The use of life review to enhance spiritual well-being in patients with terminal illnesses: An integrative review.
To conduct an integrative review of the current literature on using life review as an intervention to address the spiritual need of patients with terminal illnesses. Palliative care highlights the holistic approach of care including the spiritual aspect. Life review has been used in palliative nursing intending to enhance patients' emotional and spiritual well-being, and quality of life. However, there is a lack of publications that provide a structured overview on life review programmes and their effectiveness. Integrative review. The Whittemore and Knafl integrative review method was used. Five major online databases were included in our literature search. The keywords used were "life review" and "palliative care, terminal care, terminally ill, death & dying, hospice, spiritual wellbeing, spirituality". Seven primary papers were identified, critically appraised and synthesised in the final review. There are limited clinical studies on life review programmes for patients with terminal illness. The research design of these studies is too widely varied for meta-analysis. Here, we identified two major programmes of life review as an intervention to address the spiritual well-being of patients with terminal illness. However, repeated studies on the effectiveness of these two programmes are lacking. The shorter programme of life review is more likely to be applicable and effective for terminal patients. Further research in this area is required to provide strong evidence on the effectiveness and applicability of life review in patients receiving palliative care. This review adds weight to the need of a better understanding on the use of life review in addressing the spiritual needs of patients with terminal illness. Such understanding would provide evidence for the use of life review as an alternative approach in palliative care delivery.


Regulation of adenylyl cyclase in polarized renal epithelial cells by G protein-coupled receptors.
We employed two guanine nucleotide binding protein (G protein)-coupled receptors known to be targeted to opposite domains in renal epithelial cells to test the hypothesis that the polarized receptor expression of receptors regulates the activity of the receptor's effector molecule, adenylyl cyclase. We used LLC-PK1 cells stably transfected with cDNA encoding the alpha 2B-adrenergic receptor (alpha 2B-AR) or A1-adenosine receptor (A1-AdR). Immunohistochemistry and Western blot analysis confirmed the basolateral and apical expression of alpha 2B-ARs and A1-AdRs, respectively. Adenylyl cyclase activity was assessed by measuring cAMP accumulation following the addition of forskolin (10 microM) in the presence of 3-isobutyl-1-methylxanthine to apical or basolateral chambers of confluent monolayers. A five- to sixfold increase in cAMP accumulation occurred following apical (or basolateral) stimulation of LLC-PK1 cells expressing apical (or basolateral) receptors in comparison to forskolin stimulation of corresponding domains of untransfected cells. We conclude 1) adenylyl cyclase activity is present at or near the apical and basolateral domains of LLC-PK1 cells, and 2) factors that regulate the polarized expression of inhibitory G protein-coupled receptors may also regulate local adenylyl cyclase activity.


Modeling chemotherapy induced neurotoxicity with human induced pluripotent stem cell (iPSC) -derived sensory neurons.
Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent, potentially irreversible adverse effect of cytotoxic chemotherapy often leading to a reduction or discontinuation of treatment which negatively impacts patients' prognosis. To date, however, neither predictive biomarkers nor preventive treatments for CIPN are available, which is partially due to a lack of suitable experimental models. We therefore aimed to evaluate whether sensory neurons derived from induced pluripotent stem cells (iPSC-DSN) can serve as human disease model system for CIPN. Treatment of iPSC-DSN for 24 h with the neurotoxic drugs paclitaxel, bortezomib, vincristine and cisplatin led to axonal blebbing and a dose dependent decline of cell viability in clinically relevant IC50 ranges, which was not observed for the non-neurotoxic compounds doxorubicin and 5-fluorouracil. Paclitaxel treatment effects were less pronounced after 24 h but prominent when treatment was applied for 72 h. Global transcriptome analyses performed at 24 h, i.e. before paclitaxel-induced cell death occurred, revealed the differential expression of genes of neuronal injury, cellular stress response, and sterol pathways. We further evaluated if known neuroprotective strategies can be reproduced in iPSC-DSN and observed protective effects of lithium replicating findings from rodent dorsal root ganglia cells. Comparing sensory neurons derived from two different healthy donors, we found preliminary evidence that these cell lines react differentially to neurotoxic drugs as expected from the variable presentation of CIPN in patients. In conclusion, iPSC-DSN are a promising platform to study the pathogenesis of CIPN and to evaluate neuroprotective treatment strategies. In the future, the application of patient-specific iPSC-DSN could open new avenues for personalized medicine with individual risk prediction, choice of chemotherapeutic compounds and preventive treatments.


Calcitonin Gene-Related Peptide Modulators - The History and Renaissance of a New Migraine Drug Class.
Several lines of evidence pointed to an important role for CGRP in migraine. These included the anatomic colocalization of CGRP and its receptor in sensory fibers innervating pain-producing meningeal blood vessels, its release by trigeminal stimulation, the observation of elevated CGRP in the cranial circulation during migraine with normalization concomitant with headache relief by sumatriptan, and translational studies with intravenous (IV) CGRP that evoked migraine only in migraineurs. The development of small molecule CGRP receptor antagonists (CGRP-RAs) that showed clinical antimigraine efficacy acutely and prophylactically in randomized placebo-controlled clinical trials subsequently gave definitive pharmacological proof of the importance of CGRP in migraine. More recently, CGRP target engagement imaging studies using a CGRP receptor PET ligand [11 C]MK-4232 demonstrated that there was no brain CGRP receptor occupancy at clinically effective antimigraine doses of telcagepant, a prototypic CGRP-RA. Taken together, these data indicated that (1) the therapeutic site of action of the CGRP-RAs was peripheral not central; (2) that IV CGRP had most likely evoked migraine through an action at sites outside the blood-brain barrier; and (3) that migraine pain was therefore, at least in part, peripheral in origin. The evolution of CGRP migraine science gave impetus to the development of peripherally acting drugs that could modulate CGRP chronically to prevent frequent episodic and chronic migraine. Large molecule biologic antibody (mAb) approaches that are given subcutaneously to neutralize circulating CGRP peptide (fremanezumab, galcanezumab) or block CGRP receptors (erenumab) have shown consistent efficacy and tolerability in multicenter migraine prevention trials and are now approved for clinical use. Eptinezumab, a CGRP neutralizing antibody given IV, shows promise in late stage clinical development. Recently, orally administered next-generation small molecule CGRP-RAs have been shown to have safety and efficacy in acute treatment (ubrogepant and rimegepant) and prevention (atogepant) of migraine, giving additional CGRP-based therapeutic options for migraine patients.


Pan-Trk Immunohistochemistry Is an Efficient and Reliable Screen for the Detection of NTRK Fusions.
Activating neurotrophic tyrosine receptor kinase (NTRK) fusions, typically detected using nucleic-acid based assays, are highly targetable and define certain tumors. Here, we explore the utility of pan-TRK immunohistochemistry (IHC) to detect NTRK fusions. NTRK rearrangements were detected prospectively using MSK-IMPACT, a DNA-based next-generation sequencing assay. Transcription of novel NTRK rearrangements into potentially functional fusion transcripts was assessed via Archer Dx fusion assay. Pan-Trk IHC testing with mAb EPR17341 was performed on all NTRK rearranged cases and 20 cases negative for NTRK fusions on Archer. Of 23 cases with NTRK rearrangements, 15 had known activating fusions. Archer detected fusion transcripts in 6 of 8 novel NTRK rearrangements of uncertain functional significance. Pan-Trk IHC was positive in 20 of 21 cases with NTRK fusion transcripts confirmed by Archer. The discordant negative case was a mismatch repair- deficient colorectal carcinoma with an ETV6-NTRK3 fusion. All 20 additional Archer-negative cases had concordant pan-TRK IHC results. Pan-Trk IHC sensitivity and specificity for transcribed NTRK fusions was 95.2% and 100%, respectively. All positive IHC cases had cytoplasmic staining while the following fusion partner-specific patterns were discovered: all 5 LMNA-NTRK1 fusions displayed nuclear membrane accentuation, all 4 TPM3/4 fusions displayed cellular membrane accentuation, and half (3/6) of ETV6-NTRK3 fusions displayed nuclear staining. Pan-Trk IHC is a time-efficient and tissue-efficient screen for NTRK fusions, particularly in driver-negative advanced malignancies and potential cases of secretory carcinoma and congenital fibrosarcoma. Pan-Trk IHC can help determine whether translation occurs for novel NTRK rearrangements.


The positional behavior of pygmy marmosets (Cebuella pygmaea) in northwestern Bolivia.
Pygmy marmosets are distinctive given their diminutive body size, their year-round reliance upon exudates, and their use of morphologically adapted tegulae to engage in a high degree of claw-clinging behaviors associated with exudate exploitation. This project examined the positional behavior and habitat preferences of one group of pygmy marmosets in a secondary forest within the Department of Pando, northwestern Bolivia. Results from this study indicate that pygmy marmosets primarily use claw-clinging during feeding (89.6%) with preferential use of large vertical trunks. Claw-clinging was also the dominant postural mode during exudate foraging (43.1%) with preferential use of large vertical trunks. Quadrupedalism was the dominant locomotor mode during travel (55.7%) with preferential use of bamboo and medium-sized substrates. These results support previous notions that claw-climbing is a solution to overcome the constraints of small body size while suggesting that quadrupedalism is a habitat-dependent locomotor mode.


Microtubule network facilitates nuclear targeting of human cytomegalovirus capsid.
We assessed the requirement of the host cytoskeleton for the intracytosolic transport of incoming human cytomegalovirus (HCMV) capsids. Treatments with microtubule (MT)-depolymerizing drugs nocodazole and colchicine led to a drastic decrease in levels of IE1 antigen, whereas cytochalasin B had no effect on the level of IE1 as determined by Western blot analyses. Sequential treatment including nocodazole washout and removal of cell surface virion revealed that HCMV entry into the cells occurred normally in the absence of the MT network. This finding was also supported by data obtained by monitoring pUL83 signals with an immunofluorescent assay (IFA). Furthermore, we demonstrated a close association of incoming HCMV capsids with MTs by IFA and ultrastructural analyses. In the absence of the MT network, the capsids which had entered the cytoplasm did not move to close proximity of the nucleus. These data suggest that HCMV capsids associate with the MT network to facilitate their own movement to the nucleus before the onset of immediate-early (IE) gene expression and that this association is required to start efficient IE gene expression.


