Hemodynamic Response to Glucose-Insulin Infusion and Meals during Hemodialysis.
Intradialytic nutrition may improve nutritional status and reduce mortality in patients on maintenance hemodialysis (HD) but has been associated with adverse events, mainly hemodynamic instability. Some dialysis centers therefore restrict intradialytic meals. In 2 clinical studies, we investigated the effects of intradialytic glucose-insulin infusion (GII) and meal intake on blood pressure (BP), pulse wave velocity (PWV), pulse wave analysis (PWA), and cardiac output (CO). PWA yielded augmentation index standardized with heart rate 75 (AIx@HR75). In the GII study, 12 nondiabetic HD patients had BP, PWV, PWA, and CO measured during 3 HD sessions: standard HD, HD with glucose infusion, and HD with GII. In the Meal study, 12 nondiabetic patients had BP and PWA measured on 3 study days: meal alone (non-HD), meal and HD, 2 meals and HD. Twelve matched healthy controls completed the non-HD day. In the GII study, glucose or GII had no additional effects on hemodynamic parameters compared with standard HD. HD resulted in a decrease in systolic BP of 13%, in diastolic BP of 9%, in AIx@HR75 of 17%, and CO of 18%. PWV was reduced by only 5%. In the Meal study, a meal alone did not change BP, whereas the combined influence of HD and meal intake reduced systolic BP with 22% and diastolic BP with 19%. Furthermore, AIx@HR75 decreased by 37% on HD days and by 36% in controls, but was unaffected on non-HD days. In the GII study, HD significantly reduced BP, AIx@75, and CO, whereas PWV remained almost constant. No additional effects were observed by concomitant GII during HD. BP reductions seemed larger in the Meal study compared with the GII study. Taken together, HD per se appears as the main discriminant for intradialytic hypotension but in hemodynamically unstable patients the timing and route of nutrition provision should be considered carefully.


Nondeletional T-cell receptor transgenic mice: model for the CD4(+) T-cell repertoire in chronic hepatitis B virus infection.
Chronicity after infection with the hepatitis B virus (HBV) can occur for a variety of reasons. However, once established, chronicity may be maintained by high levels of viral proteins circulating in the serum. To examine the characteristics of T cells capable of coexisting with the secreted hepatitis B e antigen (HBeAg), T-cell receptor (TCR) transgenic (Tg) mice were produced. To ensure that HBeAg-specific T cells would not be deleted in the presence of serum HBeAg, the TCR alpha- and beta-chain genes used to produce the TCR-Tg mice were derived from T-cell hybridomas produced from immunizing HBeAg-Tg mice. A TCR-Tg lineage (11/4-12) was produced that possessed a high frequency ( approximately 67%) of CD4(+) T cells that expressed a Tg TCR specific for the HBeAg. As predicted, when 11/4-12 TCR-Tg mice were bred with HBeAg-Tg mice no deletion of the HBeAg-specific CD4(+) T cells occurred in the thymus or the spleen. Functional analysis of the TCR-Tg T cells revealed that the HBeAg-specific CD4(+) T cells escaped deletion in the thymus and periphery by virtue of low avidity. Regardless of their low avidity, HBeAg-specific TCR-Tg T cells could be activated by exogenous HBeAg, as measured by cytokine production in vitro and T-helper-cell function for anti-HBe antibody production in vitro and in vivo. Furthermore, activated TCR-Tg HBeAg-specific T cells polarized to the Th1 subset were able to elicit liver injury when transferred into HBeAg or HBcAg-Tg recipients. Therefore, HBeAg-specific CD4(+) T cells that can survive deletion or anergy in the presence of circulating HBeAg nonetheless are capable of being activated and of mediating liver injury in vivo. The 11/4-12 TCR-Tg lineage may serve as a monoclonal model for the HBe/HBcAg-specific CD4(+) T-cell repertoire present in chronically infected HBV patients.


Feasibility and safety of setting up a donor breastmilk bank in a neonatal prem unit in a resource limited setting: An observational, longitudinal cohort study.
The beneficial effects of human milk on decreasing rates of paediatric infections such as necrotizing enterocolitis (NEC) and sepsis have been clearly demonstrated. Donor breastmilk has been encouraged as the milk of choice when a mother's own breastmilk is not available. The objectives of this study were to assess feasibility of providing donor breastmilk to infants in a resource limited Neonatal Prem Unit (NPU). In addition we sought to determine whether donor breastmilk could be safely pasteurized and administered to infants without any adverse events. Low birth weight infants < 1800 g and under 32 weeks gestational age were followed up in the NPU over a 3 week period; feeding data and morbidity data was collected in order to determine if there were any adverse events associated with donor breastmilk. Samples of pasteurized breastmilk were cultured to check for any bacterial contamination. 191 infants met the inclusion criteria of whom 96 received their mother's own breastmilk. Of the 95 infants who were potentially eligible to receive donor milk, only 40 did in fact receive donor milk. There was no evidence of bacterial contamination in the samples analyzed, and no evidence of adverse events from feeding with donor breastmilk. It is feasible to supply donor breastmilk to infants in an NPU in a resource limited setting, however staff needs to be sensitized to the importance of donor breastmilk to improve uptake rates. Secondly we showed that it is possible to supply donor breastmilk according to established guidelines with no adverse events therefore making it possible to prevent NEC and other side effects often associated with formula feeding of premature infants.


Topographic organization of macaque area LIP.
Despite several attempts to define retinotopic maps in the macaque lateral intraparietal area (LIP) using histological, electrophysiological, and neuroimaging methods, the degree to which this area is topographically organized remains controversial. We recorded blood oxygenation level-dependent signals with functional MRI from two macaques performing a difficult visual search task on stimuli presented at the fovea or in the periphery of the visual field. The results revealed the presence of a single topographic representation of the contralateral hemifield in the ventral subdivision of the LIP (LIPv) in both hemispheres of both monkeys. Also, a foveal representation was localized in rostral LIPv rather than in dorsal LIP (LIPd) as previous experiments had suggested. Finally, both LIPd and LIPv responded only to contralateral stimuli. In contrast, human studies have reported multiple topographic maps in intraparietal cortex and robust responses to ipsilateral stimuli. These blood oxygenation level-dependent functional MRI results provide clear evidence for the topographic organization of macaque LIP that complements the results of previous electrophysiology studies, and also reveal some unexpected characteristics of this organization that have eluded these previous studies. The results also delineate organizational differences between LIPv and LIPd, providing support for these two histologically defined areas may subserve different visuospatial functions. Finally, these findings point to potential evolutionary differences in functional organization with human posterior parietal cortex.


Stereotactic body radiotherapy for unresectable pancreatic cancer.
Pancreatic cancer is a devastating disease with few effective treatment modalities. Recent technological advances have made possible the delivery of single-fraction stereotactic body radiotherapy (SBRT) to patients with locally advanced pancreatic tumors. This paper presents experience at Stanford University with SBRT for patients with unresectable pancreatic cancer. Pancreatic tumors of up to 100 cm3 could be treated. Patients achieved greater than 90% local control for the remainder of their lives. Currently, the standard dose for pancreatic tumors treated at this institution is 25 Gy given in a single fraction. Four-dimensional CT and PET scans have been essential for optimal treatment planning. PET-CT scanning may be a more effective method for evaluating tumor response than conventional CT scanning. Adjuvant systemic therapies could be administered in coordination with SBRT. SBRT is an effective method of treating patients resulting in excellent local control. Current research is aimed at defining the optimal method of combining this treatment with other cancer therapies.


Performance of tonpilz transducers with segmented piezoelectric stacks using materials with high electromechanical coupling coefficient.
Tonpilz acoustic transducers for use underwater often include a stack of piezoelectric material pieces polarized along the length of the stack and having alternating polarity. The pieces are interspersed with electrodes, bonded together, and electrically connected in parallel. The stack is normally much shorter than a quarter wavelength at the fundamental resonance frequency so that the mechanical behavior of the transducer is not affected by the segmentation. When the transducer bandwidth is less than a half octave, as has conventionally been the case, for example, with lead zirconate titanate (PZT) material, stack segmentation has no significant effect on the mechanical behavior of the device in its normal operating band near the fundamental resonance. However, when a high coupling coefficient material such as lead magnesium niobate-lead titanate (PMN-PT) is used to achieve a wider bandwidth with the tonpilz, the performance difference between a segmented stack and a similar piezoelectric section with electrodes only at the two ends can be significant. This paper investigates the effects of stack segmentation on the performance of wideband underwater tonpilz acoustic transducers. Included is a discussion of a particular tonpilz transducer design using single crystal piezoelectric material with high coupling coefficient compared with a similar design using more traditional PZT ceramics.


Soft Tissue Attenuation Patterns Associated with Upright Acquisition SPECT Myocardial Perfusion Imaging: A Descriptive Study.
Little is known about soft tissue attenuation artifacts when an upright patient-position SPECTmyocardial perfusion imaging (MPI) system is used. In this investigation we sought to describe the patterns and frequency of attenuation artifacts associated with this type of instruments and we explored the impact of gender and body habitus on these artifacts. In a cross-sectional study, we described the prevalence of various soft-tissue attenuation patterns in 212 normal SPECT-MPI studies acquired with an upright patient-position imaging system. In these 212 normal, clinically-indicated, upright-acquisition SPECT-MPIs the attenuation patterns observed were: anterior (6.1%), inferior (63.7%) and lateral (24.1%). Though uncommon, anterior attenuation trended to being more prevalent among women [9.5% vs. 3.4%, P=0.07] and was independently associated with chest circumference. Lateral attenuation was more common among women [34.7% vs. 15.4%, p=0.001] and was strongly associated with obesity (p<0.001). Inferior attenuation was more prevalent among men than women (75.2% vs. 49.5% respectively, P<0.001). Soft-tissue attenuation artifacts are common in upright-acquisition SPECT-MPI. Recognizing the frequency of these attenuation patterns and their interaction with gender and body habitus is critical for the accurate interpretation of SPECT-MPI.


