL-6 and IFN-gamma, contribute to a cytokine storm formerly known as "toxemia." A more precise understanding of disease pathogenesis should provide targets for therapeutic intervention, to be used alone or in combination with inhibitors of variola virus replication.


Long-term survival in rhinocerebral mucormycosis. Case report.
Mucormycosis refers to a group of rapidly progressive infections caused by fungi belonging to the order Mucorales. Infection most often develops in individuals with immunological or metabolic compromise, although patients without underlying abnormalities have been affected. Specific clinical manifestations are associated with various predisposing factors. Rhinocerebral mucormycosis is the most common form and most frequently develops in individuals with poorly controlled diabetes mellitus. The extent of anatomical involvement and clinical course are unpredictable, depending on the intrinsic factors of the host. Over the past 20 years the prognosis for patients with rhinocerebral mucormycosis, once considered to be a uniformly fatal disease, has improved. Coordinated medical and surgical treatment, including rapid diagnosis, the advent of systemic antifungal agents, aggressive surgical debridement, and control of the underlying disease process, have been credited with its successful management. The range of survival rates recorded with the regimen of combined therapies is wide because the number of patients reported is limited and anatomical involvement is diverse. Survival with intracerebral abscess is rare. The authors describe the successful management of a patient who developed a bifrontal fungal abscess during treatment for rhinocerebral mucormycosis associated with ketoacidosis and diabetes mellitus. The patient remains without radiographic or clinical evidence of infection more than 2 years after treatment. The authors review the characteristic clinical, radiographic, and pathological features of previously reported infections and emphasize the importance of early detection and aggressive treatment in the management of this frequently fulminant and fatal disease.


Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent DC functions and regulates experimental graft-versus-host disease in mice.
Histone deacetylase (HDAC) inhibitors are antitumor agents that also have antiinflammatory properties. However, the mechanisms of their immunomodulatory functions are not known. We investigated the mechanisms of action of 2 HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and ITF 2357, on mouse DC responses. Pretreatment of DCs with HDAC inhibitors significantly reduced TLR-induced secretion of proinflammatory cytokines, suppressed the expression of CD40 and CD80, and reduced the in vitro and in vivo allostimulatory responses induced by the DCs. In addition, injection of DCs treated ex vivo with HDAC inhibitors reduced experimental graft-versus-host disease (GVHD) in a murine allogeneic BM transplantation model. Exposure of DCs to HDAC inhibitors increased expression of indoleamine 2,3-dioxygenase (IDO), a suppressor of DC function. Blockade of IDO in WT DCs with siRNA and with DCs from IDO-deficient animals caused substantial reversal of HDAC inhibition-induced in vitro suppression of DC-stimulated responses. Direct injection of HDAC inhibitors early after allogeneic BM transplantation to chimeric animals whose BM-derived cells lacked IDO failed to protect from GVHD, demonstrating an in vivo functional role for IDO. Together, these data show that HDAC inhibitors regulate multiple DC functions through the induction of IDO and suggest that they may represent a novel class of agents to treat immune-mediated diseases.


U4 snRNA nucleolar localization requires the NHPX/15.5-kD protein binding site but not Sm protein or U6 snRNA association.
All small nuclear RNAs (snRNAs) of the [U4/U6.U5] tri-snRNP localize transiently to nucleoli, as visualized by microscopy after injection of fluorescein-labeled transcripts into Xenopus laevis oocyte nuclei. Here, we demonstrate that these RNAs traffic to nucleoli independently of one another, because U4 snRNA deleted in the U6 base-pairing region still localizes to nucleoli. Furthermore, depletion of endogenous U6 snRNA does not affect nucleolar localization of injected U4 or U5. The wild-type U4 transcripts used here are functional: they exhibit normal nucleocytoplasmic traffic, associate with Sm proteins, form the [U4/U6] di-snRNP, and localize to nucleoli and Cajal bodies. The nucleolar localization element (NoLE) of U4 snRNA was mapped by mutagenesis. Neither the 5'-cap nor the 3'-region of U4, which includes the Sm protein binding site, are essential for nucleolar localization. The only region in U4 snRNA required for nucleolar localization is the 5'-proximal stem loop, which contains the binding site for the NHPX/15.5-kD protein. Even mutation of just five nucleotides, essential for binding this protein, impaired U4 nucleolar localization. Intriguingly, the NHPX/15.5-kD protein also binds the nucleolar localization element of box C/D small nucleolar RNAs, suggesting that this protein might mediate nucleolar localization of several small RNAs.


Applications of Ruthenium Complexes Covalently Linked to Nucleic Acid Derivatives.
Oligonucleotides are biopolymers that can be easily modified at various locations. Thereby, the attachment of metal complexes to nucleic acid derivatives has emerged as a common pathway to improve the understanding of biological processes or to steer oligonucleotides towards novel applications such as electron transfer or the construction of nanomaterials. Among the different metal complexes coupled to oligonucleotides, ruthenium complexes, have been extensively studied due to their remarkable properties. The resulting DNA-ruthenium bioconjugates have already demonstrated their potency in numerous applications. Consequently, this review focuses on the recent synthetic methods developed for the preparation of ruthenium complexes covalently linked to oligonucleotides. In addition, the usefulness of such conjugates will be highlighted and their applications from nanotechnologies to therapeutic purposes will be discussed.


A potentiometric tattoo sensor for monitoring ammonium in sweat.
The development and analytical characterization of a novel ion-selective potentiometric cell in a temporary-transfer tattoo platform for monitoring ammonium levels in sweat is presented. The fabrication of this skin-worn sensor, which is based on a screen-printed design, incorporates all-solid-state potentiometric sensor technology for both the working and reference electrodes, in connection to ammonium-selective polymeric membrane based on the nonactin ionophore. The resulting tattooed potentiometric sensor exhibits a working range between 10(-4) M to 0.1 M, well within the physiological levels of ammonium in sweat. Testing under stringent mechanical stress expected on the epidermis shows that the analytical performance is not affected by factors such as stretching or bending. Since the levels of ammonium are related to the breakdown of proteins, the new wearable potentiometric tattoo sensor offers considerable promise for monitoring sport performance or detecting metabolic disorders in healthcare. Such combination of the epidermal integration, screen-printed technology and potentiometric sensing represents an attractive path towards non-invasive monitoring of a variety of electrolytes in human perspiration.