Viral infection and host defense.
Double-stranded RNA, made as an intermediary substance in the replication of most, if not all, viruses, may play a much more important role in the pathogenesis and the recovery from virus infections than has hitherto been suspected. Apparently, dsRNA is used by both the challenge virus and the host cell in an attempt to gain "molecular control." Double-stranded RNA exerts a set of effects, which may be well balanced, not only at the level of the individual cell but also at the complex assemblage of these cells termed the organism (Fig. 1). In the cell, interferon synthesis is triggered, although interferon mRNA translation may not occur if dsRNA shuts off protein synthesis too quickly. In the whole organism, the disease severity will depend on how certain toxic reactions evoked by infection (such as cell necrosis and fever) are counterbalanced by an increase in the host defense mechanisms (for example, immune responsiveness and interferon production). Many aspects of the response, relating to either progress of, or recovery from, the disease, can be explained on the basis of a dsRNA. In addition to drawing attention to the biodynamic role of dsRNA, our hypothesis suggests specific experimental vectors designed to enhance our information on the molecular basis of the morbid process which occurs with viral infection. Finally, we suggest that, although the dsRNA molecule may be viewed as a rather simple unit structure, the opportunity for further diversity in the biological activity of a given dsRNA molecule always exists. Namely, each deviation from a perfectly double-helical arrangement introduces the possibility for emphasizing one biological reactivity at the expense of another. This latter structure-activity property may partially account for the extreme apparent diversity, commonly encountered, in the presentations of virologic illness. Appendix note added in proof. Subsequent to submission of this text, we have found that the potent mitogen effect of dsRNA for lymphocytes (murine and human) is also exquisitively sensitive to the fidelity in base pairing of the input polymer pair (59). For example, infrequent "loops" (one nucleotide per 20 base pairs) in an otherwise perfectly helical rI(n) (.) rC(n) molecule [for example, rI(n) (.) r(C(19,)U)(n)] strongly changes its mitogenic properties. This observation, which supports our thesis that a "fine structure" term can be developed for other reactions triggered by dsRNA's in biological systems, emphasizes that diverse biological effects may be encountered with an ostensibly uniform family of dsRNA's.


Cellular events in the lymph node and lung of mice with influenza. Consequences of depleting CD4+ T cells.
The cellularity of the mediastinal lymph nodes of mice infected intranasally with a high dose of an H3N2 influenza A virus increases massively within 5 days. All classes of lymphocytes are involved. A similar, but much smaller, expansion in cell numbers occurs after exposure to a comparable dilution of normal chick allantoic fluid. In the control group, this increase in lymph node size is totally prevented by the in vivo depletion of CD4+ T cells whereas there is only a 50% reduction in the virus-infected mice. The lymphocyte component of the cellular exudate in the lungs of infected mice is dominated by activated, CD8+ T cells, which are also prevalent in the mediastinal lymph nodes. Elimination of the CD4+ subset does not greatly diminish the severity of this inflammatory process. The CD4-depleted mice clear the virus from the lung, and there is little effect on the frequency of virus-specific, cytotoxic T lymphocyte precursors in either the lymph node or the lung. Substantial involvement of CD4+ T cells is not essential for the development of effective cell-mediated immunity in mice with influenza.


Time to colonoscopy, cancer probability, and precursor lesions in the Danish colorectal cancer screening program.
The aim of this study was to investigate the effect of response time from the Fecal Immunochemical Test (FIT) based screening invitation to the conclusive screening Optical Colonoscopy (OC) on the risk of detecting colorectal cancer (CRC), advanced stage disease and precursor lesions. We used a cross-sectional study design and included all 62,554 screening participants registered in the Danish Colorectal Cancer Screening Database who tested FIT-positive between March 2014 and December 2016. The main exposure was response time, measured as the time from initial invitation to the conclusive OC. Our main outcomes were the probability of being diagnosed with CRC, advanced stage disease or precursor lesions. Of the 62,554 FIT-positive participants, 53,171 (85%) received an OC and were eligible for analysis (median age 63.7 years, 56% men). In this group, 3,639 cancers were registered, 2,890 of which were registered with a defined stage of disease (79%), and 1,042 (36%) of these were advanced stage (UICC III & IV). In addition, 17,732 high-risk and 10,605 low-risk adenomas were identified. Compared to participants receiving the conclusive examination within 30 days, those receiving the examination more than 90 days after initial invitation were 3.49 times more likely to be diagnosed with any CRC (OR 3.49 [95% CI, 3.13-3.89]) and 2.10 times more likely to have advanced stage disease (OR 2.10 [95% CI, 1.73-2.56]). Those waiting for the longest were also more likely to have one or more high-risk adenomas (OR 1.59 [95% CI, 1.50-1.68]). Increased screening response time was associated with a higher probability of detecting high-risk adenomas, any stage CRC and advanced stage cancer. More research is needed to explain what causes these associations.


Use of phosphosynapsin I-specific antibodies for image analysis of signal transduction in single nerve terminals.
We have developed a semi-quantitative method for indirectly revealing variations in the concentration of second messengers (Ca(2+), cyclic AMP) in single presynaptic boutons by detecting the phosphorylation of the synapsins, excellent nerve terminal substrates for cyclic AMP- and Ca(2+)/calmodulin-dependent protein kinases. For this purpose, we employed polyclonal, antipeptide antibodies recognising exclusively synapsin I phosphorylated by Ca(2+)/calmodulin-dependent protein kinase II (at site 3) or synapsins I/II phosphorylated by either cAMP-dependent protein kinase or Ca(2+)/calmodulin-dependent protein kinase I (at site 1). Cerebellar granular neurones in culture were double-labelled with a monoclonal antibody to synapsins I/II and either of the polyclonal antibodies. Digitised images were analysed to determine the relative phosphorylation stoichiometry at each individual nerve terminal. We have found that: (i) under basal conditions, phosphorylation of site 3 was undetectable, whereas site 1 exhibited some degree of constitutive phosphorylation; (ii) depolarisation in the presence of extracellular Ca(2+) was followed by a selective and widespread increase in site 3 phosphorylation, although the relative phosphorylation stoichiometry varied among individual terminals; and (iii) phosphorylation of site 1 was increased by stimulation of cyclic AMP-dependent protein kinase but not by depolarisation and often occurred in specific nerve terminal sub-populations aligned along axon branches. In addition to shedding light on the regulation of synapsin phosphorylation in living nerve terminals, this approach permits the spatially-resolved analysis of the activation of signal transduction pathways in the presynaptic compartment, which is usually too small to be studied with other currently available techniques.


Identifying depression and its determinants upon initiating treatment: ChatGPT versus primary care physicians.
To compare evaluations of depressive episodes and suggested treatment protocols generated by Chat Generative Pretrained Transformer (ChatGPT)-3 and ChatGPT-4 with the recommendations of primary care physicians. Vignettes were input to the ChatGPT interface. These vignettes focused primarily on hypothetical patients with symptoms of depression during initial consultations. The creators of these vignettes meticulously designed eight distinct versions in which they systematically varied patient attributes (sex, socioeconomic status (blue collar worker or white collar worker) and depression severity (mild or severe)). Each variant was subsequently introduced into ChatGPT-3.5 and ChatGPT-4. Each vignette was repeated 10 times to ensure consistency and reliability of the ChatGPT responses. For mild depression, ChatGPT-3.5 and ChatGPT-4 recommended psychotherapy in 95.0% and 97.5% of cases, respectively. Primary care physicians, however, recommended psychotherapy in only 4.3% of cases. For severe cases, ChatGPT favoured an approach that combined psychotherapy, while primary care physicians recommended a combined approach. The pharmacological recommendations of ChatGPT-3.5 and ChatGPT-4 showed a preference for exclusive use of antidepressants (74% and 68%, respectively), in contrast with primary care physicians, who typically recommended a mix of antidepressants and anxiolytics/hypnotics (67.4%). Unlike primary care physicians, ChatGPT showed no gender or socioeconomic biases in its recommendations. ChatGPT-3.5 and ChatGPT-4 aligned well with accepted guidelines for managing mild and severe depression, without showing the gender or socioeconomic biases observed among primary care physicians. Despite the suggested potential benefit of using atificial intelligence (AI) chatbots like ChatGPT to enhance clinical decision making, further research is needed to refine AI recommendations for severe cases and to consider potential risks and ethical issues.


Infection control strategies for preventing the transmission of meticillin-resistant Staphylococcus aureus (MRSA) in nursing homes for older people.
Nursing homes for older people provide an environment likely to promote the acquisition and spread of meticillin-resistant Staphylococcus aureus (MRSA), putting residents at increased risk of colonisation and infection. It is recognised that infection prevention and control strategies are important in preventing and controlling MRSA transmission. To determine the effects of infection prevention and control strategies for preventing the transmission of MRSA in nursing homes for older people. In August 2013, for this third update, we searched the Cochrane Wounds Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), Database of Abstracts of Reviews of Effects (DARE, The Cochrane Library), Ovid MEDLINE, OVID MEDLINE (In-process and Other Non-Indexed Citations), Ovid EMBASE, EBSCO CINAHL, Web of Science and the Health Technology Assessment (HTA) website. Research in progress was sought through Current Clinical Trials, Gateway to Reseach, and HSRProj (Health Services Research Projects in Progress). All randomised and controlled clinical trials, controlled before and after studies and interrupted time series studies of infection prevention and control interventions in nursing homes for older people were eligible for inclusion. Two review authors independently reviewed the results of the searches. Another review author appraised identified papers and undertook data extraction which was checked by a second review author. For this third update only one study was identified, therefore it was not possible to undertake a meta-analysis. A cluster randomised controlled trial in 32 nursing homes evaluated the effect of an infection control education and training programme on MRSA prevalence. The primary outcome was MRSA prevalence in residents and staff, and a change in infection control audit scores which measured adherence to infection control standards. At the end of the 12 month study, there was no change in MRSA prevalence between intervention and control sites, while mean infection control audit scores were significantly higher in the intervention homes compared with control homes. There is a lack of research evaluating the effects on MRSA transmission of infection prevention and control strategies in nursing homes. Rigorous studies should be conducted in nursing homes, involving residents and staff to test interventions that have been specifically designed for this unique environment.