How to rapidly design and operationalise PPE donning and doffing areas for a COVID-19 care facility: quality improvement initiative.
Effective implementation of standard precautions specific to COVID-19 is a challenge for hospitals within the existing constraints of time and resources. To rapidly design and operationalise personal protective equipment (PPE) donning and doffing areas required for a COVID-19 care facility. Literature review was done to identify all issues pertaining to donning and doffing in terms of Donabedian's structure, process and outcome. Training on donning and doffing was given to hospital staff. Donning and doffing mock drills were held. 5S was used as a tool to set up donning and doffing areas. Instances of donning and doffing were observed for protocol deviations and errors. Plan-do-study-act cycles were conducted every alternate day for 4 weeks. The initiative was reported using Standards for QUality Improvement Reporting Excellence (SQUIRE) guidelines. Best practices in donning and doffing were described. Our study recommends a minimum area of 16 m2 each for donning and doffing rooms. Verbally assisted doffing was found most useful than visual prompts. Challenges included sustaining the structure and process of donning and doffing, varied supplies of PPE which altered sequencing of donning and/or doffing, and training non-healthcare workers such as plumbers, electricians and drivers who were required during emergencies in the facility. Our study used evidence-based literature and quality improvement (QI) tools to design and operationalise donning and doffing areas with focus on people, task and environment. Our QI will enable healthcare facilities to rapidly prototype donning and doffing areas in a systematic way.


Isolation and characterization of the murine C-FGR genomic locus: exons IB-XII.
The c-fgr proto-oncogene is a member of the src family of intracellular protein tyrosine kinases. C-fgr is selectively expressed in hematopoietic cells, particularly in monocytes, neutrophils and natural killer cells. Although c-fgr is presumed to play a role in signal transduction, its normal function has not been completely elucidated. In contrast to all other members of the src family, the presumed murine and human c-fgr homologues have a low degree of homology in their amino terminal domains which likely mediate the association of c-fgr proteins with signalling complexes and other targets; murine and human c-fgr proteins exhibit other functional differences as well. In contrast to human C-FGR, the murine C-FGR genomic locus has not been characterized. We have now isolated and mapped three overlapping phage clones spanning 33 kb of the murine C-FGR genomic locus. Contained within these clones are 18 kb of DNA containing the C-FGR coding exons (exons II-XII), one 5' untranslated region exon (exon Ib) located 1.7 kb upstream of exon II, 6.5 kb of DNA upstream of exon Ib and 6.7 kb of DNA downstream of the polyadenylation site in exon XII. From exons Ib-XII, the exon-intron organization, exon-intron junctions and intron lengths of the murine and human C-FGR genomic loci are quite similar; with the exception of exon II, the exon lengths are also quite similar. Although these studies suggest that the murine and human C-FGR genes are in fact homologues, the organization of these genes upstream of exon Ib is quite divergent.


Mesectodermal leiomyoma of the ciliary body. An ultrastructural study.
Electron microscopic observation of a mesectodermal leiomyoma of the ciliary body, in which clear perinuclear halos were present, revealed the ultrastructural characteristics of smooth muscle cells, which include myofilaments with fusiform densities, dense attachments, external lamina, and pinocytotic vesicles. In addition, fibrillary cytoplasmic processes containing large numbers of myofilaments with fusiform densities were notably arranged in a neurogenic pattern when observed under a light microscope. These are characteristic of and specific to mesectodermal leiomyomas. Masses or cords of large, polygonal cells with clear halos surrounding the large, round-to-oval nuclei were found to contain only a few myofilaments. Such features are atypical of mesectodermal leiomyomas. Melanocytes were scattered throughout the tumor, providing additional evidence for the neural crest theory of origination of mesectodermal leiomyomas, since melanocytes are well-recognized descendants of the neural crest. A small number of lipid droplets, abundant lysosomes, and, occasionally, phagosomes were also observed in the cells of this mesectodermal leiomyoma.


Decreased Cardiovascular Mortality in Patients with Incident Rheumatoid Arthritis (RA) in Recent Years: Dawn of a New Era in Cardiovascular Disease in RA?
To assess trends in cardiovascular (CV) mortality in patients with incident rheumatoid arthritis (RA) in 2000-07 versus the previous decades, compared with non-RA subjects. The study population consisted of Olmsted County, Minnesota, USA residents with incident RA (age ≥ 18 yrs, 1987 American College of Rheumatology criteria was met in 1980-2007) and non-RA subjects from the same underlying population with similar age, sex, and calendar year of index. All subjects were followed until death, migration, or December 31, 2014. Followup was truncated for comparability. Aalen-Johansen methods were used to estimate CV mortality rates, adjusting for competing risk of other causes. Cox proportional hazards models were used to compare CV mortality by decade. The study included 813 patients with RA and 813 non-RA subjects (mean age 55.9 yrs; 68% women for both groups). Patients with incident RA in 2000-07 had markedly lower 10-year overall CV mortality (2.7%, 95% CI 0.6-4.9%) and coronary heart disease (CHD) mortality (1.1%, 95% CI 0.0-2.7%) than patients diagnosed in 1990-99 (7.1%, 95% CI 3.9-10.1% and 4.5%, 95% CI 1.9-7.1%, respectively; HR for overall CV death: 0.43, 95% CI 0.19-0.94; CHD death: HR 0.21, 95% CI 0.05-0.95). This improvement in CV mortality persisted after accounting for CV risk factors. Ten-year overall CV mortality and CHD mortality in 2000-07 RA incidence cohort was similar to non-RA subjects (p = 0.95 and p = 0.79, respectively). Our findings suggest significantly improved overall CV mortality, particularly CHD mortality, in patients with RA in recent years. Further studies are needed to examine the reasons for this improvement.


Postsplenectomy sepsis and its mortality rate: actual versus perceived risks.
A collective critical review of the literature on postsplenectomy sepsis from 1952 to 1987 has been undertaken. The reports cover a cohort of 12,514 patients undergoing splenectomy but of these only 5902 reports were sufficiently detailed to allow a useful analysis. The incidence of infection after splenectomy in children under 16 years old was 4.4 per cent with a mortality rate of 2.2 per cent. The corresponding figures for adults were 0.9 per cent and 0.8 per cent respectively. The present analysis of well documented patients has shown that severe infection after splenectomy for benign disease is very uncommon except in infants (infection rate 15.7 per cent) and children below the age of 5 years (infection rate 10.4 per cent). Many of these reported postsplenectomy infections may have been coincidental. It is also apparent that children contract a different type of infection after splenectomy than adults, predominantly a meningitis which is less frequently fatal. Adults, in contrast, appear to develop a septicaemic type of illness associated with a higher mortality rate. This survey has also shown that children are reported to be more susceptible to pneumococcal sepsis than to infection caused by any other organism. Although the removal of the spleen in otherwise normal people does not appear to be associated with an increased frequency of infection, the presence of a coexistent disorder, notably hepatic disease, can increase the risk substantially.


Osseointegrated proximal interphalangeal joint prostheses with a replaceable flexible joint spacer--long-term results.
Osseointegrated proximal interphalangeal joint prostheses with a replaceable joint spacer were used in 25 joints in 19 patients (five men and 14 women) aged 45 (16-67) years. Indications for surgery were post-traumatic arthrosis (nine joints in eight patients), primary osteoarthrosis (10 joints in eight patients), and rheumatoid arthritis (six joints in three patients). A silicone joint spacer was attached to titanium fixtures by short titanium stems that extended from the spacer and fitted into a central canal in the screws. The arthroplasty was done in one stage, which included resection of the joint followed by grafting of marrow and cancellous bone from the iliac crest into adjacent medullary cavities before insertion of the titanium fixture. Follow up at 8.5 (5-11) years showed that 47 out of 50 fixtures (94%) had successfully osseointegrated while 17 of 25 joint spacers (68%) had fractured. However, because of the design of the prostheses fractured joint spacers could easily be replaced and a new spacer could be connected to already osseointegrated screws. The joint spacer was replaced in 11 fingers once or several times. Range of movement (ROM) in the whole series (four fusions excluded) was 41 (0-85) degrees with an extension defect of 15 (0-55) degrees. In eight joints with permanently intact joint spacers the ROM was 39 (0-60) degrees with extension defects of 16 (0-40) degrees. In six joints in which the spacer was replaced once the ROM was 43 (0-85) degrees with an extension defect of 16 (0-55) degrees. Our data confirm good long-term osseointegration of titanium fixtures and that a joint spacer, if needed, can be replaced by a new spacer that can be attached to already osseointegrated screws without jeopardizing the ROM.


Foul or dive? Motor contributions to judging ambiguous foul situations in football.
Football (soccer) referees frequently face situations in which they have to distinguish dives and fouls. Yet, little is known about the contributing factors that characterise the ability to judge these ambiguous situations correctly. To this end, in the current article we tested the hypothesis that motor experience of observers contributes to the visual identification of deceptive actions. Thereto, we asked skilled football referees, skilled football players, wheelchair bounded football fans (thus with limited motor experience) and novices to judge whether potential tackle situations in football were either fouls or dives. Results revealed that the referees (accuracy 72.2%, s=6.2) and players (accuracy 72.0%, s=6.4) were better at discriminating fouls and dives than the fans (accuracy 61.1%, s=7.2) and the novices (accuracy 57.4%, s=7.0) (P < 0.001). The results seem to point to an added value of motor experience in detecting deceptive movements.


Nurse empowerment through context, structure, and process.
Empowerment is most often conceptualized and measured from an individual perspective. Yet, in the nursing practice environment it requires a more comprehensive perspective. In this article the author requires a more comprehensive perspective. In this article the author proposes that nurse empowerment most likely occurs when there is a congruent linkage among a nursing vision, structural components that involve nurse participation, and the use of a process of inquiry. An empowerment quotient for nursing could be measured on a continuum for each of these three components.


[Lasers and endoprosthesis in bronchopneumology].
During the past decade lasers, especially the Neodymium: Yttrium-Aluminum-Garnet (Nd: YAG), have transformed interventional bronchoscopy. Recent improvements of tracheobronchial prostheses have further increased the therapeutic possibilities of endoscopy. Tracheobronchial obstruction by intraluminal tumeur, stenosis, or extrinsic compression can now be palliated successfully. The future of therapeutic bronchoscopy is bright. New techniques of optic spectroscopy will allow improved detection of laser induced tissue fluorescence. Refinements of laser technology and development of visualisation systems such as endoscopic echography and electronic videoendoscopy will lead to improved diagnostic and therapeutic capabilities.


Acute migraine therapy: recent evidence from randomized comparative trials.
(1) A wide array of data regarding acute migraine treatment are available, but few trials strictly adhere to International Headache Society guidelines for patient inclusion criteria.(2) Triptans appear to have similar efficacy profiles, but among newer triptans, almotriptan offers improved tolerability over sumatriptan.(3) Combination indomethacin/caffeine/prochlorperazine most likely has similar therapeutic efficacy to triptan therapy, with further research needed to complete understanding of any potential differences between these treatments.(4) Multi-targeted combination therapy with a triptan plus a non-steroidal anti-inflammatory (NSAID), such as sumatriptan/naproxen sodium, is more effective in acute migraine treatment than monotherapy with either agent alone.(5) It is unclear whether triptans offer clinically relevant benefits over aspirin or NSAIDs in migraine patients. Thus NSAIDs, particularly effervescent aspirin, should be considered the first-line treatment of migraine attacks.


