The biology and control of leishmaniasis vectors.
Vector control remains a key component of many anti-leishmaniasis programs and probably will remain so until an effective vaccine becomes available. Technologies similar to those used for control of adult mosquitoes, specifically interior residual sprays and insecticide-treated nets, are currently at the forefront as disease control measures. This article provides a review of literature on the biology and control of sand fly vectors of leishmaniasis in the context of changing disease risks and the realities of modern vector control. The Literature Retrieval System of the Armed Forces Pest Management Board, Washington, DC, was the primary search engine used to review the literature.


Transforaminal Percutaneous Endoscopic Discectomy and Foraminoplasty after Lumbar Spinal Fusion Surgery.
The most common causes of pain following lumbar spinal fusions are residual herniation, or foraminal fibrosis and foraminal stenosis that is ignored, untreated, or undertreated. The original surgeon may advise his patient that nothing more can be done in his opinion that the nerve was visually decompressed by the original surgery. Post-operative imaging or electrophysiological assessment may be inadequate to explain all the reasons for residual or recurrent symptoms. Treatment of failed lumbar spinal fusions by repeat traditional open revision surgery usually incorporates more extensive decompression causing increased instability and back pain. The authors, having limited their practice to endoscopic surgery over the last 10 years, report on their experience gained during that period to relieve pain by transforaminal percutaneous endoscopic revision of lumbar spinal fusions. To assess the effectiveness of transforaminal percutaneous endoscopic discectomy and foraminoplasty in patients with pain after lumbar spinal fusion. Retrospective study. Inpatient surgery center. Sixteen consecutive patients with pain after lumbar spinal fusions presenting with back and leg pain that had supporting imaging diagnosis of foraminal stenosis and/or residual/recurrent disc herniation, or whose pain complaint was supported by relief from diagnostic and therapeutic injections, were offered percutaneous transforaminal endoscopic discectomy and foraminoplasty over a repeat open procedure. Each patient sought consultation following a transient successful, partially successful or unsuccessful open lumbar spinal fusions treatment for disc herniation or spinal stenosis. Endoscopic foraminoplasty was also performed to either decompress the bony foramen in the case of foraminal stenosis, or to allow for endoscopic visual examination of the affected traversing and exiting nerve roots in the axilla. The average follow-up time was 30.3 months, minimum 12 months. Outcome data at each visit included MacNab criteria, visual analog scale (VAS), and Oswestry Disability Index (ODI). The average leg VAS improved from 9.1 ± 2.0 to 2.0 ± 0.8 (P < 0.005). Ten patients had excellent outcomes, 5 had good outcomes, one had a fair outcome, and none had poor outcomes, according to the MacNab criteria. Fifteen of 16 patients had excellent or good outcomes, for an overall success rate of 93.7%. No patients required reoperation. There were no incidental durotomies, infections, vascular, or visceral injuries. There was one complication, a case of leg numbness caused by dorsal root ganglion injury. The numbness improved after 2 weeks. After 3 months, physical exam showed that the total area of numbness in the legs had decreased. At last follow-up, the patient had no pain, and only a few areas with numbness remained that did not affect the patient's activities of daily living. The patient was relieved to be able to avoid open decompression. This is a retrospective study. The transforaminal endoscopic approach is effective for patients with back or leg pain after lumbar spinal fusions due to residual/recurrent nucleus pulposus and foraminal stenosis. Failed initial index surgery may involve failure to recognize patho-anatomy in the axilla of the foramen housing the traversing and the exiting nerve. The transforaminal endoscopic approach effectively decompresses the foramen and does not further destabilize the spine needing stabilization. It also avoids going through the previous surgical site. Full-endoscopic, foraminal stenosis, recurrent herniation, surgical treatment, fusion.


Confirming a predicted selection rule in inelastic neutron scattering spectroscopy: the quantum translator-rotator H2 entrapped inside C60.
We report an inelastic neutron scattering (INS) study of a H2 molecule encapsulated inside the fullerene C60 which confirms the recently predicted selection rule, the first to be established for the INS spectroscopy of aperiodic, discrete molecular compounds. Several transitions from the ground state of para-H2 to certain excited translation-rotation states, forbidden according to the selection rule, are systematically absent from the INS spectra, thus validating the selection rule with a high degree of confidence. Its confirmation sets a precedent, as it runs counter to the widely held view that the INS spectroscopy of molecular compounds is not subject to any selection rules.


Mapping and mutation of the conserved DNA polymerase interaction motif (DPIM) located in the C-terminal domain of fission yeast DNA polymerase delta subunit Cdc27.
DNA polymerases alpha and delta play essential roles in the replication of chromosomal DNA in eukaryotic cells. DNA polymerase alpha (Pol alpha)-primase is required to prime synthesis of the leading strand and each Okazaki fragment on the lagging strand, whereas DNA polymerase delta (Pol delta) is required for the elongation stages of replication, a function it appears capable of performing on both leading and lagging strands, at least in the absence of DNA polymerase epsilon (Pol epsilon). Here it is shown that the catalytic subunit of Pol alpha, Pol1, interacts with Cdc27, one of three non-catalytic subunits of fission yeast Pol delta, both in vivo and in vitro. Pol1 interacts with the C-terminal domain of Cdc27, at a site distinct from the previously identified binding sites for Cdc1 and PCNA. Comparative protein sequence analysis identifies a protein sequence motif, called the DNA polymerase interaction motif (DPIM), in Cdc27 orthologues from a wide variety of eukaryotic species, including mammals. Mutational analysis shows that the DPIM in fission yeast Cdc27 is not required for effective DNA replication, repair or checkpoint function. A short protein sequence motif (DPIM) has been identified as mediating Pol alpha-Pol delta interactions in fission yeast. Despite being conserved across species, mutational analysis indicates the DPIM does not play an essential role in vivo, suggesting that interaction between the two polymerases is also non-essential.


Comparison of the performance of the rapid antigen detection actim Influenza A&B test and RT-PCR in different respiratory specimens.
Nowadays, influenza antigen detection test kits are used most frequently to detect influenza A or B virus to establish the diagnosis of influenza rapidly and initiate appropriate therapy. This study was conducted to evaluate the performance of the actim Influenza A&B test (Medix Biochemica). Overall, 473 respiratory specimens were analysed in the actim Influenza A&B test and the results were compared with those from an RT-PCR assay; 461 of these samples originated from paediatric patients aged 7 weeks to 6.5 years either with influenza-related symptoms or from the intensive care unit, and 12 samples originated from adults with underlying lung or haematological diseases. Diagnosis of influenza A or B virus could be established using the actim Influenza A&B test (9/473 samples for influenza A virus and 6/473 for influenza B virus). RT-PCR revealed 23 patients with influenza virus (13/473 for influenza A virus and 10/473 for influenza B virus). The sensitivity and specificity of the actim Influenza A&B test were 65 and 100 % compared with the RT-PCR assay. However, 32 external quality assessment samples containing seven different strains of influenza A subtypes H1N1 and H3N2 and the avian H5N1 were detected correctly by the actim Influenza A&B test. No cross-reactivity to a range of bacterial, fungal and other viral pathogens was observed. In conclusion, the actim Influenza A&B test is reliable for positive results due to its high specificity. Nevertheless, negative results from this test need to be confirmed by a more sensitive assay because of the low sensitivity observed with diagnostic samples.


Effects of branched-chain amino acids supplementation on patients undergoing hepatic intervention: a meta-analysis of randomised controlled trials.
The benefits of branched-chain amino acid (BCAA) administration after hepatic intervention in patients with liver diseases remain unclear. We conducted a systematic review and meta-analysis to evaluate the effects of BCAA on patients undergoing hepatectomy, trans-arterial embolisation and radiofrequency ablation. Relevant randomised controlled trials (RCT) were obtained from PubMed, EMBASE and Cochrane Library databases. A meta-analysis was performed to calculate the pooled effect size by using random-effects models. The primary outcomes were survival and tumour recurrence. The secondary outcomes were hospital stay, nutrition status, biochemistry profile, complication rate of liver treatment and adverse effect of BCAA supplementation. In total, eleven RCT involving 750 patients were included. Our meta-analysis showed no significant difference in the rates of tumour recurrence and overall survival between the BCAA and control groups. However, the pooled estimate showed that BCAA supplementation in patients undergoing hepatic intervention significantly increased serum albumin (mean difference (MD): 0·11 g/dl, 95 % CI: 0·02, 0·20; 5 RCT) at 6 months and cholinesterase level (MD: 50·00 U/L, 95 % CI: 21·08, 78·92; 1 RCT) at 12 months and reduced ascites incidence (risk ratio: 0·39, 95 % CI: 0·21, 0·71; 4 RCT) at 12 months compared with the control group. Additionally, BCAA administration significantly increased body weight at 6 months and 12 months and increased arm circumference at 12 months. In conclusion, BCAA supplementation significantly improved the liver function, reduced the incidence of ascites and increased body weight and arm circumference. Thus, BCAA supplementation may beneficial for selected patients undergoing liver intervention.