Comparison of natural and nonnative two-species communities of Anolis lizards.
Human-mediated colonizations present an informative model system for understanding assembly of organismal communities. However, it is unclear whether communities including naturalized species are accurate analogs of natural communities or unique combinations not present in nature. I compared morphology and phylogenetic structure of natural and naturalized two-species communities of Anolis lizards. Natural communities are phylogenetically clustered, whereas naturalized communities show no significant phylogenetic structure. This result likely reflects differences in colonization pools for these communities-that is, invasion from anywhere for naturalized communities but from proximal and thus phylogenetically close lineages in natural communities. Both natural and naturalized communities each include pairs of species that are significantly similar to each other in morphology, and both sets of communities are composed of species that possess traits of good colonizers. These similarities suggest that the formation of natural and naturalized communities may be at least partially governed by similar processes. Human-mediated invasions may be credibly viewed as modern incarnations of natural colonizations in this case.


An empirical characterization of the quality of DTI data and the efficacy of dyadic sorting.
Metrics calculated from images acquired using the diffusion tensor imaging (DTI) technique possess a systematic bias that depends on signal-to-noise ratio (SNR). Dyadic sorting provides a simple method for remediating some of this bias within a region(s) of interest (ROI). Although this bias and its removal using dyadic sorting have been studied previously within a theoretical framework, one can employ precise geometric knowledge of microstructures to perform an empirical comparison between expected DTI results and those measured with a scanner. In this project, the biasing effect of low SNR (approximately 1-10) on DTI eigenvalues was measured directly using water-filled capillary structures of two different sizes, and the magnitude of the corrective effect of dyadically sorting eigenvector-eigenvalue pairs was characterized. Multiple DTI series were acquired for determining DTI metrics at eight unique SNR values, using T(R) to vary signal intensity via T(1) contrast. Differences between the second and third eigenvalues, which should be equal for prolate geometry, ranged from approximately 23% to 45% and from 19% to 41% for large and small inner diameter capillaries after sorting eigenvalues by magnitude, and ranged from approximately 1% to 18% and from 1% to 4% after dyadic sorting. A high-resolution DTI series was used to observe the effect of ROI size on dyadic sorting. For restriction of diffusion on the scale of the small capillary at SNR approximately 18, an ROI with > or =50 pixels is adequate to determine fractional anisotropy to 99% accuracy, while larger ROI are required to resolve the two smaller eigenvalues to the same accuracy ( approximately 330-390 pixels). At low values of SNR, the iteration of dyadic sorting is suggested to achieve good accuracy. A method for the incorporation of empirical measurements into a bias-correction map, which would be useful for characterizing uncertainty and for reducing systematic bias in DTI data, is introduced.


Flow-field inference from neural data using deep recurrent networks.
Computations involved in processes such as decision-making, working memory, and motor control are thought to emerge from the dynamics governing the collective activity of neurons in large populations. But the estimation of these dynamics remains a significant challenge. Here we introduce Flow-field Inference from Neural Data using deep Recurrent networks (FINDR), an unsupervised deep learning method that can infer low-dimensional nonlinear stochastic dynamics underlying neural population activity. Using population spike train data from frontal brain regions of rats performing an auditory decision-making task, we demonstrate that FINDR outperforms existing methods in capturing the heterogeneous responses of individual neurons. We further show that FINDR can discover interpretable low-dimensional dynamics when it is trained to disentangle task-relevant and irrelevant components of the neural population activity. Importantly, the low-dimensional nature of the learned dynamics allows for explicit visualization of flow fields and attractor structures. We suggest FINDR as a powerful method for revealing the low-dimensional task-relevant dynamics of neural populations and their associated computations.


Current understanding and importance of histone phosphorylation in regulating chromatin biology.
The core histones H2A, H2B, H3 and H4, undergo various post-translational modifications, such as acetylation, methylation and phosphorylation. Core histone phosphorylation has roles in several biological responses, including transcription, mitosis, DNA repair and apoptosis. Histone phosphorylation may disrupt chromatin structure and/or provide a 'code' for the recruitment or occlusion of non-histone chromosomal proteins to chromatin. Among the better-characterized histone phosphorylation events are the phosphorylation of H3 at Ser10 and Ser 28, and the phosphorylation of the H2A variant H2A.X at Ser139. Much remains to be learned about the function of the many other core histone phosphorylation events in chromatin. This review provides an overview of the biological roles of core histone phosphorylation in mammalian cells.


High rates of burnout among maternal health staff at a referral hospital in Malawi: A cross-sectional study.
Burnout among maternal healthcare workers in sub-Saharan Africa may have a negative effect on services provided and efforts to mitigate high maternal mortality rates. In Malawi, research on burnout is limited and no empirical research has been conducted specifically among maternal health staff. Therefore, the aims of the study were to examine the prevalence and degree of burnout reported by healthcare workers who provide antenatal, intrapartum, and postnatal services in a district referral hospital in Malawi; and, to explore factors that may influence the level of burnout healthcare workers experience. In the current cross-sectional study, levels of burnout among staff working in obstetrics and gynaecology at a referral hospital in Malawi were examined, in addition to individual and job characteristics that may be associated with burnout. In terms of the three dimensions of burnout, of the 101 participants, nearly three quarters (72%) reported emotional exhaustion, over one third (43%) reported depersonalization while almost three quarters (74%) experienced reduced personal accomplishment. Based on these findings, burnout appears to be common among participating maternal health staff and they experienced more burnout than their colleagues working in other medical settings and countries. Further research is needed to identify factors specific to Malawi that contribute to burnout in order to inform the development of prevention and treatment within the maternal health setting.


Interhemispheric asymmetry of EEG coherence as a reflection of different functional states of the human brain.
EEG coherence analysis was used to study aspects of the synchronisation of electrical processes in the left and right cerebral hemispheres of right-handed and left-handed healthy subjects in a state of calm wakefulness. Right-handed subjects showed a greater coherence in the left hemisphere and left-handed subjects in the right hemisphere. There were also differences between right-handed and left-handed subjects in the regional profiles of interhemispheric asymmetry and in the interhemispheric asymmetry of individual spectral bands. These differences may reflect variations in the involvement of cortical and subcortical cerebral structures in the formation of the hemispheric specificity. Changes in interhemispheric coherence with the onset of drowsiness were also observed. This suggests that changes in the interconnections of neural networks are also involved in changes in arousal. Certain characteristic regional interhemispheric asymmetry patterns and asymmetries in the spectral bands appear to be necessary for normal human brain function.


Dysfunctional and Proinflammatory Regulatory T-Lymphocytes Are Essential for Adverse Cardiac Remodeling in Ischemic Cardiomyopathy.
Heart failure (HF) is a state of inappropriately sustained inflammation, suggesting the loss of normal immunosuppressive mechanisms. Regulatory T-lymphocytes (Tregs) are considered key suppressors of immune responses; however, their role in HF is unknown. We hypothesized that Tregs are dysfunctional in ischemic cardiomyopathy and HF, and they promote immune activation and left ventricular (LV) remodeling. Adult male wild-type C57BL/6 mice, Foxp3-diphtheria toxin receptor transgenic mice, and tumor necrosis factor (TNF) α receptor-1 (TNFR1)-/- mice underwent nonreperfused myocardial infarction to induce HF or sham operation. LV remodeling was assessed by echocardiography as well as histological and molecular phenotyping. Alterations in Treg profile and function were examined by flow cytometry, immunostaining, and in vitro cell assays. Compared with wild-type sham mice, CD4+Foxp3+ Tregs in wild-type HF mice robustly expanded in the heart, circulation, spleen, and lymph nodes in a phasic manner after myocardial infarction, beyond the early phase of wound healing, and exhibited proinflammatory T helper 1-type features with interferon-γ, TNFα, and TNFR1 expression, loss of immunomodulatory capacity, heightened proliferation, and potentiated antiangiogenic and profibrotic properties. Selective Treg ablation in Foxp3-diphtheria toxin receptor mice with ischemic cardiomyopathy reversed LV remodeling and dysfunction, alleviating hypertrophy and fibrosis, while suppressing circulating CD4+ T cells and systemic inflammation and enhancing tissue neovascularization. Tregs reconstituted after ablation exhibited restoration of immunosuppressive capacity and normalized TNFR1 expression. Treg dysfunction was also tightly coupled to Treg-endothelial cell contact- and TNFR1-dependent inhibition of angiogenesis and the mobilization and tissue infiltration of CD34+Flk1+ circulating angiogenic cells in a C-C chemokine ligand 5/C-C chemokine receptor 5-dependent manner. Anti-CD25-mediated Treg depletion in wild-type mice imparted similar benefits on LV remodeling, circulating angiogenic cells, and tissue neovascularization. Proinflammatory and antiangiogenic Tregs play an essential pathogenetic role in chronic ischemic HF to promote immune activation and pathological LV remodeling. The restoration of normal Treg function may be a viable approach to therapeutic immunomodulation in this disease.


Unilateral versus bilateral percutaneous kyphoplasty for osteoporotic vertebral compression fractures: A meta-analysis.
The debate on the efficacy of unilateral percutaneous kyphoplasty (UPKP) and bilateral percutaneous kyphoplasty (BPKP) for the treatment of osteoporotic vertebral compression fractures (OVCFs) is ongoing.This meta-analysis aimed to evaluate the clinical results of UPKP and BPKP in the treatment of OVCFs. Web of Science, PubMed, Embase, and the Chinese Biomedical Database publication databases were searched using a date range of January 2008 to November 2016, for studies comparing UPKP and BPKP for the treatment of OVCFs. The clinical effectiveness was assessed by comparing perioperative outcomes (surgery time, the volume of injected cement, X-ray exposure time, and kyphotic angle reduction), clinical outcomes (visual analogue scale [VAS] for pain relief and Oswestry Disability Index [ODI] for quality of life), and surgery-related complications (cement leakage and adjacent vertebral fractures). Data were analyzed using Stata/SE11.0 software. Fourteen trials with 1194 patients were retrieved. The pooled results showed significant differences in surgery time (weighted mean difference [WMD] -21.44, 95% confidence interval [CI] [-23.57 to -19.30]; P < .001); volume of injected cement [WMD -1.90, 95% CI [-2.26 to -1.54); P < .001); and X-ray exposure time (WMD -13.66, 95%CI [-19.59 to -7.72]; P < .001) between UPKP and BPKP treatments. However, the pooled results showed no significant differences in kyphotic angle reduction, VAS in the short-term, VAS in the long-term, ODI, cement leakage, or adjacent vertebral fractures between the 2 surgical procedures. Following a subgroup analysis, the results based on randomized controlled trials (RCTs) indicated that there were significant differences in surgery time (WMD -24.65, 95%CI [-26.53 to -22.77]; P < .001) and the volume of injected cement (WMD -1.66, 95%CI [-1.97 to -1.36]; P < .001) between UPKP and BPKP treatment procedures, respectively. The results based on RCTs indicated that there were no significant differences, either in kyphotic angle reduction or in X-ray exposure time, between the 2 surgical procedures. Compared to BPKP procedures, UPKP procedures may achieve similar clinical results in the treatment of OVCFs when assessed in terms of the pain relief, improvements in life quality, and surgery-related complications. However, UPKP procedures had a shorter operation time and volume of injected cement compared with BPKP procedures. Additional high quality and multicenter RCTs are needed to provide further robust evidence.