The world of touch--from evoked potentials to conscious perception.
Microelectrode recordings have enabled several maps of the body surface to be recognized in the mammalian somatosensory cortex. The maps appear to represent increasingly complex levels of analysis of the sensory message. At present the prevailing opinion is that the different components of the ERPs (event related potentials) represent sequential steps in such an analysis, and such an interpretation is supported by the enhancement of the ERPs when attention is paid to a somatic stimulus. However, there are a number of critical observations which are inconsistent with this view and suggest that the ERP enhancement may be an epiphenomenon. An alternative explanation for the ERPs is that they reflect discharges from the non-specific thalamic nuclei, and are essentially similar to the long latency responses which can be recorded from the cortex during sleep or anaesthesia. Lastly, a hypothesis is proposed for the neuronal events in the somatosensory cortex which culminate in a conscious perception. In this "RULER" model, the deep pyramidal neurones read out the sensory information which has been retained in the apical dendrites of more superficial cells, and do so at the end of successive "time-chunks".


Passive trauma.
Wives of military personnel in action living on bases located in areas of armed conflict in Colombia before the peace negotiations with the Revolutionary Armed Forces of Colombia (FARC), were first-hand observers of the war, their husbands' participation in the war and the consequences and effects of the combat in which others participated. To offer a hypothesis regarding these women's experience of direct trauma and characterise the dimensions of their experience as observers of the suffering of others. Qualitative study and secondary discourse analysis in intentional snowball sampling of wives of military personnel (officers and chiefs) with whom semi-structured interviews were conducted. Direct trauma is not the sole cause of psychosomatic and psychopathological consequences; the experience of constantly observing the suffering and deaths of others also generates a cumulative effect that can affect physical and mental health. This experience is called passive trauma.


Hypereosinophilia with abnormal T cells, trisomy 7 and elevated TARC serum level.
The idiopathic hypereosinophilic syndrome (HES) is a rare heterogeneous disorder, characterized by persistent blood eosinophilia with possible organ involvement. We describe here the case of a 20-year-old atopic male presenting chronic hypereosinophilia and eczema since childhood. Biological findings included hypereosinophilia (9.5 x 10(9)/L), hyperlymphocytosis (10.9 x 10(9)/L), polyclonal hypergammaglobulinemia and elevated IgE serum level. Flow cytometric analysis of blood lymphoid cells showed a population of CD2+CD3-CD4+TCRab-TCRgd- lymphocytes. These cells displayed a Th0/Th2 cytokine profile, and a clonal TCR rearrangement pattern. A high serum TARC level was observed. Karyotype studies on blood stimulated culture or lymph nodes revealed a cellular hyperdiploïd clone 47, XY, +7. To our knowledge, this chromosomal aberration has never been reported in such case.


Diagnosis of gastrointestinal parasites in reptiles: comparison of two coprological methods.
Exotic reptiles have become increasingly common domestic pets worldwide and are well known to be carriers of different parasites including some with zoonotic potential. The need of accurate diagnosis of gastrointestinal endoparasite infections in domestic reptiles is therefore essential, not only for the well-being of captive reptiles but also for the owners. Here, two different approaches for the detection of parasite stages in reptile faeces were compared: a combination of native and iodine stained direct smears together with a flotation technique (CNF) versus the standard SAF-method. A total of 59 different reptile faeces (20 lizards, 22 snakes, 17 tortoises) were coprologically analyzed by the two methods for the presence of endoparasites. Analyzed reptile faecal samples contained a broad spectrum of parasites (total occurence 93.2%, n = 55) including different species of nematodes (55.9%, n = 33), trematodes (15.3%, n = 9), pentastomids (3.4%, n = 2) and protozoans (47.5%, n = 28). Associations between the performances of both methods to detect selected single parasite stages or groups of such were evaluated by Fisher's exact test and marginal homogeneity was tested by the McNemar test. In 88.1% of all examined samples (n = 52, 95% confidence interval [CI] = 77.1 - 95.1%) the two diagnostic methods rendered differing results, and the McNemar test for paired observations showed highly significant differences of the detection frequency (P < 0.0001). The combination of direct smears/flotation proved superior in the detection of flagellates trophozoites, coccidian oocysts and nematode eggs, especially those of oxyurids. SAF-technique was superior in detecting larval stages and trematode eggs, but this advantage failed to be statistically significant (P = 0.13). Therefore, CNF is the recommended method for routine faecal examination of captive reptiles while the SAF-technique is advisable as additional measure particularly for wild caught animals and individuals which are to be introduced into captive collections.


Diagnosis and Management of Pediatric Influenza in the Era of Rapid Diagnostics.
Influenza is a significant cause of childhood morbidity and death; it contributes to up to 16% of hospitalizations for respiratory illnesses worldwide. Novel rapid viral diagnostic tests, including molecular diagnostic tests, have the potential to significantly affect both time to diagnosis and selection of optimal anti-infective therapy. However, little is known about current treatment algorithms used in US hospitals. In this study, for hospitalized children in the United States, we aimed to define the current approaches to influenza diagnosis and treatment and to explore reasons for their potential variation. In this study, we aimed to define the current approaches to pediatric influenza diagnosis and treatment in US hospitals, and to explore reasons for their potential variation. Our results suggest a rise in the availability and use of rapid molecular diagnostic testing in addition to continued variability in anti-infective management, particularly with regard to antiviral use.


Receptor reserve in the calcium-dependent cyclic AMP response of astrocytoma cells to muscarinic receptor stimulation: demonstration by agonist-induced desensitization, receptor inactivation, and phorbol ester treatment.
Activation of muscarinic cholinergic receptors on 1321N1 human astrocytoma cells results in attenuation of cyclic AMP accumulation, apparently as a consequence of increases in phosphoinositide hydrolysis, Ca2+ mobilization, and the activation of a Ca2+ calmodulin-regulated phosphodiesterase. Preincubation of these cells with carbachol for 30-90 min resulted in a 15-30-fold shift to the right of the concentration effect curves for carbachol or methacholine for attenuation of cyclic AMP accumulation, with no change occurring in the maximal effect observed with either agonist. In contrast, preincubation with carbachol for 30-90 min resulted in an essentially complete loss of effects on cyclic AMP accumulation of the muscarinic receptor agonists oxotremorine, arecoline, and bethanechol. In contrast to carbachol and methacholine, oxotremorine, arecoline, and pilocarpine were much less effective inducers of desensitization. Inactivation of muscarinic receptors with propylbenzylcholine mustard, or preincubation of cells with 4 beta-phorbol 12 beta-myristate 13 alpha-acetate, which has been shown to markedly decrease the phosphoinositide response of 1321N1 cells to cholinergic agonists, produced differential effects on the cyclic AMP response to carbachol and oxotremorine that were similar to those observed after preincubation with carbachol. The data can be explained by the presence of "reserve" in the series of steps that result in muscarinic receptor-mediated activation of phosphodiesterase. That is, it is proposed that carbachol and methacholine mobilize much more Ca2+ than is necessary for maximal activation of phosphodiesterase, whereas oxotremorine and several other muscarinic receptor agonists do not.


Smart capsules for sensing and sampling the gut: status, challenges and prospects.
Smart capsules are developing at a tremendous pace with a promise to become effective clinical tools for the diagnosis and monitoring of gut health. This field emerged in the early 2000s with a successful translation of an endoscopic capsule from laboratory prototype to a commercially viable clinical device. Recently, this field has accelerated and expanded into various domains beyond imaging, including the measurement of gut physiological parameters such as temperature, pH, pressure and gas sensing, and the development of sampling devices for better insight into gut health. In this review, the status of smart capsules for sensing gut parameters is presented to provide a broad picture of these state-of-the-art devices while focusing on the technical and clinical challenges the devices need to overcome to realise their value in clinical settings. Smart capsules are developed to perform sensing operations throughout the length of the gut to better understand the body's response under various conditions. Furthermore, the prospects of such sensing devices are discussed that might help readers, especially health practitioners, to adapt to this inevitable transformation in healthcare. As a compliment to gut sensing smart capsules, significant amount of effort has been put into the development of robotic capsules to collect tissue biopsy and gut microbiota samples to perform in-depth analysis after capsule retrieval which will be a game changer for gut health diagnosis, and this advancement is also covered in this review. The expansion of smart capsules to robotic capsules for gut microbiota collection has opened new avenues for research with a great promise to revolutionise human health diagnosis, monitoring and intervention.


The Fever Tree: from Malaria to Neurological Diseases.
This article describes the discovery and use of the South American cinchona bark and its main therapeutic (and toxic) alkaloids, quinine and quinidine. Since the introduction of cinchona to Europe in the 17th century, it played a role in treating emperors and peasants and was central to colonialism and wars. Over those 400 years, the medical use of cinchona alkaloids has evolved from bark extracts to chemical synthesis and controlled clinical trials. At the present time, the use of quinine and quinidine has declined, to a large extent due to their toxicity. However, quinine is still being prescribed in resource-limited settings, in severe malaria, and in pregnant women, and quinidine made a limited comeback in the treatment of several cardiac and neurological syndromes. In addition, the article presents more recent studies which improved our understanding of cinchona alkaloids' pharmacology. The knowledge gained through these studies will hopefully lead to a wider use of these drugs in precision medicine and to design of new generation, safer quinine and quinidine derivatives.


Increases in maternal depressive symptoms during pregnancy and infant cortisol reactivity: Mediation by placental corticotropin-releasing hormone.
Maternal depressive symptoms in pregnancy may affect offspring health through prenatal programming of the hypothalamic-pituitary-adrenal (HPA) axis. The biological mechanisms that explain the associations between maternal prenatal depressive symptoms and offspring HPA axis regulation are not yet clear. This pre-registered investigation examines whether patterns of maternal depressive symptoms in pregnancy are associated with infant cortisol reactivity and whether this association is mediated by changes in placental corticotropin-releasing hormone (pCRH). A sample of 174 pregnant women completed assessments in early, mid, and late pregnancy that included standardized measures of depressive symptoms and blood samples for pCRH. Infant cortisol reactivity was assessed at 1 and 6 months of age. Greater increases in maternal depressive symptoms in pregnancy were associated with higher cortisol infant cortisol reactivity at 1 and 6 months. Greater increases in maternal depressive symptoms in pregnancy were associated with greater increases in pCRH from early to late pregnancy which in turn were associated with higher infant cortisol reactivity. Increases in maternal depressive symptoms and pCRH over pregnancy may contribute to higher infant cortisol reactivity. These findings help to elucidate the prenatal biopsychosocial processes contributing to offspring HPA axis regulation early in development.