[Epidemiologic panorama of cancer mortality in the Mexican Institute of Social Security: 1991-1995].
This paper describes the global cancer mortality and the specific mortality patterns for the main neoplasms among adult members of the Mexican Institute of Social Security (IMSS). Using official death certificates and information about the population of the IMSS members during 1991-1995, national and regional annual global cancer mortality as well as specific mortality rates for the 10 most important malignant neoplasms by sex were estimated among people older than 20 years of age. The trends for these neoplasms during the study period were estimated by means of Poisson regression. The rate differences in specific cancer mortality by region and sex, for the two major neoplasms, were calculated subtracting specific regional rates from the respective national rate in 1995. The global mortality rate for cancer among men increased from 76.2 in 1991 to 94.8 x 100000 IMSS' members in 1995; and among women from 85.6 to 105.8 x 100000 IMSS' members, representing an increment of 24.4 and 24% men and women, respectively, during the study period. Among men, neoplasm of kidney, leukemia, pancreas, prostate and lung showed the major increment; among women, neoplasm of colon, breast, pancreas, leukemia and liver showed the most significant increment. In the IMSS it is necessary the integration of a population based cancer registry. The registry will play a main role in disease surveillance and control; will give basic information over incidence and temporal variation, and could be the main source of information for epidemiologic research, as well as planning and evaluation of the quality of medical attention services such as prevention and early diagnosis and treatment.


The "Grass-Fed" Milk Story: Understanding the Impact of Pasture Feeding on the Composition and Quality of Bovine Milk.
Milk is a highly nutritious food that contains an array of macro and micro components, scientifically proven to be beneficial to human health. While the composition of milk is influenced by a variety of factors, such as genetics, health, lactation stage etc., the animal's diet remains a key mechanism by which its nutrition and processing characteristics can be altered. Pasture feeding has been demonstrated to have a positive impact on the nutrient profile of milk, increasing the content of some beneficial nutrients such as Omega-3 polyunsaturated fatty acids, vaccenic acid, and conjugated linoleic acid (CLA), while reducing the levels of Omega-6 fatty acids and palmitic acid. These resultant alterations to the nutritional profile of "Grass-Fed" milk resonate with consumers that desire healthy, "natural", and sustainable dairy products. This review provides a comprehensive comparison of the impact that pasture and non-pasture feeding systems have on bovine milk composition from a nutritional and functional (processability) perspective, highlighting factors that will be of interest to dairy farmers, processors, and consumers.


Copper-64-alloyed gold nanoparticles for cancer imaging: improved radiolabel stability and diagnostic accuracy.
Gold nanoparticles, especially positron-emitter- labeled gold nanostructures, have gained steadily increasing attention in biomedical applications. Of the radionuclides used for nanoparticle positron emission tomography imaging, radiometals such as (64) Cu have been widely employed. Currently, radiolabeling through macrocyclic chelators is the most commonly used strategy. However, the radiolabel stability may be a limiting factor for further translational research. We report the integration of (64) Cu into the structures of gold nanoparticles. With this approach, the specific radioactivity of the alloyed gold nanoparticles could be freely and precisely controlled by the addition of the precursor (64) CuCl2 to afford sensitive detection. The direct incorporation of (64) Cu into the lattice of the gold nanoparticle structure ensured the radiolabel stability for accurate localization in vivo. The superior pharmacokinetic and positron emission tomography imaging capabilities demonstrate high passive tumor targeting and contrast ratios in a mouse breast cancer model, as well as the great potential of this unique alloyed nanostructure for preclinical and translational imaging.


Oxcarbazepine free or loaded PLGA nanoparticles as effective intranasal approach to control epileptic seizures in rodents.
The brain as a target for drug delivery is a challenge in pharmaceutical research. Among the several proposed strategies, the intranasal route represents a good strategy to deliver drugs to the brain. The goal of this study was to investigate the potential use of oxcarbazepine (OXC) to enhance brain targeting efficiency after intranasal (IN) administration. As well as attempting to use as low a dose as possible to obtain therapeutic effect. Our results showed that, after IN administrations, the dose of OXC that was effective in controlling epileptic seizures was 0.5 mg/kg (1 dose, every 20 min for 1 h) in rodents, confirmed by Cerebral Spinal Fluid (CSF) bioavailability. With the aim of reducing the number of administrations, sustaining drug release and increasing brain targeting, OXC was loaded into poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs). The selected nanoformulation for in vivo studies was obtained re-suspending the freeze-dried and cryo-protected OXC loaded PLGA NPs. The translocation of 1-1'-Dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine Iodide loaded PLGA NPs, from nose to the brain, was confirmed by Fluorescence Molecular Tomography, which also evidenced an accumulation of NPs in the brain after repeated IN administrations. IN administrations of OXC loaded PLGA NPs reduced the number of administrations to 1 over 24 h compared to the free drug thus controlling seizures in rats. Immunohistochemical evaluations (anti-neurofilament, anti-beta tubulin, and anti-caspase3) demonstrated a neuroprotective effect of OXC PLGA NPs after 16 days of treatment. These encouraging results confirmed the possibility of developing a novel non-invasive nose to brain delivery system of OXC for the treatment of epilepsy.


Easily accessible, up-to-date and standardised training model in Urology: E-Learning Residency training programme (ERTP).
There is no standardised and up-to-date education model for urology residents in our country. We aimed to describe our National E-learning education model for urology residents. The ERTP working group; consisting of urologists was established by the Society of Urological Surgery to create E-learning model and curriculum in April 2018. Learning objectives were set up in order to determine and standardise the contents of the presentations. In accordance with the Bloom Taxonomy, 834 learning objectives were created for a total of 90 lectures (18 lectures for each PGY year). Totally 90 videos were shot by specialised instructors and webcasts were prepared. Webcasts were posted at uropedia.com.tr, which is the web library of the Society of Urological Surgery. The satisfaction of residents and instructors was evaluated with feedbacks. An assessment of knowledge was measured with the multiple-choice exam. A total of 43 centres and 250 urology residents were included in ERTP during the academic year 2018/2019. There were 93/55/43/34/25 urology residents at 1st/2nd/3rd/4th and 5th year of residency, respectively. Majority of the residents (99.1%) completed the ERTP. The overall satisfaction rate of residents and instructors were 4.29 and 4.67 (min: 1 so bad, max: 5 so good). An assessment exam was performed to urology residents at the end of the ERTP and the mean score was calculated as 57.99 points (min: 20, max: 82). As a result of the COVID-19 pandemic, most of the educational programmes had to move online platforms. We used this reliable and easily accessible e-learning platform for the standardisation of training in urology on national basis. We aim to share this model with international residency training programmes.


Prevalence, Spectrum, and Outcome of Deliberate Self-harm Presenting to Emergency Department during COVID-19 Pandemic of 2020.
The coronavirus disease-2019 (COVID-19) pandemic, and the lockdown imposed, has had profound social and economic consequences and thereby implications on psychological health. This study aims to understand the effects of the pandemic and the lockdown on the prevalence, spectrum, and outcome of patients presenting with deliberate self-harm (DSH) to the emergency department (ED). This was a retrospective, observational study done in the ED of a tertiary care hospital in South India on DSH victims presenting from January to August 2020, spanning the prelockdown, lockdown, and unlock phases of the pandemic, and compared with data from a similar period in 2018. Our study population included 507 DSH victims (prevalence: 1.2%) from January to August 2020. The percentage of DSH cases showed a slight increase among the prelockdown (203/17,234: 1.18%), the lockdown (179/14,687: 1.22%), and the unlock phases (125/9,977: 1.25%). There was a female preponderance (286/507: 56.4%), and the mean age was 33.2 years. Of the 507 patients, 369 (72.8%) were admitted and 19 (3.7%) died. The lockdown period in 2020 showed a 40.9% absolute decrease in the number of DSH victims presenting to the ED as compared to an equivalent period in 2018. The proportion of patients taking plant poisons was significantly lower [odds ratio (OR) 0.38, 95% confidence intervals (CI) 0.18-0.81, p = 0.012] and that of corrosive ingestion was significantly higher (OR 2.94, 95% CI 1.57-5.48, p = 0.001) in the lockdown phase as compared to a lockdown-control phase of 2018. There was a reduction in the absolute number of patients presenting with DSH to the ED during January-August 2020, and more so during the lockdown phase (March 24-June 30), as compared to a similar period in 2018. There was no significant difference in the hospital outcome of DSH patients between the two periods. John SM, John A, Hazra D, Murugan S, Abhilash KPP. Prevalence, Spectrum, and Outcome of Deliberate Self-harm Presenting to Emergency Department during COVID-19 Pandemic of 2020. Indian J Crit Care Med 2021;25(12):1387-1394.


Substance use disorders: a theory-driven approach to the integration of genetics and neuroimaging.
The etiology of substance use disorders is related to changes in neuronal systems involved in reward anticipation, negative affect, and withdrawal, as well as to alterations in inhibition and executive control. Genetic and epigenetic variation associated with individual differences in these mechanisms may be important for predicting the effectiveness of current treatments and informing future pharmacogenomic investigations. Genetic research efforts have increasingly involved the use of approaches that leverage neurobiological phenotypes to link changes at the molecular level (e.g., genetic and epigenetic variation) to changes in intermediate neuroimaging phenotypes, and ultimately to clinical outcomes. The current review summarizes recent efforts that utilize neuroimaging and genetic approaches in the context of a three-stage model of addiction. In addition, this review explores how these approaches have been used to study the progression from impulsive, recreational substance use to the compulsive, addicted state. Finally, this review describes future ways that research may incorporate these approaches to examine important stage-specific mechanisms of addiction.