African biogeographical ancestry, atopic and non-atopic asthma and atopy: A study in Latin American children.
Genetic variants underlying African ancestry have been suggested be implicated in the ethnic-racial inequalities reported for asthma and allergies. To investigate the association between individual African ancestry and asthma symptoms, atopic and non-atopic asthma, and atopy in children. A cross-sectional study encompassing 1190 individuals was conducted. African biogeographic ancestry was estimated using 370 539 genome-wide SNPs. Serum levels of specific IgE were measured, and skin prick test (SPT) performed for the most common local aeroallergens. Information on asthma symptoms was obtained by applying the International Study of Allergy and Asthma in Childhood questionnaire. The associations between the proportion of individual African ancestry and the outcomes investigated were analyzed through multivariate models adjusted for socio-environmental variables, infections markers, and psychosocial factors. Each 20% increase in the proportion of African ancestry was negatively associated with SPT reactivity (OR: 0.79, 95%CI: 0.66-0.96) and positively associated with asthma symptoms in non-atopic individuals (OR: 1.40, 95%CI: 1.03-1.89). We estimated that socioeconomic status and number of infections mediated 28.4% of the effect of African ancestry on SPT reactivity, while 20.2% of the effect on non-atopic asthma was explained by socioeconomic status and behavioral problems in children. The negative association observed between African ancestry and atopy is most probably explained by unobserved environmental or social factors that covariate with ancestry. For non-atopic asthma, in turn, putative genetic variants of risk underlying African ancestry may play some role.


Nucleating a Different Coordination in a Crystal under Pressure: A Study of the B1-B2 Transition in NaCl by Metadynamics.
Here we propose an NPT metadynamics simulation scheme for pressure-induced structural phase transitions, using coordination number and volume as collective variables, and apply it to the reconstructive structural transformation B1-B2 in NaCl. By studying systems with size up to 64 000 atoms we reach a regime beyond collective mechanism and observe transformations proceeding via nucleation and growth. We also reveal the crossover of the transition mechanism from Buerger-like for smaller systems to Watanabe-Tolédano for larger ones. The scheme is likely to be applicable to a broader class of pressure-induced structural transitions, allowing study of complex nucleation effects and bringing simulations closer to realistic conditions.


Candidate composite biomarker to inform drug treatments for diabetic kidney disease.
Current guidelines recommend renin angiotensin system inhibitors (RASi) as key components of treatment of diabetic kidney disease (DKD). Additional options include sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP1a), and mineralocorticoid receptor antagonists (MCRa). The identification of the optimum drug combination for an individual is difficult because of the inter-, and longitudinal intra-individual heterogeneity of response to therapy. Using data from a large observational study (PROVALID), we identified a set of parameters that can be combined into a meaningful composite biomarker that appears to be able to identify which of the various treatment options is clinically beneficial for an individual. It uses machine-earning techniques to estimate under what conditions a treatment of RASi plus an additional treatment is different from the treatment with RASi alone. The measure of difference is the annual percent change (ΔeGFR) in the estimated glomerular filtration rate (ΔeGFR). The 1eGFR is estimated for both the RASi-alone treatment and the add-on treatment. Higher estimated increase of eGFR for add-on patients compared with RASi-alone patients indicates that prognosis may be improved with the add-on treatment. The personalized biomarker value thus identifies which patients may benefit from the additional treatment.


Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy: a primer for radiologists.
Nephrogenic systemic fibrosis (NSF) is a rare, idiopathic systemic fibrosing disorder that is predominantly characterized by a clinicopathologically distinct symmetric dermopathy and debilitating joint contractures. The condition affects patients with renal insufficiency and appears to show improvement with prompt restoration of renal function. Although NSF was initially reported in the United States as nephrogenic fibrosing dermopathy, it has subsequently been described in patients in Europe and Asia. More than 215 cases of NSF have been reported in the nephrogenic fibrosing dermopathy/NSF registry that is currently maintained at the Yale University. Recent reports suggest a possible etiologic link between systemic administration of gadolinium-containing magnetic resonance imaging contrast agents in patients with renal insufficiency and the development of NSF.


The latent structure of self-harm.
The underlying structure of self-harm behaviors is not well-understood; for example, whether suicidality and nonsuicidal self-injury (NSSI) lie on a single dimension or two separate dimensions is unknown. We used confirmatory factor analyses to examine the factor structure of self-harm items in a clinical/community sample (N = 641). Of three alternative factor structures (one-factor, correlated-factors, bifactor), the bifactor model fit best. The general factor, representing overlap between suicidality and NSSI, captured the majority of model variance and was the strongest predictor of psychosocial correlates. The NSSI-specific factor captured a moderate amount of variance and correlated uniquely with both antagonistic traits and obsessive-compulsive tendencies; this factor was named NSSI. The suicidality-specific factor explained little model variance and was weakly associated with external criteria; this factor was named low attraction to life. Results are interpreted as preliminary evidence for the utility of bifactor modeling in understanding the latent structure of self-harm. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Online personalized feedback intervention reduces cannabis-related problems among college students with high problem distress.
Despite experiencing problems related to using cannabis, very few undergraduate cannabis users are interested in treatment for cannabis-related problems or benefit from cannabis-focused online personalized feedback interventions (PFIs). Thus, it may be important to determine whether individuals perceive their problems as distressing, as only those who are distressed by their problems may be motivated to change their cannabis use or benefit from cannabis-related interventions. The current study examined cannabis-related problem distress, its relation to motivation to change cannabis use, and whether problem distress impacted outcomes of a problem-focused online PFI. Past-month cannabis-using undergraduates who endorsed experiencing at least one cannabis-related problem in the past 3 months were randomized to a PFI (n = 102) or a personalized normative feedback (PNF)-only condition (n = 102). Problem distress was robustly related to readiness, importance, and confidence to change cannabis use at baseline. Among those with high levels of problem distress at baseline, those in the PFI condition reported a greater decrease in problems than those in the PNF-only condition. This was not the case among those with lower levels of problem distress. Further, the number of cannabis-related problems did not moderate intervention outcomes. Cannabis users who perceive their problems as more distressing may be more motivated to change their cannabis use and more likely to benefit from a problem-focused PFI relative to a PNF-only intervention. Results have implications for the personalization of cannabis-focused interventions to maximize the impacts of interventions and decrease cannabis-related problems. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


The effects of RAMPs upon cell signalling.
G protein-coupled receptors (GPCRs) play a vital role in signal transduction. It is now clear that numerous other molecules within the cell and at the cell surface interact with GPCRs to modulate their signalling properties. Receptor activity modifying proteins (RAMPs) are a group of single transmembrane domain proteins which have been predominantly demonstrated to interact with Family B GPCRs, but interactions with Family A and C receptors have recently begun to emerge. These interactions can influence cell surface expression, ligand binding preferences and G protein-coupling, thus modulating GPCR signal transduction. There is still a great deal of research to be conducted into the effects of RAMPs on GPCR signalling; their effects upon Family B GPCRs are still not fully documented, in addition to their potential interactions with Family A and C GPCRs. New interactions could have a significant impact on the development of therapeutics.


Chronic stress increases the tyrosine phosphorylation in female reproductive organs: An experimental study.
Changes in tyrosine-phosphorylated (TyrPho) protein expressions have demonstrated stress in males. In females, chronic stress (CS) is a major cause of infertility, especially anovulation. However, the tyrosine phosphorylation in the female reproductive system under stress conditions has never been reported. To investigate the alteration of TyrPho protein expression in ovary, oviduct, and uterus of CS rats. In this experimental study, 16 female Sprague-Dawley rats (5 wk: 220-250 gr) were divided into control and CS groups (n = 8/group). Every day, the CS animals were immobilized within a restraint cage and individually forced to swim in cold water for 60 consecutive days. Following the stress induction, the ovary, oviduct, and uterus of all rats were observed for their morphologies. The total protein profiles of all tissues were revealed by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) before detecting TyrPho proteins using western blot. Intensity analysis was used to compare the expression of proteins between groups. The results showed that the morphology and weights of ovary and oviduct in the CS group were not different from control. In contrast, the CS significantly increased the uterine weight as compared to control. Moreover, the expressions of TyrPho proteins in the ovary (72, 43, and 28 kDas), oviduct (170, 55, and 43 kDas), and uterus (55, 54, and 43 kDas) were increased in CS group as compared to those of control. The increased expressions of TyrPho proteins in ovary, oviduct, and uterus could be potential markers used to explain some machanisms of female infertility caused from chronic stress.


Forfeiture of proceeds of drug-related crimes: a British Commonwealth perspective.
The forfeiture of the proceeds of drug-related offences does not seem to have received much attention as yet from British Commonwealth countries. Whereas in some of these countries specific legislation exists in relation to forfeiture, in many other countries the act of forfeiture falls within the purview of general criminal law. Forfeiture presupposes enquiry and search, two procedures which involve integral aspects of present-day human rights law, and which seem to be impeded at almost every stage of the process concluding in forfeiture. Time and the procedure for execution of judgments seem to be two significant factors in the successful enforcement of forfeiture judgments. Unfortunately, given the present practice of maintaining inviolability of bank secrecy, effective enforcement of forfeiture judgments is not possible. Perhaps an international convention may offer some assistance in the successful implementation of a forfeiture judgment, especially where the ill-gotten gains have been transferred to a foreign jurisdiction.