Even fluorescence excitation by multidirectional selective plane illumination microscopy (mSPIM).
Multidirectional selective plane illumination microscopy (mSPIM) reduces absorption and scattering artifacts and provides an evenly illuminated focal plane. mSPIM solves two common problems in light-sheet-based imaging techniques: The shadowing in the excitation path due to absorption in the specimen is eliminated by pivoting the light sheet; the spread of the light sheet by scattering in the sample is compensated by illuminating the sample consecutively from opposing directions. The resulting two images are computationally fused yielding a superior image. The effective light sheet is thinner, and the axial resolution is increased by square root 2 over single-directional SPIM. The multidirectional illumination proves essential in biological specimens such as millimeter-sized embryos. The performance of mSPIM is demonstrated by the imaging of live zebrafish embryos.


Modulation of hypothalamic beta-endorphin-regulated expression of natural killer cell cytolytic activity regulatory factors by ethanol in male Fischer-344 rats.
We have previously shown that ethanol administration suppresses natural killer (NK) cell cytolytic activity, partly by decreasing the action of hypothalamic beta-endorphin (beta-EP) on the spleens of male Fischer-344 rats. This study was conducted to examine the effects of ethanol and central administration of beta-EP on perforin, granzyme B, and the cytokine interferon (IFN)-gamma--factors that modulate NK cell cytolytic activity--to understand the mechanism involved in ethanol's suppression of NK cell activity. A group of male Fischer-344 rats were fed an ethanol-containing diet (8.7% v/v), and a control group was pair-fed an isocaloric diet. At the end of 2 weeks, both groups were infused with beta-EP 100 ng/hr into the paraventricular nucleus of the hypothalamus for 18 hr, and spleen tissues were immediately removed for analysis of perforin, granzyme B, and IFN-gamma messenger RNA (mRNA) and protein levels. The mRNA levels of perforin, granzyme B, and IFN-gamma were evaluated by quantitative real-time polymerase chain reaction, and the protein levels of perforin and granzyme B were analyzed by Western blot. Paraventricular nucleus administration of beta-EP increased the mRNA and protein expression of granzyme B and mRNA expression of IFN-gamma in pair-fed animals. Ethanol significantly reduced both basal and beta-EP-induced levels of granzyme B and IFN-gamma. These data suggest that chronic ethanol consumption suppresses beta-EP-induced NK cytolytic activity, granzyme B, and IFN-gamma in male Fischer-344 rats.


Impact of support on the effectiveness of written cognitive behavioural self-help: a systematic review and meta-analysis of randomised controlled trials.
Cognitive behavioural therapy self-help is an effective intervention for a range of common mental health difficulties. However the extent to which effectiveness may vary by type of support--guided, minimal contact, self-administered--has not been extensively considered. This review identifies the impact of support on the effectiveness of written cognitive behavioural self-help and further explores the extent to which effectiveness varies across mental health condition by type of support provided. Randomised controlled trials were identified by searching relevant bibliographic databases, clinical trials registers, conference proceedings and expert contact. 38 studies were included in the meta-analysis yielding a statistically significant overall mean effect size (Hedges' g=-0.49). Overall effect size did not significantly differ by type of support (Q=0.85, df=2, p=0.65) (guided: Hedges' g=-0.53; minimal contact: Hedges' g=-0.55; self-administered: Hedges' g=-0.42). For guided and self-administered types of support, planned comparisons revealed a trend for effect size to vary by mental health condition and for guided CBT self-help the modality of support was significant (Q=6.32, df=2, p=0.04), with the largest effect size associated with telephone delivery (Hedges' g=-0.91). Additional moderator analysis was undertaken for depression given the number of available studies. Regardless of higher baseline levels of severity the effect size for minimal contact was greater than for guided support. Greater consideration should be given to the potential that type of support may be related to the effectiveness of written cognitive behavioural self-help and that this may vary across mental health condition. Findings from this systematic review make several recommendations to inform future research.


Medical management of premenstrual dysphoric disorder.
Women who suffer from severe dysphoric premenstrual complaints can now be accurately diagnosed. A diagnosis of premenstrual dysphoric disorder is best made by ruling out other psychiatric and general medical conditions and by collecting daily ratings of symptom expression across the menstrual cycle. Recent treatment findings support the use of (1) antidepressants that block the serotonin transporter, and (2) the benzodiazepine anxiolytic alprazolam. Medication administered only during the luteal phase of the cycle will result in substantial relief for patients suffering from severe premenstrual dysphoric disorder.


Comparison of Efficacy of Autologous Platelet-rich Fibrin versus Saline Dressing in Chronic Venous Leg Ulcers: A Randomised Controlled Trial.
Venous leg ulcer is a chronic condition, and various treatment modalities are available. Platelet-rich fibrin (PRF) is one of the newer modalities and it contains fibroblast growth factor (GF), vascular endothelial GF, angiopoitin and platelet-derived GF which enhances the wound healing. Hence, we conducted a randomised controlled trial to compare the efficacy of PRF versus saline dressing in chronic venous leg ulcers. This study aims to compare the efficacy of autologous PRF with saline dressing in patients with chronic venous leg ulcer and to compare the mean reduction in ulcer area at the end of 4 weeks. Fifteen patients with chronic venous leg ulcers of >6 months duration having an ulcer area of 1 cm × 1 cm to 5 cm × 5 cm were taken into the study and were randomly divided into two groups. Group 1: Patients received PRF dressing. Ten millilitres of patient's blood was taken and centrifuged at 3000 rpm for 15 min. A fibrin clot obtained in the middle of the tube was removed and used for dressing over the wound surface. It was repeated every week for 4 weeks. Group 2: Patients received saline dressings once a week for 4 weeks. The assessment of the ulcer size was done with the help of photographs, and ulcer area was measured. The mean reduction in the area of the ulcer size in PRF group was 85.51%, and the mean reduction in the area of the ulcer size in Saline group was 42.74% which was statistically significant with a P < 0.001 and t = 4.11. We conclude that PRF dressing can be used as it is effective, inexpensive, safe and an outpatient procedure.


Immune response to Thomsen-Friedenreich disaccharide and glycan engineering.
Cancer-associated mucins show frequent alterations of their oligosaccharide chain profile, with a switch to unmask normally cryptic O-glycan backbone and core regions. Epithelial tumour cells typically show overexpression of the uncovered Gal(beta)1-3GalNAc(alpha)-O-Ser/Thr (Core 1) structure, known as the T antigen or the Thomsen-Friedenreich antigen, the oligosaccharide chain of which is called the Thomsen-Friedenreich disaccharide (TFD). T antigen expression has been associated with immunosuppression, metastasis dissemination, and the proliferation of cancer cells. Several different strategies have been used to trigger a specific immune response to TFD. Natural T antigen and synthetic TFD residues have low immunodominance. In the T antigen, flexibility of the glycosidic bond reduces the immunogenicity of the sugar residue. Enhanced rigidity should favour certain glycan conformations and thereby improve TFD immunotargeting. We propose the term 'glycan engineering' for this approach. Such engineering of TFD should reduce the flexibility of its glycan moiety and thereby enhance its stability, rigidity and immunogenicity.


Study of light transport inside scintillation crystals for PET detectors.
Scintillation crystal design is a critical component in positron emission tomography system development, which impacts a number of performance parameters including energy resolution, time resolution and spatial resolution. Our work aims to develop a generalized simulation tool to model the light transport inside scintillation crystals with good accuracy, taking into account surface treatments, reflectors, temporal dependence of scintillation decay, and comprehensive experimental validations. The simulation has been validated against both direct analytical calculation and experimental measurements. In this work, the studies were performed for a lutetium-yttrium oxyorthosilicate crystal of 3×3×20 mm(3) dimension coupled to a Hamamatsu silicon photomultiplier, with respect to light output, rise-time slope, energy resolution and time resolution. Four crystal surface treatment and reflector configurations were investigated: GroundMetal, GroundPaint, PolishMetal and PolishPaint. The experiments were performed to validate the Monte Carlo simulation results. The results indicate that the best time resolution (0.96±0.05 ns) and good energy resolution (10.6±0.4%) could be produced by using a polished surface with specular reflector, while the configuration of a polished surface with diffusive reflector produces the best energy resolution (10.2±0.9%). The results indicate that a polished surface with diffusive reflector achieves the best energy resolution (10.2±0.9%) for 511 keV high energy photons, and a polished surface with specular reflector achieves the best time resolution (0.96±0.05 ns) measured against a Hamamatsu fast photomultiplier tube. The ground surface treatment is not recommended for its inferior performance in terms of energy and time resolution. Possible explanations and future improvements to be made to the developed simulation tool are discussed.