Akkermansia muciniphila promotes testosterone-mediated hair growth inhibition in mice.
The beneficial effects of Akkermansia muciniphila (Akk) on gut health and inflammation reduction have been demonstrated; however, scientific evidence of hair growth enhancement by Akk has not been reported. Therefore, this study was undertaken to investigate the effect of Akk on improving testosterone-mediated hair growth inhibition. Hair growth inhibition was induced through subcutaneous injection of testosterone into the shaved dorsal skin of C57BL/6 male mice. Live and pasteurized Akk were orally administered at a concentration of 1 × 108 colony-forming unit. After 5 weeks, hair length and skin tissues were analyzed. The live and pasteurized Akk significantly stimulated hair growth, countering the inhibitory effect of testosterone compared to the testosterone-alone group. Hematoxylin and eosin staining revealed a significant increase in hair follicle size in the Akk-treated group. An increase in β-catenin levels, which are associated with hair growth and cell cycle progression, was also observed. Moreover, the Akk-treated group exhibited increased levels of fibroblast growth factors, including Fgf7, Igf1, Fgf7, Fgf10, and Fgf21. However, no significant difference was observed between the live and pasteurized Akk groups. These results underscore the potential of live and pasteurized Akk in improving testosterone-mediated hair growth inhibition.


[Surgical treatment of burns of the bones of the cranial vault].
In the paper an experience with treatment of 51 patients having burn lesions of the cranial vault bones is reported. The problems of surgical tactics in treatment of subjects with burn lesions such as terms and character of operative interventions, methods of replacement of the resulting wound defects of the cranial vault by means of various technic of skin plasty are discussed.


Pancreatic exocrine response to long-term high-fat diets in rats.
Although the synthesis and secretion of pancreatic enzymes are dependent on the composition of diet, little is known about the long-term adaptation of the exocrine pancreas to the chronic intake of high-fat, low-carbohydrate diets. The effects of long-term (48-weeks) high-fat, low-carbohydrate feeding on the intracellular activity as well as on the secretory activities of the pancreas regarding the secretion of amylase and lipase in isolated pancreatic lobules of rats were investigated. Twenty-six male Sprague-Dawley rats were randomly divided into two groups. The high-fat diet group was fed a diet containing 12.3% Kcal of carbohydrates, 76.0% Kcal of fats, and 11.7% Kcal of proteins for 48 weeks. In the control group, the rats were fed a standard diet (50.3% Kcal of carbohydrates, 33.2% Kcal of fats, and 16.5% Kcal of proteins) for the same period of time. The intracellular activity of alpha-amylase and lipase were defined as enzyme activity per 1 mg protein in the pancreatic homogenate. The secretory activity of the pancreatic enzymes was defined as enzyme activity per 1 mg protein or as the mean percentage of released enzyme activity in the medium to that initially retained in the lobules over the entire 90 minute incubation period. The intracellular activity as well as the secretory activities of pancreatic amylase in the basal and in the cholecystokinin (10 pmol/L)-stimulated states of high-fat, low-carbohydrate diet fed rats were significantly lower than that in the control rats. Nevertheless, those of lipase were not significantly different between the two groups. However, when the secretory enzyme activity was illustrated as the percentage released, basal as well as CCK-stimulated amylase and lipase activity were not significantly different between the two groups. The reduction of the intracellular amylase activity and the secretory amylase activity may be a long-term adaptive response of the pancreas to the reduced carbohydrate composition of the diets. Moreover, the reduction of the secretory amylase activity may be due to reduced intracellular amylase activity rather than to the altered sensitivity of the acinar cells to cholecystokinin. However, we failed to observe a long-term adaptive response of pancreatic lipase to increased fat composition of diets.


Retinoic acid disintegrated desmosomes and hemidesmosomes in stratified oral keratinocytes.
Although it is known that retinoic acid (RA) regulates the cellular differentiation of skin keratinocytes, the effects of RA on the anchoring junction have not been clarified. The effects of all-trans RA on cell-cell and cell-matrix connections of gingival epithelial (GE)1 cells in a multilayered culture were investigated. Ultrastructures of GE1 cells were observed and immunohistochemistry was used to detect keratin 4, keratin 13, and desmoglein expression. Reverse transcription-polymerase chain reaction was performed to detect expression of desmosome and hemidesmosome-associating adhesion molecules, keratin 13, and keratin14. Retinoic acid caused immunohistochemical diminution of keratin 4, keratin 13, and desmoglein. Ultrastructurally, RA induced drastic loss of typical desmosomes and complete loss of hemidesmosomes. RA significantly decreased the transcript levels of keratin 13, keratin 14, desmoglein 1, and desmocollin 1 in a dose-dependent manner. The 230-kD bullous pemphigoid antigen (BPAG1) gene expression was also reduced by RA, whereas transcript levels of integrin alpha6, integrin beta4, the 180-kD bullous pemphigoid antigen (BPAG2), and laminin 5 were not affected. These results indicated that RA disintegrated not only desmosomes by depriving the cells of desmoglein 1, desmocollin 1, keratin 13, and keratin 4, but also hemidesmosomes by reducing the expression of BPAG1 and keratin 14 in basal keratinocytes.


Shiga toxin-negative attaching and effacing Escherichia coli: distinct clinical associations with bacterial phylogeny and virulence traits and inferred in-host pathogen evolution.
Attaching and effacing Escherichia coli (AEEC) that lack Shiga toxin genes (stx) and the enteropathogenic E. coli adherence factor (EAF) plasmid (stx-/EAF-) are classified as atypical enteropathogenic E. coli and cause diarrhea worldwide. However, it is unknown whether there are bacterial lineage-specific human disease phenotypes. We compared stx-/EAF- AEEC recovered from patients (mostly children) with bloody and nonbloody diarrhea. stx-/EAF- AEEC were isolated using eae colony blot hybridization and were serotyped, tested (by polymerase chain reaction) for putative virulence genes, and analyzed for phylogenetic relationships by use of multilocus sequence typing. During the period 1995-2007, stx-/EAF- AEEC were isolated as the only bacterial pathogens from stool specimens obtained from 18 (15.3%) of 118 patients with bloody diarrhea and from 141 (1.3%) of 10,550 patients with nonbloody diarrhea (P<.001). All but 1 of 18 strains recovered from patients with bloody diarrhea resembled enterohemorrhagic E. coli (EHEC) on the basis of serotypes, non-stx virulence profiles, and multilocus sequence types. In contrast, most (75.9%) of 141 stx-/EAF- AEEC recovered from patients with nonbloody diarrhea belonged to other serotypes and differed from the former strains phylogenetically and with regard to virulence genes. Three of 18 patients with bloody diarrhea and none of 141 patients with nonbloody diarrhea who shedded stx-/EAF- AEEC developed hemolytic uremic syndrome. Most stx-/EAF- AEEC associated with bloody diarrhea are plausibly EHEC that lost Shiga toxin during infection (EHEC-LST). To prevent serious complications of such infections, Shiga toxin-independent diagnostic strategies to accurately and rapidly identify such patients should be developed and applied. Multilocus sequence typing has potential to distinguish EHEC-LST from less pathogenic stx-/EAF- AEEC.


Calcein labelling and electrophysiology: insights on coral tissue permeability and calcification.
The mechanisms behind the transfer of molecules from the surrounding sea water to the site of coral calcification are not well understood, but are critical for understanding how coral reefs are formed. We conducted experiments with the fluorescent dye calcein, which binds to calcium and is incorporated into growing calcium carbonate crystals, to determine the permeability properties of coral cells and tissues to this molecule, and to determine how it is incorporated into the coral skeleton. We also compared rates of calcein incorporation with rates of calcification measured by the alkalinity anomaly technique. Finally, by an electrophysiological approach, we investigated the electrical resistance of coral tissues in order to better understand the role of tissues in ionic permeability. Our results show that (i) calcein passes through coral tissues by a paracellular pathway, (ii) intercellular junctions control and restrict the diffusion of molecules, (iii) intercellular junctions should have pores of a size higher than 13 Å and lower than 20 nm, and (iv) the resistance of the tissues owing to paracellular junctions has a value of 477 ± 21 Ohm cm(2). We discuss the implication of our results for the transport of calcium involved in the calcification process.


Cellular STAT3 functions via PCBP2 to restrain Epstein-Barr Virus lytic activation in B lymphocytes.
A major hurdle to killing Epstein-Barr virus (EBV)-infected tumor cells using oncolytic therapy is the presence of a substantial fraction of EBV-infected cells that does not support the lytic phase of EBV despite exposure to lytic cycle-promoting agents. To determine the mechanism(s) underlying this refractory state, we developed a strategy to separate lytic from refractory EBV-positive (EBV(+)) cells. By examining the cellular transcriptome in separated cells, we previously discovered that high levels of host STAT3 (signal transducer and activator of transcription 3) curtail the susceptibility of latently infected cells to lytic cycle activation signals. The goals of the present study were 2-fold: (i) to determine the mechanism of STAT3-mediated resistance to lytic activation and (ii) to exploit our findings to enhance susceptibility to lytic activation. We therefore analyzed our microarray data set, cellular proteomes of separated lytic and refractory cells, and a publically available STAT3 chromatin immunoprecipitation sequencing (ChIP-Seq) data set to identify cellular PCBP2 [poly(C)-binding protein 2], an RNA-binding protein, as a transcriptional target of STAT3 in refractory cells. Using Burkitt lymphoma cells and EBV(+) cell lines from patients with hypomorphic STAT3 mutations, we demonstrate that single cells expressing high levels of PCBP2 are refractory to spontaneous and induced EBV lytic activation, STAT3 functions via cellular PCBP2 to regulate lytic susceptibility, and suppression of PCBP2 levels is sufficient to increase the number of EBV lytic cells. We expect that these findings and the genome-wide resources that they provide will accelerate our understanding of a longstanding mystery in EBV biology and guide efforts to improve oncolytic therapy for EBV-associated cancers. Most humans are infected with Epstein-Barr virus (EBV), a cancer-causing virus. While EBV generally persists silently in B lymphocytes, periodic lytic (re)activation of latent virus is central to its life cycle and to most EBV-related diseases. However, a substantial fraction of EBV-infected B cells and tumor cells in a population is refractory to lytic activation. This resistance to lytic activation directly and profoundly impacts viral persistence and the effectiveness of oncolytic therapy for EBV(+) cancers. To identify the mechanisms that underlie susceptibility to EBV lytic activation, we used host gene and protein expression profiling of separated lytic and refractory cells. We find that STAT3, a transcription factor overactive in many cancers, regulates PCBP2, a protein important in RNA biogenesis, to regulate susceptibility to lytic cycle activation signals. These findings advance our understanding of EBV persistence and provide important leads on devising methods to improve viral oncolytic therapies.