25th anniversary article: Bulk heterojunction solar cells: understanding the mechanism of operation.
The status of understanding of the operation of bulk heterojunction (BHJ) solar cells is reviewed. Because the carrier photoexcitation recombination lengths are typically 10 nm in these disordered materials, the length scale for self-assembly must be of order 10-20 nm. Experiments have verified the existence of the BHJ nanostructure, but the morphology remains complex and a limiting factor. Three steps are required for generation of electrical power: i) absorption of photons from the sun; ii) photoinduced charge separation and the generation of mobile carriers; iii) collection of electrons and holes at opposite electrodes. The ultrafast charge transfer process arises from fundamental quantum uncertainty; mobile carriers are directly generated (electrons in the acceptor domains and holes in the donor domains) by the ultrafast charge transfer (≈70%) with ≈30% generated by exciton diffusion to a charge separating heterojunction. Sweep-out of the mobile carriers by the internal field prior to recombination is essential for high performance. Bimolecular recombination dominates in materials where the donor and acceptor phases are pure. Impurities degrade performance by introducing Shockly-Read-Hall decay. The review concludes with a summary of the problems to be solved to achieve the predicted power conversion efficiencies of >20% for a single cell.


Prevention of pressure ulcers in acute and long-term care facilities in Finland: results of a survey.
The purpose of this study was to identify those healthcare organizations that have a high incidence of pressure ulcers, and to determine what their staffs do to prevent pressure ulcer formation. The sample was formed from 11 hospitals in one large city on a certain day in Finland in 1998. The researchers sent questionnaires to 154 hospital units and achieved a 94% response rate. Psychiatric; gynecologic; obstetric; and eye, ear, nose, and throat units were not included. The data were collected using two questionnaires: The first gathered data about the organization and the second about the patients. Fifty-seven percent of the units surveyed reported having patients with pressure ulcers. Of these units, 45% were acute and 55% were long-term care. Thirty-nine percent of all units had a pressure ulcer team. Units with pressure ulcer patients had a staffing level of 0.6 registered nurses and practical nurses per bed, compared with 0.7 registered nurses and practical nurses per bed for those units without pressure ulcer patients. The average length of stay on the unit was less for those without pressure ulcers compared to those with ulcers (P < 0.001) and only 18% of the units without pressure ulcers had a pressure ulcer team. According to the results, those units with pressure ulcer patients identified the need for more preventive measures more frequently than the units without ulcer patients. In conclusion, pressure ulcers seem to predominate in long-term care settings, and the educational level of healthcare staffing seems to impact the occurrence of pressure ulcers. Common preventive measures are used by the staff in both acute and long-term care settings.


Impact of the the COVID-19 pandemic on a queen conch (Aliger gigas) fishery in The Bahamas.
The onset of the coronavirus (COVID-19) pandemic in early 2020 led to a dramatic rise in unemployment and fears about food-security throughout the Caribbean region. Subsistence fisheries were one of the few activities permitted during emergency lockdown in The Bahamas, leading many to turn to the sea for food. Detailed monitoring of a small-scale subsistence fishery for queen conch was undertaken during the implementation of coronavirus emergency control measures over a period of twelve weeks. Weekly landings data showed a surge in fishing during the first three weeks where landings were 3.4 times higher than subsequent weeks. Overall 90% of the catch was below the minimum legal-size threshold and individual yield declined by 22% during the lockdown period. This study highlights the role of small-scale fisheries as a 'natural insurance' against socio-economic shocks and a source of resilience for small island communities at times of crisis. It also underscores the risks to food security and long-term sustainability of fishery stocks posed by overexploitation of natural resources.


Drug Therapy in the Progressed CML Patient with multi-TKI Failure.
The aim of this paper is to outline pharmacotherapy of the 'third-line management of CML' (progressive disease course after sequential TKI drugs). Current management of CML with multi-TKI failure is reviewed. TKI (bosutinib, ponatinib, dasatinib, nilotinib) and non-TKI (omacetaxine mepussecinate, IFN or PEG-IFN) drugs are available. The literature search was made in PubMed with particular focus on the clinical trials, recommendations, guidelines and expert opinions, as well as international recommendations. Progressing CML disease with multi-TKI failure should be treated with alloSCT based on the availability of the donor and EBMT transplant risk scores. The TKI and non-TKI drugs shall be used to get best promising (hematological, cytogenetic, molecular) response. During the CP-CML phase of multi-TKI failure, 2nd generation TKIs (nilotinib or dasatinib) should be tried if not previously utilized. Bosutinib and ponatinib (3rd-generation TKIs) should be administered in double- or triple-TKI (imatinib and nilotinib and dasatinib) resistant patients. The presence of T315I mutation at any phase requires ponatinib or omacetaxine mepussecinate therapy before allografting. During the AP/BC-CML phase of multi-TKI failure, the most powerful TKI available (ponatinib or dasatinib if not previously used) together with chemotherapy should be given before alloSCT. Monitoring of CML disease and drug off-target risks (particularly vascular thrombotic events) are vital.


Amphiphilic poly(ether ester amide) multiblock copolymers as biodegradable matrices for the controlled release of proteins.
Amphiphilic poly(ether ester amide) (PEEA) multiblock copolymers were synthesized by polycondensation in the melt from hydrophilic poly(ethylene glycol) (PEG), 1,4-dihydroxybutane and short bisester-bisamide blocks. These amide blocks were prepared by reaction of 1,4-diaminobutane with dimethyl adipate in the melt. A range of multiblock copolymers were prepared, with PEG contents varying from 23-66 wt %. The intrinsic viscosity of the PEEA polymers varied from 0.58-0.78. Differential scanning calorimetry showed melting transitions for the PEG blocks and for the amide-ester blocks, suggesting a phase separated structure. Both the melting temperature and the crystallinity of the hard amide-ester segments decreased with increasing PEG content of the polymers. The equilibrium swelling ratio in phosphate buffered saline (PBS) increased with increasing amount of PEG in the polymers and varied from 1.7 to 3.7, whereas the polymer that contained 66 wt % PEG was soluble in PBS. During incubation of PEEA films in PBS, weight loss and a continuous decrease in the resulting inherent polymer viscosity was observed. The rate of degradation increased with increasing PEG content. The composition of the remaining matrices did not change during degradation. A preliminary investigation of the protein release characteristics of these PEEA copolymers showed that release of the model protein lysozyme was proportional to the square root of time. The release rate was found to increase with increasing degree of swelling of the polymers.


Health status and quality of life in patients with diabetes in Switzerland.
We aimed to assess the health status and quality of life (QoL) of patients with diabetes and explore the associated factors in a French-speaking region of Switzerland. This cross-sectional study analyzed self-reported data from 585 patients with diabetes. We ran univariate and multivariate regressions analyses on health status (Physical and Mental Component Summary scores (PCS, MCS) of the SF-12) and diabetes-specific QoL (ADDQoL score). Mean PCS was 43.1±10.4 and mean MCS was 46.7±11.1. The overall ADDQoL score was -1.6±1.6; the life domains of the ADDQoL with the lowest scores were freedom to eat, sex life and freedom to drink. Being older was independently and significantly associated with higher mental health and QoL, while lower income was associated with lower physical health, mental health, and QoL. Having diabetes for over 10 years was associated with lower QoL, while insulin treatment and complications were correlated with lower physical health and QoL. This study provides key information on the health status and QoL of patients with diabetes in Switzerland and their associated factors, which can help healthcare providers to identify patients at higher risk of lower health and QoL.


Virus-inspired mimics: self-assembly of dendritic lipopeptides into arginine-rich nanovectors for improving gene delivery.
With inspirations from natural viruses, arginine-containing dendritic lipopeptides were designed for bioinspired fabrication. Self-assembling the defined amphiphilic lipopeptides generated virus-inspired nanovectors with an arginine-rich corona. These nanovectors provided some remarkable benefits for gene delivery, including well-defined nanostructure, high transfection efficiency, serum resistance and low cytotoxicity.


Distribution and degradation of biotin-containing carboxylases in human cell lines.
Incubation of cultured cells with [3H]biotin leads to the labelling of acetyl-CoA carboxylase, pyruvate carboxylase, propionyl-CoA carboxylase and methylcrotonyl-CoA carboxylase. The biotin-containing subunits of the last two enzymes from rat cell lines are not separated by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis, but adequate separation is achieved with the enzymes from human cells. Since incorporated biotin is only released upon complete protein breakdown, the loss of radioactivity from gel slices coinciding with fluorograph bands was used to quantify degradation rates for each protein. In HE(39)L diploid human fibroblasts, the degradation rate constants are 0.55, 0.40, 0.31 and 0.19 day-1 for acetyl-CoA carboxylase, pyruvate carboxylase, methylcrotonyl-CoA carboxylase and propionyl-CoA carboxylase respectively. A similar series of rate constants is found for AG2804 transformed fibroblasts. The degradation rate constants are decreased by 31-67% in the presence of 50 micrograms of leupeptin/ml plus 5 mM-NH4Cl. Although the largest percentage effect was noted with the most stable enzyme, propionyl-CoA carboxylase, the absolute change in rate constant produced by the lysosomotropic inhibitors was similar for the three mitochondrial carboxylases, but greater for the cytosolic enzyme acetyl-CoA carboxylase. The heterogeneity in degradation rate constants for the mitochondrial carboxylases indicates that only part of their catabolism can occur via the autophagy-mediated unit destruction of mitochondria. Calculations showed that the autophagy-linked process had degradation rate constants of 0.084 and 0.102 day-1 respectively in HE(39)L and AG2804 cells. It accounted for two-thirds of the catabolic rate of propionyl-CoA carboxylase and a lesser proportion for the other enzymes.