Depot flupenthixol decanoate for schizophrenia or other similar psychotic disorders.
Anti-psychotic drugs are the mainstay treatment for schizophrenia and similar psychotic disorders. Long-acting depot injections of drugs such as flupenthixol decanoate are extensively used as a means of long-term maintenance treatment. To evaluate the effects flupenthixol decanoate in comparison with placebo, oral antipsychotics and other depot neuroleptic preparations for people with schizophrenia and other severe mental illnesses, in terms of clinical, social and economic outcomes. Relevant trials were identified by searching Biological Abstracts (1982-1998), Cochrane Library (Issue 2, 1998), Cochrane Schizophrenia Group's Register (December 1998), EMBASE (1980-1998), MEDLINE (1966-1998) and PsycLIT (1974-1998). The references of all identified trials were inspected for more studies and the first author of each included trial and relevant pharmaceutical companies were contacted. All randomised controlled trials that focused on people with schizophrenia or other similar psychotic disorders where flupenthixol decanoate had been compared to placebo or other antipsychotic drugs. All clinically relevant outcomes were sought. Studies were reliably selected, quality rated and data extracted. For dichotomous data Peto odds ratios (OR) with 95% confidence intervals (CI) were estimated. Where possible, the number needed to treat statistic (NNT) was also calculated. Analysis was by intention-to-treat. Normal continuous data were summated using the weighted mean difference (WMD). Scale data were presented only for those tools that had attained pre-specified levels of quality. No trials compared flupenthixol decanoate to placebo. One small study compared flupenthixol decanoate with an oral antipsychotic (penfluridol). There were no clear differences between the two preparations. When flupenthixol decanoate was compared to other depot preparations, there were no differences between depots for outcomes such as death, global impression, relapse (OR 1.16 CI 0.7-1.9) or leaving the study early (OR 1.00 CI 0.6-1.7). Two small studies suggest that flupenthixol decanoate is responsible for less movement disorders than other depot antipsychotic drugs (OR 0.23 CI 0.08-0.7, NNT 5). This finding did not hold for specific side effects, such as tremor (OR 1.2 CI 0.3-4) and tardive dyskinesia (OR 1.60 CI 0.4-6). Two trials comparing high doses of flupenthixol decanoate to the standard approximately 40mg per injection reported no significant difference for the outcome of relapse (OR 0.32 CI 0.09-1.2). One small (n=59) trial comparing a very low dose of flupenthixol decanoate ( approximately 6 mg/IM) to a very low dose approximately 9 mg per injection also reported no difference in relapse rates (OR 0.3 CI 0.1-1.1). From the data reported in clinical trials, it would be understandable if those suffering from schizophrenia, who are willing to take flupenthixol decanoate, would request the standard dose rather than the high dose. In the current state of evidence, there is nothing to choose between flupenthixol decanoate and other depot antipsychotics. The choice of which depot to use must therefore be based on clinical judgement and the preferences of people with schizophrenia and their carers. Managers and policy makers should expect better data than the research community has provided thus far. This review highlighted the need for large, well-designed and reported randomised clinical trials to address the effects of flupenthixol decanoate, in particular when compared to oral antipsychotics. Future studies should also consider hospital and service outcomes, satisfaction with care and record economic data.


Inhibition of glioma growth by minocycline is mediated through endoplasmic reticulum stress-induced apoptosis and autophagic cell death.
We have reported that minocycline (Mino) induced autophagic death in glioma cells. In the present study, we characterize the upstream regulators that control autophagy and switch cell death from autophagic to apoptotic. Western blotting and immunofluorescence were used to detect the expressions of eukaryotic translation initiation factor 2α (eIF2α), transcription factor GADD153 (CHOP), and glucose-regulated protein 78 (GRP78). Short hairpin (sh)RNA was used to knock down eIF2α or CHOP expression. Autophagy was assessed by the conversion of light chain (LC)3-I to LC3-II and green fluorescent protein puncta formation. An intracranial mouse model and bioluminescent imaging were used to assess the effect of Mino on tumor growth and survival time of mice. The expression of GRP78 in glioma was high, whereas in normal glia it was low. Mino treatment increased GRP78 expression and reduced binding of GRP78 with protein kinase-like endoplasmic reticulum kinase. Subsequently, Mino increased eIF2α phosphorylation and CHOP expression. Knockdown of eIF2α or CHOP reduced Mino-induced LC3-II conversion and glioma cell death. When autophagy was inhibited, Mino induced cell death in a caspase-dependent manner. Rapamycin in combination with Mino produced synergistic effects on LC3 conversion, reduction of the Akt/mTOR/p70S6K pathway, and glioma cell death. Bioluminescent imaging showed that Mino inhibited the growth of glioma and prolonged survival time and that these effects were blocked by shCHOP. Mino induced autophagy by eliciting endoplasmic reticulum stress response and switched cell death from autophagy to apoptosis when autophagy was blocked. These results coupled with clinical availability and a safe track record make Mino a promising agent for the treatment of malignant gliomas.


Moisture chamber goggles for the treatment of postoperative dry eye in patients receiving SMILE and FS-LASIK surgery.
The incidence of refractive surgery-related dry eye disease (DED) is rising due to the increasing popularity of corneal refractive surgery. The moisture chamber goggles (MCGs) have been shown to tear evaporation by increasing local humidity and minimizing airflow. The current study aims to evaluate the efficacy of moisture chamber goggles for refractive surgery-related DED. In this nonrandomized open-label controlled study, 78 participants (156 eyes) receiving refractive surgery were enrolled between July 2021 and April 2022, and sequentially allocated to MGC and control groups. 39 participants were allocated to the MGC groups, of which 53.8% received small-incision lenticule extraction (SMILE) and 46.2% received femtosecond laser-assisted in situ keratomileusis (FS-LASIK), and were instructed to wear MCGs for the duration of 1 month postoperatively, in addition to the standard postoperative treatment received by the control groups (56.4% SMILE, 43.6% FS-LASIK). Participants underwent full ophthalmic examinations, including visual acuity, manifest refraction, DED evaluations, and higher-order aberrations (HOAs), both preoperatively and at routine follow-ups 1 day, 1 week, and 1 month after surgery. DED parameters included non-invasive tear film break-up time (NIBUT), tear meniscus height (TMH), conjunctival congestion, lipid layer thickness (LLT), and ocular surface disease index (OSDI) questionnaires. Student's t-test was used for comparisons between control and MCG groups, and between preoperative and postoperative parameters within groups. Postoperative NIBUT decreased in both SMILE and FS-LASIK control groups 1 day after the surgery (SMILE, P = 0.001; FS-LASIK, P = 0.008), but not in the corresponding MCG groups (SMILE, P = 0.097; FS-LASIK, P = 0.331). TMH in the MCG group was significantly higher at 1 week (P = 0.039) and 1 month (P = 0.015) in SMILE, and 1 day (P = 0.003) in FS-LASIK groups. In FS-LASIK participants, significantly lower HOAs and coma levels in the MCG group were observed 1 day (total HOAs, P = 0.023; coma, P = 0.004) and 1 week (total HOAs, P = 0.010, coma, P = 0.004) after surgery. No consistent statistically significant intergroup difference was observed between MCG and control groups in conjunctival congestion, LLT, and OSDI. MCGs effectively slowed tear evaporation, increased tear film stability, and improved HOAs in patients receiving SMILE and FS-LASIK surgeries. MCG is an effective adjuvant therapy in the comprehensive management of refractive surgery-related DED.


Familial amyloidotic polyneuropathy: current and emerging treatment options for transthyretin-mediated amyloidosis.
Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a fatal clinical disorder characterized by extracellular deposition of abnormal fibrils derived from misfolded, normally soluble transthyretin (TTR) molecules. The disease is most commonly caused by a point mutation within the TTR gene inherited in an autosomal dominant fashion. Over 100 of such mutations have been identified, leading to destabilization of the physiological TTR tetramer. As a result, many monomers originate with a tendency for spontaneous conformational changes and self-aggregation. The main clinical feature of TTR-FAP is progressive sensorimotor and autonomic neuropathy. In the beginning, this polyneuropathy predominantly involves small unmyelinated nerve fibers with the result of dissociated sensory loss disproportionately affecting sensation of pain and temperature. Autonomic neuropathy typically accompanies sensory deficits early in the disease course. The symptoms include orthostatic hypotension, constipation alternating with diarrhea, erectile dysfunction, anhydrosis, and urinary retention or incontinence. Later, involvement of motor fibers causes rapidly progressive weakness and gait disturbances. In addition to the peripheral nervous system, the heart and the gut are frequently affected. Onset of symptoms is bimodal, with one peak at age 33 years (early onset) and another distinct peak in the sixth decade of life (late onset). The course of TTR-FAP is uniformly progressive and fatal. Death occurs an average of 10.8 years after the onset of symptoms in Portuguese patients, and 7.3 years in late-onset Japanese patients. Common causes include cachexia, cardiac failure, arrhythmia, and secondary infections. Liver transplantation is the standard therapy for patients who are in a clinical condition good enough to tolerate this intervention because it stops progression of neuropathy by removing the main source of mutant TTR. Recently, orally administered tafamidis meglumine has been approved by European authorities for treatment of FAP. The substance has been shown to stabilize the TTR tetramer, thereby improving the outcome of patients with TTR-FAP. Various other strategies have been studied in vitro to prevent TTR amyloidosis, including gene therapy, immunization, dissolution of TTR aggregates, and free radical scavengers, but none of them is ready for clinical use so far.


Networking in eHealth research: results of the IDRC SEARCH program evaluation.
The IDRC 'Strengthening Equity through Applied Research Capacity building in eHealth' (SEARCH) funded seven research projects in Bangladesh, Burkina Faso, Ethiopia, Kenya, Lebanon, Peru and Vietnam that sought to answer questions or test solutions related to the use of Internet or mobile phone technology in strengthening health systems. The evaluation accompanied these projects over two years to answer, among others, the question how cross-grant learning interactions influenced project outcomes. The evaluation team conducted repeated interviews and on-line questionnaire surveys with the research teams and analysed the information exchanges among researchers on a SharePoint site established by IDRC. The expectations of the SEARCH program in terms of cross-project learning were only partially realized. The diversity of themes, language barriers and differences in context were cited as main reasons. Non-facilitated active cross-grant networking was only observed between two teams working in English on thematically similar issues. However, networking among all projects was active during two program workshops organized by IDRC. Networking among research teams can increase the quality and the applicability of health systems research and potentially promote knowledge translation. Spontaneous networking across language barriers is, however, difficult. Effective global research networks require dedicated human and financial resources to keep them vibrant and alive. e-health, refugees.


Lysosomal changes during thyroxine-induced left ventricular hypertrophy in rabbits.
By use of a combined morphologic, immunocytochemical, and biochemical approach, this study demonstrates the changes in the lysosomal vacuolar apparatus that accompany thyroxine-induced cardiac hypertrophy. During the 1st wk of thyroxine administration, immunocytochemical studies revealed a decline in cathepsin D within many myocytes, but an increase within interstitial cells. These events transpired with only a modest rise in cathepsin D activity. During the 2nd wk, cathepsin D reappeared within most myocytes and continued to increase within the interstitial population and was associated with a general rise in lysosomal enzyme activity. These data demonstrate the importance of employing both immunocytochemical and biochemical approaches to evaluate the status of the lysosomal vacuolar apparatus, and suggests that the lysosomal vacuolar apparatus may be involved in the apparent remodeling that attends rapid cardiac growth, which may represent one component of the enhanced rates of proteolysis documented in this model of cardiac hypertrophy.