A novel, highly sensitive and specific biomarker for Niemann-Pick type C1 disease.
Lysosomal storage disorders (LSDs), are a heterogeneous group of rare disorders caused by defects in genes encoding for proteins involved in the lysosomal degradation of macromolecules. They occur at a frequency of about 1 in 5,000 live births, though recent neonatal screening suggests a higher incidence. New treatment options for LSDs demand a rapid, early diagnosis of LSDs if maximal clinical benefit is to be achieved. Here, we describe a novel, highly specific and sensitive biomarker for Niemann-Pick Type C disease type 1 (NPC1), lyso-sphingomyelin-509. We cross-validate this biomarker with cholestane-3β,5α,6β-triol and relative lysosomal volume. The primary cohort for establishment of the biomarker contained 135 NPC1 patients, 66 NPC1 carriers, 241 patients with other LSDs and 46 healthy controls. With a sensitivity of 100.0% and specificity of 91.0% a cut-off of 1.4 ng/ml was established. Comparison with cholestane-3β,5α,6β-triol and relative acidic compartment volume measurements were carried out with a subset of 125 subjects. Both cholestane-3β,5α,6β-triol and lyso-Sphingomyelin-509 were sufficient in establishing the diagnosis of NPC1 and correlated with disease severity. In summary, we have established a new biomarker for the diagnosis of NPC1, and further studies will be conducted to assess correlation to disease progress and monitoring treatment.


Looking back at 2023.
The Nanoscale Horizons Editorial Board and Editorial Office look back at 2023 and give an overview of the exciting events, activities and news for the journal from the last year.


Step free energies at faceted solid-liquid interfaces from equilibrium molecular dynamics simulations.
In this work a method is proposed for computing step free energies for faceted solid-liquid interfaces based on atomistic simulations. The method is demonstrated in an application to (111) interfaces in elemental Si, modeled with the classical Stillinger-Weber potential. The approach makes use of an adiabatic trapping procedure, and involves simulations of systems with coexisting solid and liquid phases separated by faceted interfaces containing islands with different sizes, for which the corresponding equilibrium temperatures are computed. We demonstrate that the calculated coexistence temperature is strongly affected by the geometry of the interface. We find that island radius is inversely proportional to superheating, allowing us to compute the step free energy by fitting simulation data within the formalism of classical nucleation theory. The step free energy value is computed to be γ(st) = 0.103 ± 0.005 × 10(-10) J/m. The approach outlined in this work paves the way to the calculation of step free energies relevant to the solidification of faceted crystals from liquid mixtures, as encountered in nanowire growth by the vapor-liquid-solid mechanism and in alloy casting. The present work also shows that at low undercoolings the Stillinger-Weber interatomic potential for Si tends to crystallize in the wurtzite, rather than the diamond-cubic structure.


David Ferrier's Experimental Localization of Cerebral Functions and the Anti-Vivisection Debate.
While representing one of the most important developments in the knowledge of the brain, both for its theoretical advances and its medical consequences, the work of David Ferrier met with strong criticism from conservative circles in Victorian society. At the end of 19th century certain British neurologists and neurosurgeons – including Ferrier – faced vehement public attacks by those aristocrats who, under the banner of antivivisectionism and "natural theology", expressed their fears of the reorganization of medicine into a scientific discipline. The debate that developed in Victorian society after these events led not only to the diffusion of Ferrier's ideas and public recognition of the advanced neurosurgical practices that stemmed from his work, but also contributed to the affirmation of the medical community in the scientific world of the time.


Facial sebum affects the development of acne, especially the distribution of inflammatory acne.
The increased sebum secretion has been considered as one of the pathogenic factors of acne. The goal of this study was to assess the correlation between the casual sebum level and the severity of acne using objective measuring methods in a large acne patients group. We also investigated the influence of age or gender on the correlation. A total number of 914 acne patients were recruited. The standard digital photographs were taken, and the acne lesions were counted as comedones or inflammatory lesions. The casual sebum level was measured using the Sebumeter SM 815(®) . The correlation analysis was performed. The casual sebum level showed positive correlation with the number of acne lesions. The casual sebum level markedly influenced the number of inflammatory lesions and the acne lesions located in the U-zone. In the young acne patients, the casual sebum level showed significant correlations in the U-zone, whereas in the old acne patients, there were significant correlations in the T-zone. The male acne patients were more influenced by the casual sebum level. This was the first study to report the significant correlations between the casual sebum level and the number, proportion and location of acne lesions in a large acne patients group, using an objective, bioengineering method. Moreover, we also found that the influence of sebum was prominent on the inflammatory lesions. In addition, both age and gender influenced the correlation between the casual sebum level and the acne.


Inorganic geochemistry and redox dynamics in bank filtration settings.
Bank filtration induces flow of surface water through a hydraulically connected aquifer by excess pumping from a production well in the aquifer. This review presents the four main geochemical processes relevant for inorganic geochemistry, with a focus on iron (Fe) and manganese (Mn), during bank filtration: reduction near the bank, oxidation near the production well, carbonate dissolution, and sorption to aquifer materials. Physical and transport processes affect these geochemical processes and influence the redox state of the infiltrate. The presence of Fe and Mn in bank infiltrate is directly related to its redox status and can necessitate drinking water treatment after extraction. Long-term, in situ sequestration of Fe and Mn requires precipitation of oxide or carbonate solids, since a sorption front can breakthrough at the production well.


Strip and Cka negatively regulate JNK signalling during Drosophila spermatogenesis.
One fundamental property of a stem cell niche is the exchange of molecular signals between its component cells. Niche models, such as the Drosophila melanogaster testis, have been instrumental in identifying and studying the conserved genetic factors that contribute to niche molecular signalling. Here, we identify jam packed (jam), an allele of Striatin interacting protein (Strip), which is a core member of the highly conserved Striatin-interacting phosphatase and kinase (STRIPAK) complex. In the developing Drosophila testis, Strip cell-autonomously regulates the differentiation and morphology of the somatic lineage, and non-cell-autonomously regulates the proliferation and differentiation of the germline lineage. Mechanistically, Strip acts in the somatic lineage with its STRIPAK partner, Connector of kinase to AP-1 (Cka), where they negatively regulate the Jun N-terminal kinase (JNK) signalling pathway. Our study reveals a novel role for Strip/Cka in JNK pathway regulation during spermatogenesis within the developing Drosophila testis.


Physician Documentation of Access to Firearms in Suicidal Patients in the Emergency Department.
Suicide is the 10th leading cause of death in the United States. An estimated 50% of these deaths are due to firearms. Suicidal ideation (SI) is a common complaint presenting to the emergency department (ED). Despite these facts, provider documentation on access to lethal means is lacking. Our primary aim was to quantify documentation of access to firearms in patients presenting to the ED with a chief complaint of SI. This was a cross-sectional study of consecutive patients, nearly all of whom presented to an academic, urban ED with SI during July 2014. We collected data from all provider documentation in the electronic health record. Primary outcome assessed was whether the emergency physician (EP) team documented access to firearms. Secondary outcomes included demographic information, preexisting psychiatric diagnoses, and disposition. We reviewed 100 patient charts. The median age of patients was 38 years. The majority of patients had a psychiatric condition. EPs documented access to firearms in only 3% of patient charts. EPs do not adequately document access to firearms in patients with SI. There is a clear need for educational initiatives regarding risk-factor assessment and counseling against lethal means in this patient cohort.


Effects of whole-body vibration on neuropathic pain and the relationship between pain and spasticity in persons with spinal cord injury.
Whole-body vibration (WBV) appears to modulate reflex hyperexcitability and spasticity. Due to common underlying neural mechanisms between spasticity and neuropathic pain, WBV may also reduce chronic pain after spinal cord injury (SCI). Our objective was to determine whether there are dose-related changes in pain following WBV and to examine the relationships between neuropathic pain and reflex excitability. Secondary analysis of a sub-population (participants with neuropathic pain, n = 16) from a larger trial comparing the effects of two different doses of WBV on spasticity in persons with SCI. Hospital/Rehabilitation Center in Atlanta, GA, USA. Participants were randomized to 8-bout or 16-bout WBV groups. Both groups received ten sessions of sham intervention, followed by ten sessions of WBV. Primary measures included the Neuropathic Pain Symptom Inventory (NPSI) for pain symptom severity and H-reflex paired-pulse depression (PPD) for reflex excitability. Mean change in NPSI scores were not significantly different between the groups (7 ± 6; p = 0.29; ES = 0.57); however, 8-bouts of WBV were consistently beneficial for participants with high neuropathic pain symptom severity (NPSI total score >30), while 16-bouts of WBV appeared to increase pain in some individuals with high NPSI scores. A baseline NPSI cut score of 30 predicted PPD response (sensitivity = 1.0, specificity = 0.83), with higher NPSI scores associated with decreased PPD in response to WBV. WBV in moderate doses appears to decrease neuropathic pain symptoms and improve reflex modulation. However, at higher doses neuropathic pain symptoms may be aggravated. Lower baseline NPSI scores were associated with improved reflex modulation.