Guidelines and training initiatives that support communication in cross-cultural primary-care settings: appraising their implementability using Normalization Process Theory.
Guidelines and training initiatives (G/TIs) available to support communication in cross-cultural primary health care consultations are not routinely used. We need to understand more about levers and barriers to their implementation and identify G/TIs likely to be successfully implemented in practice. To report a mapping process used to identify G/TIs and to prospectively appraise their implementability, using Normalization Process Theory (NPT). RESTORE is a 4-year EU FP-7 project. We used purposeful and network sampling to identify experts in statutory and non-statutory agencies across Austria, England, Greece, Ireland, Scotland and the Netherlands who recommended G/TI data from the grey literature. In addition, a peer review of literature was conducted in each country. Resulting data were collated using a standardized Protocol Mapping Document. G/TIs were identified for inclusion by (i) initial elimination of incomplete G/TI material; (ii) application of filtering criteria; and (iii) application of NPT. 20 G/TIs met selection criteria: 8 guidelines and 12 training initiatives. Most G/TIs were identified in the Netherlands (n = 7), followed by Ireland (n = 6) and England (n = 5). Fewer were identified in Scotland (n = 2), and none in Greece or Austria. The majority (n = 13) were generated without the inclusion of migrant service users. All 20 were prospectively appraised for potential implementability by applying NPT. NPT is useful as a means of prospectively testing G/TIs for implementability. Results indicate a need to initiate meaningful engagement of migrants in the development of G/TIs. A European-based professional standard for development and assessment of cross-cultural communication resources is advised.


Clinical spectrum of woolly hair: indications for cerebral involvement.
Woolly Hair is an uncommon congenital anomaly of the scalp hair presenting with strongly coiled hair involving a localized area of the scalp or covering the entire side and occurring in non-black people. Isolated or localized wooly hair is usually benign and is not related to other disorders and/or complications. On the contrary, the generalized type may be related to disorders and syndromes affecting heart, cutis, liver and gastrointestinal organs. Among the syndromes presenting with wooly hair, the most known are the Naxos syndrome, the Carvajal-Huerta syndrome, the wooly hair/hypotrichosis, the ectodermal dysplasia-skin fragility, the tricho-hepato-enteric syndrome. To our knowledge, no cases of wooly hair syndromes has been associated to neurologic involvement. Among the clinical notes of patients admitted in the Pediatric Units of the Catania University, we have selected four individuals presenting wooly hair, who showed different clinical features and course: case 1 presenting with a localized wooly hair type; case 2, member of a family affected by WH with autosomal dominant inheritance, not associated to complications; case 3, a wooly hair patient who displayed a progressive, severe form of Rasmussen's encephalitis with fatal evolution, and case 4, wooly hair associated to brain malformation and drug-resistant epilepsy. With this report, we aim to underline the wide spectrum of clinical presentation of individuals with WH and in particular we wish to give an annotation on a possible association of WH with severe neurologic disorders.


Organochlorine-mediated potentiation of the general coactivator p300 through p38 mitogen-activated protein kinase.
The activity of nuclear transcription factors is often regulated by specific kinase-signaling pathways. We have previously shown that the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) stimulates activator protein-1 activity through the p38 mitogen-activated protein kinase (MAPK). Here, we show that DDT and its metabolites also stimulate the transcriptional activity of cyclic adenosine monophosphate response element-binding protein and Elk1 and potentiate gene expression through cyclic adenosine monophosphate and hypoxia response elements. Because DDT stimulates gene expression through various transcription factors and hence multiple response elements, we hypothesized that p38 signaling targets a common shared transcriptional activator. Here, we demonstrate using both pharmacological and molecular techniques, the general coactivator p300 is phosphorylated and potentiated by the p38 MAPK signaling cascade. We further show that p38 directly phosphorylates p300 in its N-terminus. These results, together with our previous work, suggest that p38 stimulates downstream transcription factors in part by targeting the general coactivator p300.


Association of the NLR, BNP, PCT, CRP, and D-D with the Severity of Community-Acquired Pneumonia in Older Adults.
This study aimed to investigate the value of the neutrophil-to-lymphocyte ratio (NLR), B-type natriuretic peptide (BNP), and D-dimer (D-D) in predicting pneumonia severity in older adults with community-acquired pneumonia (CAP). The retrospective study included older adults with CAP at the General Hospital of Northern Theater Command from January 2017 to December 2019. Patient demographic information and clinical characteristics were collected. Logistic multivariable analysis was used to analyze the factors associated with CAP severity. Receiver operating curve (ROC) analysis was used to evaluate the value of each biomarker in severity prediction. A total of 158 patients were included: 85 with mild-moderate CAP and 73 with severe CAP. The multivariable logistic analysis showed that CRP (OR = 1.011; 95% CI: 1.011 - 1.022; p = 0.039), BNP (OR = 1.003; 95% CI: 1.001 - 1.004; p = 0.001), D-D (OR = 1.289; 95% CI: 1.031 - 1.611; p = 0.026), and NLR (OR = 1.111; 95% CI: 1.011 - 1.222; p = 0.030) were independent factors associated with pneumonia severity. ROC analysis demonstrated the value of each biomarker in pneumonia severity prediction: CRP (AUC = 0.791, 95% CI: 0.720 - 0.861), BNP (AUC = 0.803, 95% CI: 0.649 - 0.806), D-D (AUC = 0.727, 95% CI: 0.734 - 0.872), and NLR (AUC = 0.817, 95% CI: 0.751 - 0.883). The positive and negative predictive values were 0.68 and 0.81 for CRP, 0.79 and 0.75 for BNP, 0.62 and 0.80 for D-D, and 0.80 and 0.76 for NLR. CRP, BNP, D-D, and NLR might be helpful independent factors in predicting pneumonia severity in older adults with CAP.


Investigations of the possible glycosylation of monoamine oxidase B from pig leucocytes.
Monoamine oxidase B (MAO B) from pig liver has been reported to be a sialoglycoprotein. However, when that enzyme from pig lymphocytes and granulocytes was separated by polyacrylamide gel electrophoresis after labelling with the specific irreversible inhibitor [3H]pargyline, staining with 1-ethyl-2-[3-(1-ethyl-naphtho [1,2d] thiazolin-2-ylidene)-2-methylpropenyl] naphtho [1,2d] thiazolium bromide ("Stains-all") failed to detect the presence of sialic acid residues. Treatment of the enzyme in disrupted lymphocytes and granulocytes, or in mitochondrial fractions prepared from them, with neuraminidase resulted in a decrease in MAO activity. However, after the enzyme was rendered soluble by treatment with octylglucoside, treatment with neuraminidase had no effect on the activity. These results indicate that sialic acid residues are not an intrinsic component of MAO B, although associated material containing such groups appears to affect the activity of the membrane-bound enzyme. The activities of membrane-bound preparations of MAO B from pig lymphocytes and granulocytes were unaffected by treatment with trypsin or beta-chymotrypsin. After the preparations had been rendered soluble by treatment with octylglucoside there was a decrease in the activity on treatment with beta-chymotrypsin, but trypsin treatment had no effect. Thus solubilization resulted in residues sensitive to cleavage by the former enzyme becoming accessible to it. Tryptic and chymotryptic peptides separated from the sodium dodecyl sulphate denatured enzymes by polyacrylamide gel electrophoresis revealed no differences between MAO B prepared from lymphocytes and granulocytes.


Adiponectin and insulin resistance in childhood obesity.
To measure adiponectin serum levels in Greek children and adolescents and correlate them with body fat and insulin resistance. Forty-six obese prepubertal children (19 M, 27 F) and 34 obese adolescents (17 M, 17 F) ages 9.33 +/- 1.57 and 13.6 +/- 1.42 years, respectively, and 43 matched control individuals were studied. Body mass index standard deviation score and percent body fat were measured by bioelectric impedance analysis. Fasting indices of insulin resistance (HOMA-IR and fasting glucose-to-insulin ratio) were calculated for all participants. Indices of insulin resistance derived from oral glucose tolerance tests were estimated in obese participants. Adiponectin was measured by enzyme-linked immunosorbent assay. (MEAN +/- SD):: Adiponectin serum levels were significantly lower in obese participants than in nonobese participants (8.11 +/- 3.80 vs 11.81 +/- 4.98 microg/mL, P < 0.001), in obese children than in nonobese children (8.86 +/- 3.86 vs 13.08 +/- 5.48 microg/mL, P < 0.001), in obese adolescents than in nonobese adolescents (7.04 +/- 3.43 vs 10.47 +/- 4.10 microg/mL, P = 0.002), and in obese adolescent boys than in obese adolescent girls (5.87 +/- 3.52 vs 8.31 +/- 3.16 microg/mL, P = 0.042). There were significant correlations between adiponectin and age, body mass index, body mass index standard deviation score, homeostasis model assessment for insulin resistance, and fasting glucose-to-insulin ratio. Adiponectin correlated with percent body fat after adjustment for sex. Adiponectin correlated significantly with several indices of insulin resistance, such as the areas under the curves for glucose and insulin, whole-body insulin sensitivity index, glucose 120', and insulin 30', in obese participants. Adiponectin was significantly lower in obese participants than in nonobese participants in general, and it correlated significantly with fasting indices of insulin resistance and with indices derived from oral glucose tolerance tests. It is worthwhile to further investigate the option of applying a simple measurement of serum adiponectin as a screening tool before applying more time-consuming techniques in young obese individuals.


Integrated treatment of schizophrenia.
The importance of combining psychosocial and pharmacologic interventions for optimum outcome in the treatment of schizophrenia is now well recognized. However, less research is available on ways in which the two types of treatment may affect each other. This article reviews research and principles applying to the integrated use of current psychosocial and pharmacologic treatments for schizophrenia. Emphasis is placed on areas of interaction, including patient adherence and the effect of antipsychotic medications on cognitive functioning. Recommendations are presented for specific clinical situations.


Clinical impact of real-time evaluation of the biological activity and degradation of hepatocyte growth factor.
Hepatocyte growth factor (HGF) is essential for injury repair. Despite high HGF levels in chronic ulcers, up-regulation of HGF receptor in ulcer tissue and decreased biological activity of HGF in ulcer secretions have been observed. With a surface plasmon resonance-based method, we assessed the binding of HGF to antibodies, receptors, and the basement membrane and identified binding interactions that are indispensable for the biological activity of HGF. Recombinant HGF (rHGF) lots were tested for activity, structural integrity, and degradation, and the results were verified in an in vitro model of cell injury. Biologically active rHGF, as well as plasma from healthy volunteers, bound to heparan sulphate proteoglycan (HSPG) and to anti-HGF antibodies. Decreased binding to HSPG was the first event in rHGF degradation. This study established the feasibility of identifying patients with chronic inflammation who need exogenous HGF and of using ligand-binding assessment to evaluate rHGF lots for biological activity.