Effects of castration on plasminogen activator activities and plasminogen activator inhibitor type 1 in the rat ventral prostate.
The involution of the prostate gland after castration is an active process which requires the induction of new proteins. The plasminogen activator urokinase has been proposed to be a gene repressed by androgen which is activated upon castration and thus participating in the atrophy of the gland. However, urokinase is secreted by the ventral lobe of the rat prostate and this should be positively affected by androgens. The purpose of this study was to examine further the effects of castration upon plasminogen activator (PA) activities in the rat prostate and to determine possible explanations to this apparent dilemma. Castration of young sexually mature adult rats resulted in a substantial increase in PA activities at 4 days after castration in the ventral prostate, but then the activities returned to within the range of untreated animals with a longer duration of castration. Urokinase was the predominant molecular form of PA in the normal ventral prostate and it was the molecular form increased after castration; based upon its sensitivity to amiloride and its molecular size determined in zymograms. In contrast to the effect of castration, there was no increase in PA activities in the ventral prostate with treatment of rats with the antiandrogen flutamide, but rather a decrease when specific activity was expressed per unit DNA. In addition, the effect of castration was specific for the ventral lobe for there was no change in the PA activity in the dorsolateral prostate after androgen ablation. The diminished PA activities in the ventral prostates of rats castrated for 7 days or longer appeared to be due at least in part to an increase in plasminogen activator inhibitor type-1 (PAI-1). Immunoreactive PAI-1 was found predominantly in high molecular weight forms which indicates that the inhibitor was complexed with PA. Daily treatment of rats upon castration with agents known to retard the rate of regression of the involuting prostate gave dichotomous results. Hydrocortisone prevented the increase in PA activity, whereas treatment with actinomycin D, an inhibitor of RNA synthesis, not only did not prevent an increase in PA activity, but actually produced a superinduction in PA activity at 4 days orchiectomy. These data may be interpreted to mean that hydrocortisone stimulated PAI activity and that actinomycin D treatment blocked its induction. However, the actinomycin D data may also indicate that an increase in urokinase protein and mRNA after castration may result from some mechanism to conserve these molecules suggesting that this inhibitor of RNA synthesis prevented the transcription of messages for proteins involved in the degradation of urokinase message.


Emerging applications of the single cell gel electrophoresis (Comet) assay. I. Management of invasive transitional cell human bladder carcinoma. II. Fluorescent in situ hybridization Comets for the identification of damaged and repaired DNA sequences in individual cells.
ABSTRACT I: Management of invasive transitional cell human bladder carcinoma. The two main treatment options for invasive transitional cell bladder carcinoma are radiotherapy or primary cystectomy with urinary diversion or bladder substitution. Approximately 50% of patients fail to respond to radiotherapy and such patients so treated are disadvantaged by the absence of predictive information regarding their radiosensitivity, since the tumour gains additional time for metastatic spread before cystectomy is performed. The SF2 clonogenic assay, which measures the surviving fraction of tumour cells after 2 Gy X-ray irradiation, is regarded as a good measure of radiosensitivity. However, the assay is time consuming and provides results for only approximately 70% of human tumours. In this paper three bladder transitional cell carcinoma cell lines (HT1376, UMUC-3 and RT112) were exposed to X-irradiation (0-10 Gy). We have compared the responses obtained using a clonogenic assay and a more clinically feasible alkaline single cell gel electrophoresis (Comet) assay. A very good inverse correlation was obtained between cell survival (clonogenic assay) and mean tail moment (Comet assay) for the three cell lines, indicating that the Comet assay can be used to predict the radio-responsiveness of individual cell lines. The clinical usefulness of the assay for predicting response to radiotherapy in bladder cancer patients is currently being investigated. ABSTRACT II: Fluorescent in situ hybridization (FISH) Comets for the identification of damaged and repaired DNA sequences in individual cells. In mammalian cells the extent of DNA damage is partly and the rate of DNA repair very considerably dependent on DNA position and transcription. This has been established by biochemical techniques which are labour intensive and require large numbers of cells. The Comet assay for overall DNA damage and repair is relatively simple and allows individual cells to be examined. Here we present a protocol for combination of the Comet assay with fluorescent in situ hybridization (FISH) using a p53 gene probe which allows specific observation of p53 sequences within DNA comets. Chromosome-specific probes can also be used. Optimization of the FISH/Comet protocol to include automation of the analysis is currently underway to facilitate future application of the technique to study selective DNA damage and repair in defined sequences in single mammalian cells.


Steps expressed relative to body fat mass predicts body composition and cardiometabolic risk in adults eating ad libitum.
Excess body fatness is a consequence of a chronic energy surplus (energy intake is greater than energy expenditure). Given the serious health consequences of excess body fatness, factors that influence energy balance and body composition are increasingly important to understand. A total of 34 adults between the ages of 19-40 years made a laboratory visit in which height, weight, body composition, and cardiometabolic risk (CMR) factors were quantified. Participants wore accelerometers for 21-28 days, then returned to the laboratory for a second body composition assessment. Changes in weight and body composition were used to quantify energy balance, and data derived from accelerometers provided markers of physical activity (PA) and sedentariness. Of the markers of PA that we measured, daily step counts expressed relative to fat mass was most strongly and consistently associated with body fatness and CMR status. Step counts expressed relative to fat mass were strongly associated with body composition and CMR in adults eating ad libitum. Longitudinal interventional studies are necessary to determine the efficacy of step count prescriptions expressed relative to existing and target body fatness and CMR levels for improving weight management and metabolic outcomes.


Return to Play After Revision Anterior Cruciate Ligament Reconstruction in National Football League Players.
National Football League (NFL) players who undergo anterior cruciate ligament (ACL) reconstruction have been shown to have a lower return to play (RTP) than previously expected. However, RTP in the NFL after revision ACL reconstruction (RACLR) is not well defined. The purpose of this study is to determine the RTP of NFL players after RACLR and evaluate factors that predict RTP. Our hypothesis was that more experienced and established players would be more likely to RTP after RACLR. Cohort study; Level of evidence, 3. A total of 24 NFL players who underwent RACLR between 2007 and 2014 were reviewed and evaluated. Return to NFL play, time to return, seasons and games played prior to and after revision surgery, draft status, and demographic data were collected. Overall RTP was determined, and players who did RTP were compared with those unable to RTP. Data were also compared with control players matched for age, position, size, and experience. After RACLR, 79% (19/24) of NFL players returned to NFL regular-season play at an average of 12.6 months. All players who were drafted in the first 4 rounds, played in at least 55 games, or played 4 seasons of NFL play prior to injury were able to RTP. Players drafted in the first 4 rounds of the NFL draft were more likely to RTP than those who were not (odds ratio, 0.1; 95% CI, 0.01-1.00; P = .05). Those who returned to NFL play played in significantly less games and seasons after their injury than before (P = .01 and P = .01, respectively). However, these values did not differ when compared with matched controls (P = .67 and P = .33). NFL players who RTP after RACLR do so at a similar rate but prolonged time period compared with after primary ACL reconstruction. Athletes who were drafted in earlier rounds were more likely to RTP than those who were not. Additionally, player experience prior to injury is an important factor when predicting RTP after RACLR.


Chronic fatigue syndrome. The patient centred clinical method--a guide for the perplexed.
Chronic fatigue states are common in general practice and over the past 20 years there has been considerable worldwide consensus developed on the criteria for chronic fatigue syndrome (CFS) also commonly known as myalgic encephalomyelitis (ME). Chronic fatigue syndrome is an illness characterised by the new onset of disabling fatigue, accompanied by cognitive, musculoskeletal and sleep symptoms. There are no specific diagnostic tests or biological markers and the diagnosis is made by ruling out other causes of fatigue. The pathophysiology of CFS is still unclear. This article discusses the application of the patient centred clinical method to the diagnosis and treatment of CFS. There is no new breakthrough in the diagnosis or management of CFS in spite of much research and controversy. There is considerable evidence that the best place to manage CFS is in primary care under the care of the patient's own general practitioner, but it has been suggested that doctors feel unable to deal with the problem. The patient centred clinical method offers a constructive guide to management. The author considers that the best hope for sufferers is self management guided by a supportive and helpful health professional, preferably the patient's own GP.


The MLH1 c.-27C>A and c.85G>T variants are linked to dominantly inherited MLH1 epimutation and are borne on a European ancestral haplotype.
Germline mutations of the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2, and deletions affecting the EPCAM gene adjacent to MSH2, underlie Lynch syndrome by predisposing to early-onset colorectal, endometrial and other cancers. An alternative but rare cause of Lynch syndrome is constitutional epimutation of MLH1, whereby promoter methylation and transcriptional silencing of one allele occurs throughout normal tissues. A dominantly transmitted constitutional MLH1 epimutation has been linked to an MLH1 haplotype bearing two single-nucleotide variants, NM_000249.2: c.-27C>A and c.85G>T, in a Caucasian family with Lynch syndrome from Western Australia. Subsequently, a second seemingly unrelated Caucasian Australian case with the same MLH1 haplotype and concomitant epimutation was reported. We now describe three additional, ostensibly unrelated, cancer-affected families of European heritage with this MLH1 haplotype in association with constitutional epimutation, bringing the number of index cases reported to five. Array-based genotyping in four of these families revealed shared haplotypes between individual families that extended across ≤2.6-≤6.4 megabase regions of chromosome 3p, indicating common ancestry. A minimal ≤2.6 megabase founder haplotype common to all four families was identified, which encompassed MLH1 and additional flanking genes and segregated with the MLH1 epimutation in each family. Our findings indicate that the MLH1 c.-27C>A and c.85G>T variants are borne on a European ancestral haplotype and provide conclusive evidence for its pathogenicity via a mechanism of epigenetic silencing of MLH1 within normal tissues. Additional descendants bearing this founder haplotype may exist who are also at high risk of developing Lynch syndrome-related cancers.


Changed histone acetylation patterns in normal-appearing white matter and early multiple sclerosis lesions.
The epigenetic identity of oligodendrocytes is modulated by posttranslational modifications of histones. Acetylation of histone H3 results from the balance between the activity of histone acetyltransferases (HATs) and histone deacetylases and modulates transcriptional activation. We have previously shown that, in rodents, histone deacetylation favors oligodendrocyte differentiation, whereas acetylation is associated with increased levels of transcriptional inhibitors of oligodendrocyte differentiation. Here, we report, in humans brains, a shift toward histone acetylation in the white matter of the frontal lobes of aged subjects and in patients with chronic multiple sclerosis (MS). Increased immunoreactivity for acetylated histone H3 was observed in the nuclei of NogoA+ oligodendrocytes in a subset of MS samples. These changes were associated with high levels of transcriptional inhibitors of oligodendrocyte differentiation (i.e., TCF7L2, ID2, and SOX2) and higher HAT transcript levels (i.e., CBP, P300) in female MS patients compared with non-neurological controls and correlated with disease duration. Chromatin immunoprecipitation from samples of MS patients revealed enrichment of acetyl-histone H3 at the promoter of the increased target genes (i.e., TCF7L2). The data in chronic lesions contrasted with findings in early MS lesions, where a marked oligodendroglial histone deacetylation was observed. Together, these data suggest that histone deacetylation is a process that occurs at the early stages of the disease and whose efficiency decreases with disease duration.