[The state of homeostasis system in patients with aplastic anemia in the period of full-fledged clinical manifestation of disease].
In most cases the immediate cause of lethal outcomes of aplastic anemia is increased hemorrhage. The multifactorial causality of development of hemorrhagic syndrome is to be taken into account to receive informative and accessible characteristics in assessing the state of homeostasis system in patients with aplastic anemia during acute period of disease. The comprehensive analysis of homeostasis system indicators during acute course of aplastic anemia established such characteristic alterations as the presence of signs of activation of homeostasis system, decrease of factor XIII level, inhibition of fibrinolysis system, qualitative deficiency of platelets in peripheral blood. Hence their significance in pathogenesis of hemorrhage in patients with aplastic anemia is approved.


Persistent sodium current and its role in epilepsy.
Sodium currents are essential for the initiation and propagation of neuronal firing. Alterations of sodium currents can lead to abnormal neuronal activity, such as occurs in epilepsy. The transient voltage-gated sodium current mediates the upstroke of the action potential. A small fraction of sodium current, termed the persistent sodium current (I(NaP)), fails to inactivate significantly, even with prolonged depolarization. I(NaP) is activated in the subthreshold voltage range and is capable of amplifying a neuron's response to synaptic input and enhancing its repetitive firing capability. A burgeoning literature is documenting mutations in sodium channels that underlie human disease, including epilepsy. Some of these mutations lead to altered neuronal excitability by increasing I(NaP). This review focuses on the pathophysiological effects of I(NaP) in epilepsy.


Korean mothers' psychosocial adjustment to their children's cancer.
During the course of adjustment to their child's illness and medical treatment, parents of children with cancer may experience numerous challenges and difficulties. Although parental adjustment has been a research topic for many years, little research has been conducted among families in different cultures and countries. To identify factors that influence maternal psychosocial adjustment to childhood cancer using a new cultural group: Korean. A sample of 200 Korean mothers of children with cancer was included in the study. Guided by the double ABCX model of family adjustment and adaptation, a series of variables (i.e. maternal stress, coping, social support and selected illness-related and demographic questions) were examined for their relationships with maternal psychosocial adjustment to childhood cancer. Using a hierarchical multiple regression, we found perceived level of stress, coping, social support, and time since diagnosis to be significant correlates of maternal psychosocial adjustment. Stress accounted for most (50%) of the total variance explained (56%) in maternal adjustment. The results suggest that the stress-coping framework may be appropriate in explaining maternal responses to childhood cancer across cultures.


[Anatomic segmental resection of the liver in surgical treatment of colorectal metastatic lesions].
The prime role of hepatic resection in the management of colorectal cancer metastatic to the liver is firmly established. At least a third of patients who undergo liver resection for colorectal metastases can expect to survive five years. Since 1999, 106 hepatic metastases were resected in 42 patients (synchr. 8, metachr. 34, pts.). We performed 12 monosegmentectomies (S2-S8), 4 bisegmentectomies (S4b, S5 and S5, S6), 6 sectorectomies (right posterior, left paramedian, left lateral), 3 polysegmentectomies (S4b, S5, S6), 8 bilateral sectionectomies (S2, S3 and S6, S7) and in 9 cases multiple segmentectomies. In 4 cases initially unresectable colorectal metastases were downstaged by transcatheter HAI regional chemotherapy (Implantoflx), and after that successfully resected. We favour vascular inflow occlusion through selective division of appropriate portal pedicle at the porta hepatis or by transparenchymal approach. Median blood loss was 330 +/- 160 ml. The complication rate amounted to 9.52% (bile fistula, abscess collection). No method related lethality occurred. During the follow-up period we registered tumor recurrence rate of 19.1% (8 pts.), of which two patients were subjected to liver re-resection. Overall 3-year survival rate (Kaplan-Meier) is 38.9%. Multivariate analysis shows a significant correlation between 3-year survival and solitary (p-0.031) and unilobar metastases (p-0.014).


Vascular burden and APOE ε4 are associated with white matter microstructural decline in cognitively normal older adults.
White matter microstructure can be measured with diffusion tensor imaging (DTI). While increasing age is a predictor of white matter (WM) microstructure changes, roles of other possible modifiers, such as cardiovascular risk factors, APOE ε4 allele status and biological sex have not been clarified. We investigated 665 cognitively normal participants from the Baltimore Longitudinal Study of Aging (age 50-95, 56.7% female) with a total of 1384 DTI scans. WM microstructure was assessed by fractional anisotropy (FA) and mean diffusivity (MD). A vascular burden score was defined as the sum of five risk factors (hypertension, obesity, elevated cholesterol, diabetes and smoking status). Linear mixed effects models assessed the association of baseline vascular burden on baseline and on rates of change of FA and MD over a mean follow-up of 3.6 years, while controlling for age, race, and scanner type. We also compared DTI trajectories in APOE ε4 carriers vs. non-carriers and men vs. women. At baseline, higher vascular burden was associated with lower FA and higher MD in many WM structures including association, commissural, and projection fibers. Higher baseline vascular burden was also associated with greater longitudinal decline in FA in the hippocampal part of the cingulum and the fornix (crus)/stria terminalis and splenium of the corpus callosum, and with greater increases in MD in the splenium of the corpus callosum. APOE ε4 carriers did not differ from non-carriers in baseline DTI metrics but had greater decline in FA in the genu and splenium of the corpus callosum. Men had higher FA and lower MD in multiple WM regions at baseline but showed greater increase in MD in the genu of the corpus callosum. Women showed greater decreases over time in FA in the gyrus part of the cingulum, compared to men. Our findings show that modifiable vascular risk factors (1) have a negative impact on white matter microstructure and (2) are associated with faster microstructural deterioration of temporal WM regions and the splenium of the corpus callosum in cognitively normal adults. Reducing vascular burden in aging could modify the rate of WM deterioration and could decrease age-related cognitive decline and impairment.


Pharmacodynamics of isavuconazole in experimental invasive pulmonary aspergillosis: implications for clinical breakpoints.
Isavuconazole, a novel triazole antifungal agent, has broad-spectrum activity against Aspergillus spp. and other pathogenic fungi. The isavuconazole exposure-response relationship in experimental invasive pulmonary aspergillosis using galactomannan index (GMI) suppression as a marker of disease clearance was explored. The impact of exposure on GMI suppression in persistently neutropenic rabbits treated with isavuconazonium sulphate (isavuconazole-equivalent dosages of 20, 40 or 60 mg/kg every 24 h, after a 90 mg/kg loading dose) for 12 days was linked using mathematical modelling. Bridging to humans using population pharmacokinetic (PK) data from a clinical trial in invasive aspergillosis was performed using Monte Carlo simulations. Mean plasma isavuconazole AUC/MIC (EC50) of 79.65 (95% CI 32.2, 127.1) produced a half-maximal effect in GMI suppression. The inhibitory sigmoid Emax curve dropped sharply after an AUC/MIC of ≥30 and was near maximum (EC80) at ∼130. Bridging the experimental PK/pharmacodynamic (PD) target to human population PK data was then used to return to the rabbit model to determine a clinically relevant PD endpoint. The clinical dosing regimen used in the trial would result in a mean GMI of 4.3 ± 1.8, which is a 50% reduction from the starting GMI in the experiment. The clinical trial results showing the non-inferiority of isavuconazole to voriconazole for all-cause mortality further support the PK-PD endpoint, thereby demonstrating the usefulness of the rabbit model and endpoint for isavuconazole and implications on interpretive breakpoints. Importantly, the analysis supports this model as an important tool for development of antifungal agents.


Small cell lung cancer cells express the late stage gBK tumor antigen: a possible immunotarget for the terminal disease.
Big Potassium (BK) ion channels have several splice variants. One splice variant initially described within human glioma cells is called the glioma BK channel (gBK). Using a gBK-specific antibody, we detected gBK within three human small cell lung cancer (SCLC) lines. Electrophysiology revealed that functional membrane channels were found on the SCLC cells. Prolonged exposure to BK channel activators caused the SCLC cells to swell within 20 minutes and resulted in their death within five hours. Transduction of BK-negative HEK cells with gBK produced functional gBK channels. Quantitative RT-PCR analysis using primers specific for gBK, but not with a lung-specific marker, Sox11, confirmed that advanced, late-stage human SCLC tissues strongly expressed gBK mRNA. Normal human lung tissue and early, lower stage SCLC resected tissues very weakly expressed this transcript. Immunofluorescence using the anti-gBK antibody confirmed that SCLC cells taken at the time of the autopsy intensely displayed this protein. gBK may represent a late-stage marker for SCLC. HLA-A*0201 restricted human CTL were generated in vitro using gBK peptide pulsed dendritic cells. The exposure of SCLC cells to interferon-γ (IFN-γ) increased the expression of HLA; these treated cells were killed by the CTL better than non-IFN-γ treated cells even though the IFN-γ treated SCLC cells displayed diminished gBK protein expression. Prolonged incubation with recombinant IFN-γ slowed the in vitro growth and prevented transmigration of the SCLC cells, suggesting IFN-γ might inhibit tumor growth in vivo. Immunotherapy targeting gBK might impede advancement to the terminal stage of SCLC via two pathways.