The persistence of pain behaviors in patients with chronic back pain is independent of pain and psychological factors.
The primary purpose of the present study was to examine the temporal stability of communicative and protective pain behaviors in patients with chronic back pain. The study also examined whether the stability of pain behaviors could be accounted for by patients' levels of pain severity, catastrophizing, or fear of movement. Patients (n=70) were filmed on two separate occasions (i.e., baseline, follow-up) while performing a standardized lifting task designed to elicit pain behaviors. Consistent with previous studies, the results provided evidence for the stability of pain behaviors in patients with chronic pain. The analyses indicated that communicative and protective pain behavior scores did not change significantly from baseline to follow-up. In addition, significant test-retest correlations were found between baseline and follow-up pain behavior scores. The results of hierarchical multiple regression analyses further showed that pain behaviors remained stable over time even when accounting for patients' levels of pain severity. Regression analyses also showed that pain behaviors remained stable when accounting for patients' levels of catastrophizing and fear of movement. Discussion addresses the potential contribution of central neural mechanisms and social environmental reinforcement contingencies to the stability of pain behaviors. The discussion also addresses how treatment interventions specifically aimed at targeting pain behaviors might help to augment the overall impact of pain and disability management programs.


The Warburg Effect in Diabetic Kidney Disease.
Diabetic kidney disease (DKD) is the leading cause of morbidity and mortality in diabetic patients. Defining risk factors for DKD using a reductionist approach has proven challenging. Integrative omics-based systems biology tools have shed new insights in our understanding of DKD and have provided several key breakthroughs for identifying novel predictive and diagnostic biomarkers. In this review, we highlight the role of the Warburg effect in DKD and potential regulating factors such as sphingomyelin, fumarate, and pyruvate kinase muscle isozyme M2 in shifting glucose flux from complete oxidation in mitochondria to the glycolytic pathway and its principal branches. With the development of highly sensitive instruments and more advanced automatic bioinformatics tools, we believe that omics analyses and imaging techniques will focus more on singular-cell-level studies, which will allow in-depth understanding of DKD and pave the path for personalized kidney precision medicine.


Non-destructive determination of fat content in green hams using ultrasound and X-rays.
This work addresses the use of ultrasound (US) and medical dual energy X-ray absorptiometry methods to predict the fat content in green pork hams. Ultrasonic velocity (υ) and X-ray absorption were measured in 78 green hams. An increase in the fat content involved an increase in υ and a decrease in the X-ray attenuation measured at 2°C. Models developed to predict the fat content from the ultrasonic velocity or X-ray parameters provided errors of 2.97% and 4.65%, respectively. The combination of both US and X-ray technologies did not improve prediction accuracy. These models allowed green hams to be classified into three levels of fatness, with 88.5% and 65.4% of the hams correctly classified when using models based on ultrasonic and X-ray parameters, respectively. Therefore, US and X-rays emerge as useful quality control technologies with which to estimate the fat content in green pork hams.


What is palliative care? Perceptions of healthcare professionals.
Despite increased attention and knowledge in palliative care, there is still confusion concerning how to interpret the concept of palliative care and implement it in practice. This can result in difficulties for healthcare professionals in identifying patients whom would benefit from palliative care, which, in turn, could lead to a delay in meeting patients' needs. To explore healthcare professionals' perceptions of palliative care. Data were collected through twelve interprofessional focus group interviews in community care and hospital wards in south Sweden (n = 74). All interviews were analysed with latent content analysis. Three domains were revealed: first, a blurred conceptual understanding as participants described palliative care using synonyms, diagnoses, phases, natural care and holism; second, a challenge to communicate transitions concerned the importance of how and when the transition to palliative care was communicated and documented; finally, a need for interprofessional collaboration was described as well as the consequences for severely ill persons, relatives and healthcare professionals when it was not established. The perceptions about how to interpret palliative care differed as well as when palliative care should be offered and decided, which might have practical consequences. How long a person has left to live is of great significance for decision-making, caregiving and preparation in palliative care. The challenge is to use interprofessional communication to promote understanding and collaborate across varied care levels. Integrating palliative care across diverse care levels could be one way to reduce the ambiguity of palliative care.


The effect of tread patterns on slip resistance of footwear outsoles based on composite materials in icy conditions.
Falls on icy surfaces are the leading cause of injuries for outdoor workers. Footwear outsole material and geometrical design parameters are the most significant factors affecting slips-and-falls. Recently, composite materials have been incorporated into outsoles to improve traction, yet the best design parameters are not fully understood. In this effort, based on Taguchi orthogonal array design, 27 outsole prototypes were fabricated with different tread pattern features using our patented composites and tested in a simulated winter condition. An analysis of variance (ANOVA) showed that surface area (p = 0.041, Contribution = 15.63%) was the only factor significantly affecting the slip-resistance of our prototypes. The best performance was observed for the maximized surface area covered by our composite material with circular and half circular plugs laid obliquely, mostly in the forefoot area. These findings suggest that some tread design features of composite-based footwear have a great role in affecting slip-resistance properties of composite-based footwear.


Daytime television viewing by hospitalized children: the effect of alternative programming.
In response to an earlier survey indicating that hospitalized children were indiscriminately watching excessive amounts of commercial television, a closed-circuit television station was instituted at the Children's Hospital of Winnipeg. The station offered patients commercial-free children's programming between 9 AM and 5 PM, including a daily one-hour live broadcast. In order to evaluate the effect of this station on children's television-viewing patterns, a second survey of the quantity and quality of daytime television viewing was carried out. This evaluative survey demonstrated an overall increase in television viewing, but a decrease in exposure to the potentially harmful effects of commercial television inasmuch as an average of nearly half of the children's viewing time was devoted to the hospital station. A dramatic increase in the viewing of children's programs (mean 43 v 147 minutes daily for the first and second surveys, respectively) along with additional viewing pattern data suggest that the closed-circuit station successfully filled a void for the patients. Overall the data indicated that alternative programming for pediatric patients has an enormous potential for alleviating the boredom and anxiety of hospitalized children.


Tissue uridine pools: evidence in vivo of a concentrative mechanism for uridine uptake.
Pools of free uridine, ranging from 7.3 to 38.0 nmol/g wet weight, have been detected in a variety of freeze-clamped murine tissues. These concentrations average 10-fold greater than that detected in plasma. The kinetics of these pools after an i.v. tracer dose of [3H]uridine suggest that the initial rapid disappearance of [3H]uridine from plasma (t1/2 = 2 min) reflects distribution into tissues as well as catabolism by the liver. Subsequently, the tissue uridine pools turn over with half-lives of 13 to 18 h. Analyses of the activity of the proximal enzymes in uridine metabolism (uridine phosphorylase and uridine kinase) suggest that the phosphorylase correlates with the size of tissue uridine pools. Further evidence for this is seen in the sustained 5- to 15-fold increase in both tissue and plasma uridine concentrations after treatment with benzylacyclouridine, a potent uridine phosphorylase inhibitor. In contrast, a nonphysiological dose of exogenous uridine (250 mg/kg) briefly increases the plasma concentration of uridine to over 1 mM but it returns to below 10 microM within 1 h. Under these conditions as well, tissue concentrations of uridine increase 5- to 10-fold in most tissues, 20-fold in spleen, and 70-fold in kidney. High cellular concentrations of free uridine relative to medium are also observed in dispersed murine splenocytes. Furthermore, splenocytes incubated in 5 microM [3H]uridine achieved a 2-fold higher intracellular concentration of [3H]uridine in less than 1 min independent of phosphorylation. Thymidine was not concentrated in this system nor did nitrobenzylthioinosine inhibit [3H]uridine uptake. These findings suggest that in normal tissues and explanted cells, pools of uridine are sustained by a concentrative transport mechanism and constitute a previously unrecognized reservoir of pyrimidine nucleosides in tissues.


Isolation and characterization of peroxisome-deficient Chinese hamster ovary cell mutants representing human complementation group III.
We made use of the 9-(1'-pyrene)nonanol/ultraviolet (P9OH/UV) method and isolated peroxisome-deficient mutant cells. TKa cells, the wild-type Chinese hamster ovary (CHO) cells, CHO-K1, that had been stably transfected with cDNA encoding Pex2p (formerly peroxisome assembly factor-1, PAF-1) were used to avoid frequent isolation of the Z65-type, PEX2-defective mutants. P9OH/UV-resistant cell colonies were examined for the intracellular location of catalase, a peroxisomal matrix enzyme, by immunofluorescence microscopy and using anti-catalase antibody. As six mutant cell clones showed cytosolic catalase, there was likely to be a deficiency in peroxisome assembly. These mutants also showed the typical peroxisome assembly-defective phenotype, including significant decrease of dihydroxyacetonephosphate acyltransferase, the first step key enzyme in plasmalogen synthesis, and loss of resistance to 12-(1'-pyrene)dodecanoic acid/UV treatment. By transfection of Pex2p and Pex6p (formerly PAF-2) cDNAs and cell fusion analysis between the CHO cell mutants, two mutants, ZP104 and ZP109, were found to belong to a novel complementation group. Further complementation analysis using fibroblasts from patients with peroxisome biogenesis disorders revealed that the mutants belonged to human complementation group III. Taken together, ZP104 and ZP109 are in a newly identified fifth complementation group in CHO mutants reported to date and represent the human complementation group III.


Preservation of acidified cucumbers with a natural preservative combination of fumaric acid and allyl isothiocyanate that target lactic acid bacteria and yeasts.
Without the addition of preservative compounds cucumbers acidified with 150 mM acetic acid with pH adjusted to 3.5 typically undergo fermentation by lactic acid bacteria. Fumaric acid (20 mM) inhibited growth of Lactobacillus plantarum and the lactic acid bacteria present on fresh cucumbers, but spoilage then occurred due to growth of fermentative yeasts, which produced ethanol in the cucumbers. Allyl isothiocyanate (2 mM) prevented growth of Zygosaccharomyces globiformis, which has been responsible for commercial pickle spoilage, as well as the yeasts that were present on fresh cucumbers. However, allyl isothiocyanate did not prevent growth of Lactobacillus plantarum. When these compounds were added in combination to acidified cucumbers, the cucumbers were successfully preserved as indicated by the fact that neither yeasts or lactic acid bacteria increased in numbers nor were lactic acid or ethanol produced by microorganisms when cucumbers were stored at 30 degrees C for at least 2 mo. This combination of 2 naturally occurring preservative compounds may serve as an alternative approach to the use of sodium benzoate or sodium metabisulfite for preservation of acidified vegetables without a thermal process.