Association of PPARG2 Pro12Ala variant with larger body mass index in Mestizo and Amerindian populations of Mexico.
Previous studies have sought to associate the Pro12Ala variant of the peroxisome proliferator-activated receptor gamma2 (PPARG2) gene with type 2 diabetes, insulin resistance, and obesity, with controversial results. We have determined the Pro12Ala variant frequency in 370 nondiabetic Mexican Mestizo subjects and in five Mexican Amerindian groups and have investigated its possible association with lipid metabolism, insulin serum levels, and obesity in three of these populations. Two independent case-control studies were conducted in 239 nondiabetic individuals: 135 case subjects (BMI > or = 25 kg/m2) and 104 control subjects (BMI < 25 kg/m2). The PPARG2 Ala12 allele frequency was higher in most Amerindian populations (0.17 in Yaquis, 0.16 in Mazahuas, 0.16 in Mayans, and 0.20 in Triquis) than in Asians, African Americans, and Caucasians. The Pro12Ala and Ala12Ala (X12Ala) genotypes were significantly associated with greater BMI in Mexican Mestizos and in two Amerindian groups. X12Ala individuals had a higher risk of overweight or obesity than noncarriers in Mestizos (OR = 3.67; 95% CI, 1.42-9.48; p = 0.007) and in Yaquis plus Mazahuas (OR = 3.21; 95% CI, 1.27-8.11; p = 0.013). Our results provide further support of the association between the PPARG2 Ala12 allele and risk of overweight or obesity in Mestizos and two Amerindian populations from Mexico.


Efficacy of pyridoxine to ameliorate the cutaneous toxicity associated with doxorubicin containing pegylated (Stealth) liposomes: a randomized, double-blind clinical trial using a canine model.
A cutaneous reaction termed palmar-plantar erythrodysesthesia (PPES) or hand-foot syndrome can be dose limiting for Doxil, a doxorubicin containing pegylated (Stealth) liposome. The objective of this study was to determine the ability of concomitant pyridoxine therapy to prevent the development of PPES during Doxil therapy. Forty-one dogs with non-Hodgkin's lymphoma were randomized in a double-blind fashion to receive either oral pyridoxine or placebo daily during Doxil chemotherapy (1.0 mg/kg, i.v., every 3 weeks for a total of five treatments). Cutaneous toxicity was determined by clinical and histological scoring. No difference was observed in remission rates (71.4 versus 75%) achieved between groups. The likelihood of developing serious PPES and having to decrease or discontinue Doxil therapy was 4.2 times (relative risk) greater in placebo group dogs than in pyridoxine group dogs (P = 0.032). Pyridoxine did not completely abrogate PPES; however, it occurred later and less dramatically than in placebo-treated dogs and resulted in fewer treatment delays or discontinuations, allowing a higher cumulative dose of Doxil to be received. Compared to the 5.0 mg/kg cumulative target dose, pyridoxine-treated dogs received a median cumulative dose of 4.7 mg/kg (mean, 4.1 mg/kg), and the placebo-treated dogs received a median of 2.75 mg/kg (mean, 2.9 mg/kg; P < 0.028). A trend (P = 0.084) toward prolongation of remission length was observed in dogs receiving pyridoxine, which was likely attributable to their ability to receive more Doxil without delay or discontinuation. We conclude that pyridoxine is effective in delaying the onset and severity of PPES in this canine model.


Inhibition properties of some flavonoids on carbonic anhydrase I and II isoenzymes purified from human erythrocytes.
Carbonic anhydrases (CAs, E.C.220.127.116.11) play a critical role in many important physiological events and treatment of some diseases. Flavonoids or phenolic compounds have been discovered as novel CAs inhibitors instead of the traditional sulfonamides, with different binding to CAs, pro-drug activities, and new inhibition mechanisms. Here, we investigated the inhibition effects of some flavonoids including malvin, callistephin, oenin, pelargonin, silychristin, and 1-(4-methoxyphenyl)-2-methyl-3-nitro-1-H-indol-6-ol (ID-8) against hCA I and II, which purified from human erythrocytes by affinity column chromatography. Both hCA isoenzymes were inhibited by flavonoids, with IC50 and Ki values in the range of 2.34 nM to 346.5 μM and 51.01-99.55 μM for hCA I and 86.60-750.00 μM for hCA II, respectively. These results showed that flavonoids especially malvin and oenin effectively inhibited hCA I and II isoenzymes. Hence, they may be used as an effective CA inhibitor in medical applications for treatment of certain diseases such as glaucoma, in the future.


Assessment of the extent of cutaneous involvement in children and adults with mastocytosis: relationship to symptomatology, tryptase levels, and bone marrow pathology.
Cutaneous involvement occurs in most patients with systemic mastocytosis. We sought to determine whether the extent of cutaneous involvement is predictive of systemic disease. In a prospective survey of 48 adults and 19 children, the extent and density of cutaneous lesions were compared with patient history, symptoms, internal organ involvement, serum total mast cell tryptase level, and bone marrow pathology. Cutaneous lesions in children were of a greater mean and maximum diameter, but similar in extent and density compared with lesions in adults. In adults with skin lesions, the extent of lesions correlated to disease duration. Adults with extensive cutaneous disease experienced more pruritus and flushing. Fatigue, splenomegaly, and hepatomegaly were more frequent in adults without cutaneous involvement; and in those with a greater density of lesions and disease duration. Increased tryptase levels were found in children and adults with systemic disease and correlated to skin lesion density and bone marrow pathology. An examination of the extent and density of cutaneous lesions in adults helps identify those with more extensive extracutaneous disease and, thus, requiring a more thorough evaluation.


Glomerular filtration rate and albuminuria for detection and staging of acute and chronic kidney disease in adults: a systematic review.
Because early-stage kidney disease is asymptomatic and is associated with both morbidity and mortality, laboratory measurements are required for its detection. To summarize evidence supporting the use of laboratory tests for glomerular filtration rate (GFR) and albuminuria to detect and stage acute kidney injury, acute kidney diseases and disorders, and chronic kidney disease in adults. We reviewed recent guidelines from various professional groups identified via the National Guideline Clearing House and author knowledge, and systematically searched MEDLINE for other sources of evidence for selected topics. The KDIGO (Kidney Disease Improving Global Outcomes) guidelines define and stage acute and chronic kidney diseases by GFR and albuminuria. For initial assessment of GFR, measuring serum creatinine and reporting estimated GFR based on serum creatinine (eGFRcr) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation is recommended. If confirmation of GFR is required because of conditions that affect serum creatinine independent of GFR (eg, extremes of muscle mass or diet), or interference with the assay, cystatin C should be measured and estimated GFR should be calculated and reported using cystatin C (eGFRcys) and serum creatinine (eGFRcr-cys) or GFR should be measured directly using a clearance procedure. Initial assessment of albuminuria includes measuring urine albumin and creatinine in an untimed spot urine collection and reporting albumin-to-creatinine ratio. If confirmation of albuminuria is required because of diurnal variation or conditions affecting creatinine excretion, such as extremes of muscle mass or diet, the albumin excretion rate should be measured from a timed urine collection. Detection and staging of acute and chronic kidney diseases can be relatively simple. Because of the morbidity and mortality associated with kidney disease, early diagnosis is important and should be pursued in at-risk populations.


Prognostic value of Pulsatility Index in acute intracerebral hemorrhage.
To investigate whether data obtained by transcranial Doppler (TCD) have prognostic value in patients with intracerebral hemorrhage (ICH). A prospective study of patients with an acute (<12 hours from onset of symptoms) spontaneous supratentorial ICH was conducted. Mortality was assessed at 30-day follow-up. TCD parameters were obtained from both middle cerebral arteries: systolic, diastolic, and mean velocities and Pulsatility Index (PI) from the affected and unaffected hemispheres. The following variables were included in a univariate analysis: age, sex, hematoma volume, hypodense volume around the hematoma, total volume, midline shift, ventricular size, Glasgow Coma Scale score, intraventricular hemorrhage, body temperature, white cell count, blood glucose, mean blood pressure, and TCD data. A multivariate analysis was performed with variables that showed significance in the univariate analysis. Receiver-operator characteristic (ROC) curves were obtained. Forty-eight patients (age 66.5 +/- 12.5 years; 28 men) were studied. Mortality at 30 days was 31%. The only predictor of mortality was the Glasgow Coma Scale score (odds ratio [OR] 0.67, CI 0.53 to 0.84, p = 0.001), whereas the PI from the unaffected hemisphere was correlated with mortality (OR 2.3, CI 0.92 to 5.72, p = 0.07). The area under the ROC curve was 0.92. A cutoff for PI from the unaffected hemisphere of 1.75 showed a specificity of 94% and a sensitivity of 80% as a predictor of death at 30 days. The PI of the unaffected hemisphere may be a predictor of death in acute ICH. These findings suggest that intracranial hypertension is the most likely cause of death in most patients with ICH.


Case Report/Case Series: Rare case of anti-LGI1 limbic encephalitis with rapidly progressive dementia, psychiatric symptoms, and frequently seizures: A case report.
Anti leucine-rich glioma inactivated 1 (LGI1) limbic encephalitis (LE) is rare autoimmune encephalitis, characterized by acute or subacute cognitive impairment, faciobrachial dystonic seizures, mental disorders, and refractory hyponatremia. As a type of treatable rapidly progressive dementia with a good prognosis, early, and accurate diagnosis is essential. We present a case of anti-LGI1 LE who was initially misdiagnosed with Alzheimer disease because his clinical manifestations were similar to Alzheimer disease. A male patient presenting with rapidly progressive dementia, faciobrachial dystonic seizures, psychiatric disturbance, and refractory hyponatremia was admitted. The scores of Mini-Mental State Examination, Montreal Cognitive Assessment, and Neuropsychiatric Inventory were 19/30, 16/30, and 91/144, respectively. Brain magnetic resonance images indicated moderate atrophy of the hippocampus and abnormally hyperintensities in the left medial temporal and hippocampus. The patient was diagnosed with anti-LGI1 LE based on the presence of LGI-1 antibodies in the cerebrospinal fluid and serum and clinical manifestations. Patient was treated with glucocorticoid against LGI1, antiepileptic drug, cholinesterase inhibitors, and other adjuvant therapy. The patient showed marked improvement on immunotherapy. Clinical symptoms were disappeared and the LGI-1 antibodies in cerebrospinal fluid and serum were both negative at the time of discharge. Recognition of the specific symptoms and LGI-1 antibody test will be helpful for the early diagnosis, prompt immunotherapy, and good prognosis. This case raises the awareness that rapidly progressive dementia with frequent seizures could be caused by immunoreactions.