Refinement of the Role of Hopelessness in the Interpersonal Theory of Suicide: An Exploration in an Inpatient Adolescent Sample.
Hopelessness is a well-established risk factor for suicidal ideation. Recent research has indicated that hopelessness can be split into two subsets: pessimism (PESS) and lack of optimism (LOO) and that LOO is more salient of the two in predicting suicide ideation (SI). The aim of this study was to examine the relationship of PESS and LOO to SI in the context of the Interpersonal Psychological Theory of Suicide (IPTS). Participants were 294 inpatient adolescents. LOO but not PESS was associated with SI. LOO interacted with the IPTS variable of perceived burdensomeness to differentiate between passive and active SI, partly consistent with the theory. These results support the value of separating the two components of hopelessness in understanding adolescent SI.


Cell-cycle-regulated transcription of A- and B-type plant cyclin genes in synchronous cultures.
Synchronously dividing cell cultures of Catharanthus roseus were used to isolate cDNAs for two mitotic cyclins, named CYS and CYM. The deduced protein sequence of CYS is similar to that of A-type cyclins, and CYM belongs to the group of B-type cyclins. In a fashion similar to the pattern of expression seen for A-type and B-type cyclins in mammalian cells, CYS is expressed before CYM in C. roseus cells during the cell cycle. CYS mRNA accumulated at the onset of S phase and disappeared early in the G2 phase, whereas CYM mRNA was detected in the G2 and M phases of the cell cycle. Tobacco homologs of the two genes showed similar cell-cycle dependent expression patterns in synchronous cultures of tobacco BY2 cells. In both systems, CYS was expressed much earlier in the cell cycle than most other plant A-type cyclins, and hence CYS along with the soybean cyc1GM can be classified into a distinct subclass. The activities of CYM and CYS promoters during the cell cycle were analyzed in stably transformed tobacco BY2 cells. Cyclin promoter sequences of 0.5 kb could confer the typical cell-cycle-dependent expression to the beta-glucuronidase (GUS) reporter gene: the CYS promoter directed S-phase-specific expression, whereas the CYM promoter drove M-phase-specific expression. These results indicate the important role of transcriptional regulation in the oscillations of cyclin mRNA levels during the cell cycle.


Analysis of the developmental roles of the Arabidopsis gibberellin 20-oxidases demonstrates that GA20ox1, -2, and -3 are the dominant paralogs.
Gibberellin (GA) biosynthesis is necessary for normal plant development, with later GA biosynthetic stages being governed by multigene families. Arabidopsis thaliana contains five GA 20-oxidase (GA20ox) genes, and past work has demonstrated the importance of GA20ox1 and -2 for growth and fertility. Here, we show through systematic mutant analysis that GA20ox1, -2, and -3 are the dominant paralogs; their absence results in severe dwarfism and almost complete loss of fertility. In vitro analysis revealed that GA20ox4 has full GA20ox activity, but GA20ox5 catalyzes only the first two reactions of the sequence by which GA(12) is converted to GA(9). GA20ox3 functions almost entirely redundantly with GA20ox1 and -2 at most developmental stages, including the floral transition, while GA20ox4 and -5 have very minor roles. These results are supported by analysis of the gene expression patterns in promoter:β-glucuronidase reporter lines. We demonstrate that fertility is highly sensitive to GA concentration, that GA20ox1, -2, and -3 have significant effects on floral organ growth and anther development, and that both GA deficiency and overdose impact on fertility. Loss of GA20ox activity causes anther developmental arrest, with the tapetum failing to degrade. Some phenotypic recovery of late flowers in GA-deficient mutants, including ga1-3, indicated the involvement of non-GA pathways in floral development.


Falling through the cracks: a qualitative study of HIV risks among women who use drugs and alcohol in Northeast India.
HIV risks for women who inject drugs and those who engage in sex work are well documented. Women who are dependent on non-injecting drugs and alcohol are also likely to have increased vulnerability to HIV infection, but until they actually inject drugs or engage in sex work, are unlikely to come to the attention of HIV prevention programs. We undertook a qualitative study involving nine focus group discussions (FGDs) and 27 key informant interviews to investigate the context of female drug and alcohol use in two high HIV prevalence states of India (Manipur and Nagaland) and to describe their HIV risks. The FGD and interview transcripts were thematically analyzed The women were relatively young (mean age 31 years in Manipur and 28 years in Nagaland), but 64% in Manipur and 35% in Nagaland were widowed or divorced. Both heroin and alcohol were commonly used by the women from Manipur, while alcohol was primarily used by the women from Nagaland, especially in the context of 'booze joints' (illicit bars). Reasons for drug and alcohol use included: to avoid symptoms of withdrawal, to suppress emotional pain, to overcome the shame of sex work, pleasure, and widowhood. HIV vulnerability was clearly described, not only in relation to injecting drug use and sex work, but also alcohol consumption. The contribution of alcohol use to the HIV vulnerability of women is not currently considered when HIV prevention programs are being designed and implemented leaving a group of high-risk women uncovered by much needed services such as treatment for a range of health problems including alcohol dependence.


Ethnic- and sex-specific associations between plasma fatty acids and markers of insulin resistance in healthy young adults.
Although evidence indicates that fatty acids (FA) can affect insulin resistance (IR), not all FA contribute equally to the process. Indeed, monounsaturated FA (MUFA) and polyunsaturated FA (PUFA) are reported to reduce IR, whereas saturated FA (SFA) and trans FA appear to increase IR. However, it is not yet clear how individual FA are associated with markers of IR, and whether these relationships are influenced by ethnicity and/or sex. Therefore, the goal of this study was to examine the ethnic- and sex-specific relationships between plasma FA and markers of IR in a cohort of healthy young Caucasian, East Asian, and South Asian adults. Gas chromatography was used to quantify fasting plasma FA from young Canadian adults (22.6 ± 0.1 yrs) of Caucasian (n = 461), East Asian (n = 362), or South Asian (n = 104) descent. Linear regression models were used to investigate associations between plasma FA and markers of IR (i.e. fasting insulin, glucose, and HOMA-IR) according to ethnicity and sex. Numerous significant associations (P < 0.05, adjusted for multiple testing) were identified between individual FA and markers of IR, with the majority identified in Caucasians. For SFA, positive associations were found between 14:0 and fasting insulin and HOMA-IR in Caucasian and East Asian populations, and 18:0 and fasting glucose in Caucasians only. Several positive associations were also found for specific MUFA (18:1t11 and 18:1t6-8 with HOMA-IR, and 18:1c9 with fasting glucose) and PUFA (18:2n6 with fasting glucose and 18:2c9t11 with HOMA-IR) in Caucasian adults only. Most of the aforementioned associations were stronger in males compared to females. Interestingly, no significant associations were found between FA and markers of IR in South Asian adults. We report numerous associations between plasma FA and markers of IR in Caucasian and East Asian populations, but not in South Asian individuals. Furthermore, these associations appeared to be more robust in men. This demonstrates the importance of investigating associations between FA and markers of IR in an ethnic- and sex-specific manner in order to better understand the contribution of plasma FA to the development of IR and type-2 diabetes.


Transcranial Evoked Potentials Can Be Reliably Recorded with Active Electrodes.
Electroencephalographic (EEG) signals evoked by transcranial magnetic stimulation (TMS) are usually recorded with passive electrodes (PE). Active electrode (AE) systems have recently become widely available; compared to PE, they allow for easier electrode preparation and a higher-quality signal, due to the preamplification at the electrode stage, which reduces electrical line noise. The performance between the AE and PE can differ, especially with fast EEG voltage changes, which can easily occur with TMS-EEG; however, a systematic comparison in the TMS-EEG setting has not been made. Therefore, we recorded TMS-evoked EEG potentials (TEPs) in a group of healthy subjects in two sessions, one using PE and the other using AE. We stimulated the left primary motor cortex and right medial prefrontal cortex and used two different approaches to remove early TMS artefacts, Independent Component Analysis and Signal Space Projection-Source Informed Recovery. We assessed statistical differences in amplitude and topography of TEPs, and their similarity, by means of the concordance correlation coefficient (CCC). We also tested the capability of each system to approximate the final TEP waveform with a reduced number of trials. The results showed that TEPs recorded with AE and PE do not differ in amplitude and topography, and only few electrodes showed a lower-than-expected CCC between the two methods of amplification. We conclude that AE are a viable solution for TMS-EEG recording.


Single-particle reconstruction using L(2)-gradient flow.
In this paper, we present an iterative algorithm for reconstructing a three-dimensional density function from a set of two dimensional electron microscopy images. By minimizing an energy functional consisting of a fidelity term and a regularization term, an L(2)-gradient flow is derived. The flow is integrated by a finite element method in the spatial direction and an explicit Euler scheme in the temporal direction. Our method compares favorably with those of the weighted back projection, Fourier method, algebraic reconstruction technique and simultaneous iterative reconstruction technique.


Information for patients about health services: a review and future developments in the Nordic countries.
Patient power, consumerism and the information revolution are leading to more pressure on care givers to provide information to patients. There are many types of information about health services, treatments and health conditions which could be made available, and different ways of giving it to patients and of helping them to use the information. This paper considers the information which would help citizens to choose a provider, as well as the information which patients could use to take a greater part in treatment decisions and to manage their care, and discusses how it could be collected and provided to people. It reviews some of the research into what information people want, how they use it, the different systems which exist, and the problems and issues involved in helping patients to make more informed choices. Although the review is selective, some general themes emerge and suggest that nurses need to experiment with different approaches and to be at the forefront of developments in enabling patients to make use of the new information which is available.