Cell cycle regulation of menin expression.
The multiple endocrine neoplasia type 1 gene product, menin, interacts with Jun D. The physiological role of menin in cell cycle control and the manner in which its inactivation contributes to tumorigenesis remain unknown. In the present study, the expression of menin was examined at various cell cycle stages in GH4C1 cells, a rat pituitary cell line. Cells synchronized at the G1-S-phase boundary expressed menin at a lower level than G0-G1-synchronized cells. The expression of menin increased as the cells entered S phase, at which time Jun D expression also increased. In contrast, cells synchronized at the G2-M phase expressed lower levels of menin. At G0-G1, G1-S, and G2-M phases of the cell cycle, menin was found predominantly in the nucleus. In summary, we show that in pituitary cells, menin is a nuclear protein whose expression is cell-cycle regulated. The data suggest that menin has an important role in cell growth regulation.


Clinical Significance and Prognosis of Right Heart Thrombi Associated With Acute Pulmonary Thromboembolism - Results of a Multicenter Registry of Thrombolysis in Japan.
Thrombolytic therapy is standard treatment in acute pulmonary thromboembolism (PTE) with hemodynamic instability. Although right heart thrombi (RHT) appear to increase mortality in acute PTE, large-scale studies of acute PTE with RHT are scarce.Methods and Results:Patient data (from August 2005 to May 2014) obtained from post-marketing surveillance of thrombolytic therapy using a tissue-type plasminogen activator were analyzed retrospectively. Of the 2,698 confirmed cases of acute PTE who underwent echocardiographic assessment, 166 (6.2%) were diagnosed with RHT. PTE patients with RHT, compared with those without RHT, had higher rates of mortality (20.2% vs. 10.4%, P<0.001), hemodynamic instability (53.0% vs. 37.7%, P<0.001), and PTE recurrence (6.6% vs. 2.3%, P=0.003). When considering PTE-related hemodynamic severity (cardiopulmonary arrest/collapse, massive, submassive, and non-massive), mortality was significantly higher in patients with RHT in the massive (19.8% vs. 7.7%, P=0.002) and submassive (8.0% vs. 2.8%, P=0.018) groups, whereas no significant differences was found between those with and without RHT in the cardiopulmonary arrest/collapse (51.7% vs. 52.1%, P=0.960) and non-massive (1.6% vs. 0%, P=0.596) groups. PTE patients with RHT had higher mortality, severity, and PTE recurrence rates. RHT was particularly associated with worse outcomes in patients with massive or submassive PTE.


Influence of the hydrophobic amino acids in the N- and C-terminal regions of pleurocidin on antifungal activity.
To investigate the influence of N- or C-terminal regions of pleurocidin (Ple) peptide on the antifungal activity, four analogues partially truncated in the N- or C-terminal regions were designed and synthesized. Circular dichroism (CD) spectroscopy demonstrated that all the analogues maintained an alpha-helical structure. The antifungal susceptibility testing also showed that the analogues exhibited antifungal activities against human fungal pathogens, without hemolytic effects against human erythrocytes. The result further indicated that the analogues had discrepant antifungal activities (Ple > Ple (1-22) > Ple (4-25) > Ple (1-19) > Ple (7-25)) and that N-terminal deletion affected the activities much more than C-terminal deletion. Hydrophobicity (Ple > Ple (1-22) > Ple (4-25) > Ple (1-19) > Ple (7-25)) was thought to have been one of the consistent factors that influenced these activity patterns, rather than the other primary factors like the helicity (Ple > Ple (4-25) > Ple (1-22) > Ple (1-19) > Ple (7-25)) or the net charge (Ple = Ple (4-25) = Ple (7-25) > Ple (1-22) = Ple (1-19)) of the peptides. Taken together, the hydrophobic amino acids in the N-terminal region of Ple is more crucial for the antifungal activity than those in the C-terminal region.


A pilot study of relationships among pain characteristics, mood disturbances, and acculturation in a community sample of Chinese American patients with cancer.
To describe the pain experience of Chinese American patients with cancer and to examine the relationships among pain characteristics, demographic characteristics, performance status, self-reported analgesic use, mood disturbances, and patients' acculturation levels. Descriptive, correlational, cross-sectional study. Three community-based oncology facilities in the San Francisco, CA, Bay area. 50 Chinese Americans who reported experiencing pain from cancer. Participants completed in their preferred language a demographic questionnaire, the Karnofsky Performance Status Scale, the Brief Pain Inventory, the Hospital Anxiety and Depression Scale, the Suinn-Lew Asian Self-Identity Acculturation Scale, and information about analgesic use. Descriptive and correlational statistics were used to evaluate data. Pain intensity, pain interference, performance status, anxiety, depression, analgesic use, and acculturation level. Most of the patients reported moderate to severe pain and moderate levels of interference. Lower levels of acculturation were associated with higher least and worst pain intensity scores and higher pain interference scores. Anxiety and depression scores were in the moderate range. Higher depression scores were associated with higher pain interference scores. Self-reported analgesic use for 62% of the patients was classified as inadequate. A significant percentage of Chinese American patients experience moderate to severe cancer pain that affects their mood and their ability to function. Nurses should assume a proactive role in assessing the physical, emotional, and cognitive dimensions of pain in Chinese American patients. Future research should evaluate the cancer pain experience of these vulnerable patients and develop and test culturally appropriate interventions.


Faithful expression of the human 5q31 cytokine cluster in transgenic mice.
Interleukins -4, -5, and -13, cardinal cytokines produced by Th2 cells, are coordinately expressed and clustered in 150-kb syntenic regions on mouse chromosome 11 and human chromosome 5q31. We analyzed two sets of human yeast artificial chromosome transgenic mice that contained the 5q31 cytokines to assess whether conserved sequences required for their coordinate and cell-specific regulation are contained within the cytokine cluster itself. Human IL-4, IL-13, and IL-5 were expressed under Th2, but not Th1, conditions in vitro. Each of these cytokines was produced during infection with Nippostrongylus brasiliensis, a Th2-inducing stimulus, and human IL-4 was generated after activation of NK T cells in vivo. Consistently fewer cells produced the endogenous mouse cytokines in transgenic than in control mice, suggesting competition for stable expression between the mouse and human genes. These data imply the existence of both conserved trans-activating factors and cis-regulatory elements that underlie the coordinate expression and lineage specificity of the type 2 cytokine genes in lymphocytes.


Collaborative essay testing: group work that counts.
Because much of a nurse's work is accomplished through working in groups, nursing students need an understanding of group process as well as opportunities to problem-solve in groups. Despite an emphasis on group activities as critical for classroom learning, there is a lack of evidence in the nursing literature that describes collaborative essay testing as a teaching strategy. In this class, nursing students worked together in small groups to answer examination questions before submitting a common set of answers. In a follow-up survey, students reported that collaborative testing was a positive experience (e.g., promoting critical thinking, confidence in knowledge, and teamwork). Faculty were excited by the lively dialog heard during the testing in what appeared to be an atmosphere of teamwork. Future efforts could include providing nursing students with direct instruction on group process and more opportunities to work and test collaboratively.


Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth.
In a screen of drugs previously tested in humans we identified itraconazole, a systemic antifungal, as a potent antagonist of the Hedgehog (Hh) signaling pathway that acts by a mechanism distinct from its inhibitory effect on fungal sterol biosynthesis. Systemically administered itraconazole, like other Hh pathway antagonists, can suppress Hh pathway activity and the growth of medulloblastoma in a mouse allograft model and does so at serum levels comparable to those in patients undergoing antifungal therapy. Mechanistically, itraconazole appears to act on the essential Hh pathway component Smoothened (SMO) by a mechanism distinct from that of cyclopamine and other known SMO antagonists, and prevents the ciliary accumulation of SMO normally caused by Hh stimulation.


Hierarchical and ontogenic positions serve to define the molecular basis of human hematopoietic stem cell behavior.
The molecular basis governing functional behavior of human hematopoietic stem cells (HSCs) is largely unknown. Here, using in vitro and in vivo assays, we isolate and define progenitors versus repopulating HSCs from multiple stages of human development for global gene expression profiling. Accounting for both the hierarchical relationship between repopulating cells and their progenitors, and the enhanced HSC function unique to early stages of ontogeny, the human homologs of Hairy Enhancer of Split-1 (HES-1) and Hepatocyte Leukemia Factor (HLF) were identified as candidate regulators of HSCs. Transgenic human hematopoietic cells expressing HES-1 or HLF demonstrated enhanced in vivo reconstitution ability that correlated to increased cycling frequency and inhibition of apoptosis, respectively. Our report identifies regulatory factors involved in HSC function that elicit their effect through independent systems, suggesting that a unique orchestration of pathways fundamental to all human cells is capable of controlling stem cell behavior.


Prevalence of genital Chlamydia trachomatis infection in the general population of Slovenia: serious gaps in control.
One of the objectives of the first national survey of sexual lifestyles, attitudes, and health in Slovenia was to estimate the prevalence of and risk factors for genital Chlamydia trachomatis infection in Slovenian adults aged 18-49 years. Data were collected over 1999-2001 from a probability sample of the general population by face to face interviews and anonymous self administered questionnaires. Respondents were invited to provide a first void urine (FVU) specimen for polymerase chain reaction testing for C trachomatis infection. We compared the results to the equivalent British survey. 1447 individuals contributed FVU specimens (82.6% of survey respondents, 55.3% of those eligible). C trachomatis infection was diagnosed in 3.0% of men and 1.6% of women. Prevalence was highest in men and women aged 18-24 years (4.1% for both). Individuals reporting first heterosexual intercourse before the age of 16, unprotected sexual intercourse with at least one heterosexual partner during the preceding year, concurrent heterosexual relationships during the preceding year, and five or more lifetime heterosexual partners had a higher prevalence. The association was statistically significant only for five or more lifetime partners (adjusted OR 3.0; 95% CI 1.3 to 6.9; p = 0.01). A relatively high prevalence of genital C trachomatis infection among 18-24 year old Slovenians, in the presence of relatively low risk sexual behaviour and low reported incidence rates of chlamydia infection, suggest serious gaps in the diagnosis and treatment of the condition. The results provide support for the introduction of chlamydia screening in Slovenia.