Coordination Engineering of Heteronuclear Fe-Mo Dual-Atom Catalyst for Promoted Electrocatalytic Nitrogen Fixation: A DFT Study.
Developing efficient nanostructured electrocatalysts for N2 reduction to NH3 under mild conditions remains a major challenge. The Fe-Mo cofactor serves as the archetypal active site in nitrogenase. Inspired by nitrogenase, we designed a series of heteronuclear dual-atom catalysts (DACs) labeled as FeMoN6-a Xa (a=1, 2, 3; X=B, C, O, S) anchored on the pore of g-C3 N4 to probe the impact of coordination on FeMo-catalyzed nitrogen fixation. The stability, reaction paths, activity, and selectivity of 12 different FeMoN6-a Xa DACs have been systematically studied using density functional theory. Of these, four DACs (FeMoN5 B1 , FeMoN5 O1 , FeMoN4 O2 , and FeMoN3 C3 ) displayed promising nitrogen reduction reaction (NRR) performance. Notably, FeMoN5 O1 stands out with an ultralow limiting potential of -0.11 V and high selectivity. Analysis of the density of states and charge/spin changes shows FeMoN5 O1 's high activity arises from optimal N2 binding on Fe initially and synergy of the FeMo dimer enabling protonation in NRR. This work contributes to the advancement of rational design for efficient NRR catalysts by regulating atomic coordination environments.


The Perceived Stress Scale is essentially unidimensional: Complementary evidence from ancillary bifactor indices and Mokken analysis.
Stress is a significant contributor to physical and mental health. However, there is considerable variability in response to stress, underscoring the role of stress perception in health outcomes. Perceptions of stress are influenced by socio-demographic and cultural factors. The Perceived Stress Scale (PSS) has been used extensively to assess stress among different populations and for cross-cultural comparisons. Given its wide-ranging application, the rigorous assessment of its psychometric properties is necessary to solidify its standing as a dependable measure. The scale was originally conceptualized as unidimensional but there has been controversy regarding its factor structure, leading to various factor models. Conclusions about the structure of the PSS were largely based on fit indices in confirmatory factor analysis and often did not go beyond fit indices. In addition, classical test theory indices are sample dependent and it is not surprising that instruments can exhibit different properties in different samples. Over reliance on fit indices can lead to overly simplistic interpretations of underlying dimensionality. Hence, the current study extends this research by using item response theory and examining ancillary bifactor indices to determine the amount of variance explained by the total scale and subscales. Participants were students (n = 322) at a South African institution who completed the PSS and a demographic questionnaire. Fit indices in confirmatory factor analysis indicated that a one-factor model, a bifactor model and a correlated-two factor model fit the data to an acceptable degree (GFI > 0.95, CFI > 0.90, RMSEA <0.08). Ancillary bifactor indices supported the essential unidimensionality of the scale as the two subscales accounted for 18.9 % and 17.2 %, of the variance, respectively, while the total scale accounted for 63.9 % of the variance. This was confirmed by Mokken analysis, which indicated that all the items loaded on one scale. The unidimensionality of the PSS suggests that it can be an effective clinical screening tool and that it is easily adaptable across different populations and contexts, enabling standardized comparisons. However, it may lose sensitivity to cultural differences in how stress is perceived and experienced. Hence, integrating the PSS with tailored assessments would facilitate a more robust and inclusive approach to stress assessment in various settings and populations. The study did not take specific sources of stress into account and was conducted among a distinct population group. Future studies undertaken among diverse populations and linking global stress with the impact of stressful life events are needed to further confirm our results and understand the interconnection between these factors.


Providing environmentally sustainable nephrology care: focus in low- and middle-income countries.
Health care on a global scale significantly contributes to carbon emissions, with high-income countries being the primary culprits. Within health care, dialysis plays a significant role as a major source of emissions. Low- and middle-income countries have a high burden of kidney disease and are facing an increasing demand for dialysis. This reality presents multiple opportunities to plan for environmentally sustainable and quality kidney care. By placing a stronger emphasis on primary and secondary prevention of kidney disease and its progression, within the framework of universal health coverage, as well as empowering patients to enhance self-care, we can significantly reduce the need for costly and environmentally detrimental kidney replacement therapy. Mandating the adoption of lean and innovative low-carbon dialysis practices while also promoting the growth of kidney transplantation would enable low- and middle-income countries to take the lead in implementing environmentally friendly nephrology practices and reducing costs, thus optimizing sustainability and the well-being of individuals living with kidney disease.


Expression, Localization and Prognosis Association of MEP50 in Breast Cancer.
Breast cancer is composed of distinct subgroups, triple-negative breast cancer (TNBC), human epidermal growth factor receptor-2 (HER2), luminal A, and luminal B, which are associated with different prognosis. MEP50 is the main partner of the arginine methyltransferase PRMT5 required for its enzymatic activity. Here, we examined MEP50 expression in the different breast cancer subgroups from the transcriptomic data obtained on human breast cancer samples and on normal breast tissues in two cohorts (Curie, n = 141; The Cancer Genome Atlas-TCGA, n = 788). We observed higher levels of MEP50 mRNA in TNBC (Curie, n = 41; TCGA, n = 106) compared to the other breast cancer subgroups and normal breast tissues. Using an online KM-plotter database, which allows survival analyses in a larger number of breast cancer patients, we found that high MEP50 mRNA levels were associated with a more favorable recurrence-free survival (RFS) in TNBC (n = 953, p = 1.2 × 10-4) and luminal B (n = 1353, p = 0.013) tumors, whereas high PRMT5 mRNA levels were associated with worse RFS in these two subgroups (TNBC: n = 442, p = 1.0 × 10-4; luminal B: n = 566, p = 6.8 × 10-3). We next determined the expression and the subcellular localization of MEP50 protein by immunohistochemistry (IHC) in our Curie cohort of breast cancer (n = 94) and normal tissues (n = 7) using a validated MEP50 antibody. MEP50 was more expressed in breast tumors compared to normal breast tissues (p = 0.02). MEP50 was more localized to the cytosol in breast cancer cells compared to normal breast tissue (p = 4 × 10-4), and was more found at the plasma membrane in normal tissues compared to breast tumors (p = 0.01). We also evaluated PRMT5 activity by IHC in our Curie cohort using a validated antibody (H4R3me2s) detecting histone H4 symmetrically dimethylated on Arg3. High levels of H4R3me2s were found in normal breast tissues, whereas the lowest levels of H4R3me2s were observed in TNBC and HER2 breast cancer subgroups. Altogether, our study reports the expression of the PRMT5 cofactor (MEP50) and substrate (H4R3me2s) in breast cancer and highlights the association of PRMT5 and MEP50 mRNA with prognosis in luminal B and TNBC breast cancer subgroups and certain TNBC subtypes.


[Psychological approach to different skin diseases: life events and tendency to complain].
For nearly two decades, dermatology has associated with psychology to find a better way to care for dermatology conditions. A scientific trend called psychosomatics is creating a link between dermatology and psychology. The purpose of this article was to examine two concepts closely linked to psychodermatology (life events and tendency to complain) and to emphasize the difference between factors playing a role in the onset of certain skin diseases (psoriasis, alopecia areata, benign tumors, eczema). We found that psoriasis patients have a greater tendency to complain than people with the other disease. This point to the importance of taking emotions into account when studying psoriasis. We also found that life events play a role in the onset of psoriasis and alopecia areata. Moreover, these events were anterior by more than 12 months in alopecia patients. We propose exploring emotions in psoriasis patients and life events over the prior year in alopecia areata patients.


Burkholderia pseudomallei: Challenges for the Clinical Microbiology Laboratory.
Melioidosis is a potentially fatal infection caused by the bacterium Burkholderia pseudomallei Clinical diagnosis of melioidosis can be challenging since there is no pathognomonic clinical syndrome, and the organism is often misidentified by methods used routinely in clinical laboratories. Although the disease is more prevalent in Thailand and northern Australia, sporadic cases may be encountered in areas where it is not endemic, including the United States. Since the organism is considered a tier 1 select agent according to the Centers for Disease Control and Prevention and the U.S. Department of Agriculture Animal and Plant Health Inspection Service, clinical laboratories must be proficient at rapidly recognizing isolates suspicious for B. pseudomallei, be able to safely perform necessary rule-out tests, and to refer suspect isolates to Laboratory Response Network reference laboratories. In this minireview, we report a case of melioidosis encountered at our institution and discuss the laboratory challenges encountered when dealing with clinical isolates suspicious for B. pseudomallei or clinical specimens from suspected melioidosis cases.


Can Molecular Quantum Interference Effect Transistors Survive Vibration?
Quantum interference in cross-conjugated molecules can be utilized to construct molecular quantum interference effect transistors. However, whether its application can be achieved depends on the survivability of the quantum interference under real conditions such as nuclear vibration. We use two simulation methods to investigate the effects of nuclear vibration on quantum interference in a meta-linked benzene system. The simulation results suggest that the quantum interference is robust against nuclear vibration not only in the steady state but also in its transient dynamics, and thus the molecular quantum interference effect transistors can be realized.


Effects of 131I-EGF on cultured human glioma cells.
Malignant glioma cells often have more epidermal growth factor (EGF) receptors than normal cells and targeting of toxic substances to the receptor might therefore be an attractive therapeutical approach. Radiation effects were analysed on human glioma cells growing as monolayers after exposure to 131I-EGF. Unspecific effects were analysed with 131I-BSA or after presaturation with nonradioactive EGF. The radiation effects were compared to the effects obtained by external 60Co gamma irradiation. Administration of the highest radioactive concentrations, 0.2-0.5 MBq/ml in the culture medium, corresponded, after 20 min incubation, to a binding of about 1.0-2.5 dpm/cell. Such an exposure to 131I decays gave effects on cell survival corresponding to about 2.5 Gy of external gamma irradiation. Somewhat less than half of this effect came from the specific bound radioactivity and the rest from nonbound radioactivity. When administrating lower concentrations of radioactivity both the binding and the radiation effects were smaller. The observations showed that it is possible to inactivate cell-proliferation of glioma cells with specific bound 131I-EGF. The possibilities to fractionate the treatments and of binding also other toxic agents than 131I to the EGF receptor are discussed.