Long-term prognosis of visual field in glaucoma simplex and glaucoma capsular.
The fate of visual fields in 42 eyes with capsular glaucoma followed for 5 to 14 years (mean 9.1 years) and 46 eyes with simple glaucoma followed for 5 to 14 years (mean 10.2 years) was studied retrospectively. In the treatment the IOP levels were around 19.5 mmHg. In both groups the visual field deteriorated in 70-80% of eyes, and 11% of patients became blind. In most cases the progression appeared during the first 4-6 years of follow-up, but in individual cases it did not occur until 8-10 years after the diagnosis. In 26 eyes disc cupping preceded the visual field loss. Five out of 42 eyes with capsular glaucoma developed retinal vein occlusion whereas this occurred in 2 out of 46 eyes with simple glaucoma. Two patients with IOP level of 9 mmHg maintained unchanged visual fields for 6 and 11 years, respectively.


Central effects of H1 and H2 antihistamines.
H1-antihistamines are usually associated with impairment of central nervous functions, but unacceptable decrements in performance may not be an inevitable sequel of their use. Effects are dependent on the ability of a particular drug to cross the blood brain barrier, and so compounds which cross so slowly that tolerance of the central nervous system can develop gradually without any immediate changes in performance are of interest. However, sustained release formulations and compounds which have a selective affinity for the peripheral receptor may also have their part to play in the management of allergic states in those involved in skilled activity. As far as H2-antagonists are concerned, it is likely that as they are less liposoluble they would be free of central effects. Studies on the central effects of H1 and H2 antagonists are reviewed, and tentative recommendations are made in respect of these findings concerning the possible use of these drugs in aircrew.


Chemoimmunotherapy of small cell bronchogenic carcinoma with VP-16-213, ifosfamide, vincristine, adriamycin, and Corynebacterium parvum.
Thirty-five consecutive patients with small cell bronchogenic carcinoma (SCBC) received chemoimmunotherapy with VP-16-213, Ifosfamide, vincristine, Adriamycin, and Corynebacterium parvum. Of 33 evaluable patients, 26 (79%) responded with complete (55%) or partial (24%) remissions. Complete remissions were more common among patients with limited disease (11/14 patients, 79%) compared with those with extensive disease (7/19 patients, 37%) and among patients (11/14 patients, 79%) compared with those with extensive disease (7/19 patients, 37%) and among patients who were ambulatory prior to therapy (16/25 patients, 64%) compared with those who were nonambulatory (2/8 patients, 25%). Myelosuppression consisted primarily of neutropenia. Eight percent of the treatment courses in 29% of the patients were associated with hematuria and/or documented episodes of infection during neutropenia. There were three deaths possibly related to treatment, in two of which there was no evidence of disease at post-mortem examination. Six patients relapsed in the central nervous system (CNS). In four instances, CNS relapse was the only site of tumor progression. Central nervous system relapse was more common among evaluable patients who did not receive prophylactic brain irradiation (5/17 patients, 29%, vs. 1/15 patients, 7%; P = 0.23). The median survival duration for all patients was 63 weeks, being slightly longer for patients with limited disease than for those with extensive disease (70.9 weeks vs. 56 weeks; P = 0.18). This was also true for patients who achieved complete rather than partial remissions (71 weeks vs. 50 weeks; P = 0.09). Patients receiving prophylactic brain irradiation experienced longer survival (100.8 weeks vs. 48 weeks; P = 0.01).


A study on impact of oral health on general health among the elderly residing in a slum of Kolkata: A cross-sectional study.
Oral health means more than only good teeth. It is a state-of-being-free from mouth and facial pain, oral and throat cancer, oral infections, periodontal diseases, tooth decay or loss, and other diseases/disorders. The age distribution of the world's population is changing. With advances in medicine, the proportion of older people continues to increase worldwide. A cross-sectional study was carried out among 158 elderly (>60 years) residing in a slum of Kolkata during the period from April 2017 to June 2017 to assess the impact of oral health on general health. Data were collected using a pretested predesigned schedule containing Geriatric Oral Health Assessment Index. Data analysis was performed in R software. Poisson regression was used to find the associates of the impact of oral health. Mean (standard deviation) age was 68.54 (5.9) years. A total of 104 (65.8%) participants reported; foul breath as a problem and 88 (55.7%) reported gum bleeding as a problem. All participants used to clean their teeth daily but only 36.1% used to clean their teeth at least twice daily. More than half the participants reported that they have limited the kind of food they eat due to dental/gum condition and trouble chewing. There is a need to provide sensitive oral health services that are accessible, affordable, appropriate, and acceptable. Knowledge regarding oral health and hygiene should be provided to all elderly, especially diabetics. Further research with the broader conceptual framework, in different age groups and in different settings are warranted.


Is there a difference in range of motion, neck pain, and outcomes in patients with ossification of posterior longitudinal ligament versus those with cervical spondylosis, treated with plated laminoplasty?
There are little data on the effects of plated, or plate-only, open-door laminoplasty on cervical range of motion (ROM), neck pain, and clinical outcomes. The purpose of this study was to compare ROM after a plated laminoplasty in patients with ossification of posterior longitudinal ligament (OPLL) versus those with cervical spondylotic myelopathy (CSM) and to correlate ROM with postoperative neck pain and neurological outcomes. The authors retrospectively compared patients with a diagnosis of cervical stenosis due to either OPLL or CSM who had been treated with plated laminoplasty in the period from 2007 to 2012 at the University of California, San Francisco. Clinical outcomes were measured using the modified Japanese Orthopaedic Association (mJOA) scale and neck visual analog scale (VAS). Radiographic outcomes included assessment of changes in the C2-7 Cobb angle at flexion and extension, ROM at C2-7, and ROM of proximal and distal segments adjacent to the plated lamina. Sixty patients (40 men and 20 women) with an average age of 63.1 ± 10.9 years were included in the study. Forty-one patients had degenerative CSM and 19 patients had OPLL. The mean follow-up period was 20.9 ± 13.1 months. The mean mJOA score significantly improved in both the CSM and the OPLL groups (12.8 to 14.5, p < 0.01; and 13.2 to 14.2, respectively; p = 0.04). In the CSM group, the mean VAS neck score significantly improved from 4.2 to 2.6 after surgery (p = 0.01), but this improvement did not reach the minimum clinically important difference (MCID). Neither was there significant improvement in the VAS neck score in the OPLL group (3.6 to 3.1, p = 0.17). In the CSM group, ROM at C2-7 significantly decreased from 32.7° before surgery to 24.4° after surgery (p < 0.01). In the OPLL group, ROM at C2-7 significantly decreased from 34.4° to 20.8° (p < 0.01). In the CSM group, the change in the VAS neck score significantly correlated with the change in the flexion angle (r = - 0.31) and the extension angle (r = - 0.37); however, it did not correlate with the change in ROM at C2-7 (r = - 0.1). In the OPLL group, the change in the VAS neck score did not correlate with the change in the flexion angle (r = 0.03), the extension angle (r = - 0.17), or the ROM at C2-7 (r = - 0.28). The OPLL group had a significantly greater loss of ROM after surgery than did the CSM group (p = 0.04). There was no significant correlation between the change in ROM and the mJOA score in either group. Plated laminoplasty in patients with either OPLL or CSM decreases cervical ROM, especially in the extension angle. Among patients who have undergone laminoplasty, those with OPLL lose more ROM than do those with CSM. No correlation was observed between neck pain and ROM in either group. Neither group had a change in neck pain that reached the MCID following laminoplasty. Both groups improved in neurological function and outcomes.


[Regulation of the use of animals in Brazil in the twentieth century and the process of forming the current regime applied to biomedical research].
The article analyzes Brazilian public policy and legislation concerning the use of animals in teaching and biomedical research. It examines the institutional and judicial framework and legal status of animal protection in Brazil, including the legislative debate that preceded enactment of Law 11.794/2008, which defined procedures to be employed in the scientific use of animals. It underscores certain features of current regulatory practice and also explores considerations of a theoretical and methodological nature, with a view to broadening our understanding of the question.


Respiratory heat loss in exercise-induced asthma. Measurement and clinical application.
The theoretical considerations of conditioning inspired air and the application of the respiratory heat loss (RHL) formula are discussed. An on-line method for measuring RHL is described together with the apparatus for generating frigid dry and warm humid air. Exercise-induced asthma (EIA) was studied using these methods. Thirteen asthmatic and 6 normal children and adolescents participated in the study. Each subject undertook two submaximal exercise tests consisting of 6 minutes' ergometric cycling against a fixed load. One test was done while breathing cold dry air (mean temperature -22 degrees C and 0% relative humidity) and the other while breathing warm humid air (mean temperature 36 degrees C and 100% relative humidity). All the other exercise parameters (e.g. heart rate, minute ventilation, oxygen uptake) were carefully matched between the two tests. In the cold dry air tests with a mean RHL of 1,43 kcal/min, all asthmatic subjects developed EIA with a mean fall in forced expiratory volume in the 1st second (FEV1) of 48% from baseline. In the warm humid air tests with negligible RHL (0,02 kcal/min) none of the asthmatics developed EIA (mean fall in FEV1 5%). The difference between the two tests was highly significant (P less than 0,001). Neither air condition caused bronchospasm in the normal subjects. A dose-response relationship was obtained between the degree of RHL and corresponding fall in FEV1.


Supporting habitat conservation with automated change detection in Google Earth Engine.
A significant limitation in biodiversity conservation has been the effective implementation of laws and regulations that protect species' habitats from degradation. Flexible, efficient, and effective monitoring and enforcement methods are needed to help conservation policies realize their full benefit. As remote sensing data become more numerous and accessible, they can be used to identify and quantify land-cover changes and habitat loss. However, these data remain underused for systematic conservation monitoring in part because of a lack of simple tools. We adapted 2 algorithms that automatically identify differences between pairs of images. We used free, publicly available satellite data to evaluate their ability to rapidly detect land-cover changes in a variety of land-cover types. We compared algorithm predictions with ground-truthed results at 100 sites of known change in the United States. We also compared algorithm predictions to manually created polygons delineating anthropogenic change in 4 case studies involving imperiled species' habitat: oil and gas development in the range of the Greater Sage Grouse (Centrocercus urophasianus); sand mining operations in the range of the dunes sagebrush lizard (Sceloporus arenicolus); loss of Piping Plover (Charadrius melodus) coastal habitat after Hurricane Michael (2018); and residential development in St. Andrew beach mouse (Peromyscus polionotus peninsularis) habitat. Both algorithms effectively discriminated between pixels corresponding to land-cover change and unchanged pixels as indicated by area under a receiver operating characteristic curve >0.90. The algorithm that was most effective differed among the case-study habitat types, and both effectively delineated habitat loss as indicated by low omission (min. = 0.0) and commission (min. = 0.0) rates, and moderate polygon overlap (max. = 47%). Our results showed how these algorithms can be used to help close the implementation gap of monitoring and enforcement in biodiversity conservation. We provide a free online tool that can be used to run these analyses (https://conservationist.io/habitatpatrol).


Paediatric home care in Tower Hamlets: a working partnership with parents.
To describe the first two years of a paediatric home care service. Observational cross sectional study, 1989-91. One inner London health district. 611 children referred to the service; 50 children selected from those referred during the first year, whose parents were interviewed and whose general practitioners were invited to complete a questionnaire. Description and costs of service; views of parents and general practitioners of selected sample of children. In its second year the team received 303 referrals and made 4004 visits at a salary cost of 98000 pounds, an average of 323 pounds/referral and 24 pounds/visit. This represented a referral rate of 3.2% (258/7939) of inpatient episodes from the main referring hospital between 1 December 1989 and 30 November 1990. Of all referrals to the service, 343(56%) came from hospital inpatient wards. The service was used by disadvantaged and ethnic minority families. The children's parents (in 28(61%) families) and the home care team did a wide range of nursing tasks in the home. Parents of 47(94%) children sampled agreed to be interviewed, and those of 43(91%) found the service useful; guidance and support were most commonly appreciated (33, 70%). Parents of 25(53%) children said that hospital stay or attendance had been reduced or avoided. Parents and general practitioners disagreed on clinical responsibility in 10 children, and communication was a problem for some general practitioners. The service enabled children to receive advanced nursing care at home. Clinical responsibility should be agreed between parents and professionals at referral.


Diagnosis and management of anaemia of chronic disease: current status.
Anaemia of chronic disease is the second most common form of anaemia worldwide, and is seen in a variety of inflammatory, infective and malignant diseases. Functional iron deficiency is fundamental to the pathogenesis of the anaemia, and the polypeptide, hepcidin, plays a key role. Diagnosis may be difficult, but new automated red cell indices, algorithms for detection of functional iron deficiency, and assays for hepcidin levels are being developed. Management of the causative disease process will usually improve haemoglobin levels, but where this is not possible, erythropoietic stimulating agents are often used, although there are still concerns about potential adverse effects, especially thromboembolism. There is increasing evidence that supplemental iron given parenterally can safely overcome the functional iron deficiency. Inhibitors of hepcidin, and various inflammatory modulators show promise for the future.


18F-FDG PET/CT in Tuberculosis: Can Interim PET/CT Predict the Clinical Outcome of the Patients?
Tuberculosis (TB) is a major health problem. Activated macrophages in TB lesions show high metabolic activity and can be assessed using F-FDG PET/CT. This retroprospective study was done to evaluate the utility of F-FDG PET/CT in initial assessment and therapeutic response in patients with TB. Eighty-seven patients (male-to-female ratio, 46:41) diagnosed with pulmonary TB and extrapulmonary TB underwent whole-body F-FDG PET/CT for initial assessment and a follow-up scan 3 to 4 months after initiation of antitubercular therapy (ATT). Visual and semiquantitative (SUVmax) analyses were used for scan assessment. Treatment responses on interim scans were categorized as complete metabolic response (CMR), favorable response to therapy (FRT), stable disease (SD), and disease progression (DP). CMR, FRT, and SD cases were considered as responders and DP cases as nonresponders. Treatment response was correlated with clinical outcome (mortality) and ATT duration. Baseline F-FDG PET/CT scans were positive in all the patients and detected additional disease sites than suspected clinically in 72% patients. On interim PET/CT, 13 patients showed CMR, 43 showed FRT, 8 showed SD, and 23 showed DP. A longer duration of ATT was seen in nonresponders (P ≤ 0.001) than responders. During follow-up, 9/87 patients died, out of which 8 patients were of DP group and 1 patient belonged to SD. Nonresponders showed 35% mortality compared with 1.6% in the responder group (P ≤ 0.001). F-FDG PET/CT is a valuable imaging modality for disease mapping and assessing therapeutic response. Treatment response in the interim PET/CT done at 3 to 4 months predicted the duration of ATT and clinical outcome of the patients.


Architecture of the Mandibular Condylar Cartilage of Elderly Individuals: A Semiquantitative Light Microscopic Histological Study.
This study aimed to categorize the constituent tissues of the mandibular condylar cartilage of elderly individuals. Thirty-three mandibular condyles were collected from 20 human cadavers of individuals between 40 years and 103 years old. Samples were stained with Masson's trichrome and Herovici's stains and, examined under a light microscope. All samples showed tissues that were categorized as fibrous and hyaline cartilage in the mandibular condylar cartilage. A thick fibrous cartilage layer was differentiated on the top of a thinner hyaline cartilage in all of the examined samples. Undifferentiated cells, as well as mature and hypertrophic chondroblasts, were observed in the layer identified as hyaline cartilage, even though they were not in an organized manner. The observations from this study confirm that both fibrocartilage and hyaline cartilage are still present in the mandibular condylar cartilage of elderly individuals. The results from this study infer that the mandibular condylar cartilage could be still able to respond to stimulus in adults. In that context, the results of the present study set the basis for future studies aiming to elucidate the biological activity and the remodeling potential of the tissues at the mandibular condyle in adults.


Hemoglobin levels and low bone mineral density in non-anemic older adults: Secondary analysis of the Korean National Health and Nutrition Examination Survey.
Although, previous studies have reported a positive association between hemoglobin levels and bone mineral density (BMD), the majority of the studies were limited in patients with chronic hypoxemic conditions and findings concerning the association among non-anemic populations are inconclusive. We aimed to examine the association between hemoglobin levels and BMD in non-anemic healthy adults. This cross-sectional study included 3626 non-anemic men and women aged ≥ 60 years who participated in the Korean National Health and Nutrition Examination Survey (KNHANES). The BMD of the lumbar spine and both femurs was measured by dual-energy X-ray absorptiometry (DXA). Participants with T-score for BMD < -1.0 SD were defined as having low BMD. The odds ratios (ORs) and 95% confidence intervals (CIs) for low BMD were calculated using multiple logistic regression analyses across sex-specific hemoglobin quartiles. The prevalence of low BMD gradually decreased in accordance with hemoglobin quartiles in both sexes. Compared with the group in the lowest quartile, the OR (95% CI) for low BMD in the lumbar spine was 0.78 (0.54-0.93) for men and 0.67 (0.50-0.93) for women after adjusting for age, BMI, tobacco smoking, alcohol intake, physical activity, walking difficulty, household income, total calorie intake, calcium intake, iron intake, 25(OH)D, alkaline phosphatase, and parathyroid hormone levels. However, these positive associations were not found in femur after adjusting for the same co-variables. Hemoglobin levels were inversely associated with low BMD in lumbar spine among non-anemic adults.


Interaction of psychological type and anxiety sensitivity on academic achievement.
The Myers-Briggs Type Indicator and the Anxiety Sensitivity Index were administered to 143 undergraduate college students. Analyses of variance were performed to assess the relationship between these indices and semester grades (Grade Point Average). The Myers-Briggs Sensing-Intuitive and Judging-Perceiving dimensions showed significant main effects on GPA. The interaction of Judging-Perceiving and Anxiety Sensitivity was also significant (F = 18.00, p<.0001), although that of Sensing-Intuition and Anxiety Sensitivity was not (F = 3.51, p=.06). These findings suggest that personality factors measured by the Myers-Briggs Type Indicator may serve as mediating variables in evaluating whether trait anxiety has a facilitating or debilitating effect on academic achievement.


Psychoeducation for schizophrenia.
Schizophrenia can be a severe and chronic illness characterised by lack of insight and poor compliance with treatment. Psychoeducational approaches have been developed to increase patients' awareness of their illness and its treatment. To assess the effects of psychoeducational interventions compared to standard levels of knowledge provision. Electronic searches of CINAHL (1982-1999), The Cochrane Library CENTRAL (Issue 1, 1999), The Cochrane Schizophrenia Group's Register (January 1999), EMbase (1980-1999), MEDLINE (1966-1999), PsycLit (1974-1999), and Sociofile (1974-1999) were undertaken. These were supplemented with reference searching and personal contact with authors of all included studies. All relevant randomised controlled trials focusing on psychoeducation for schizophrenia or related serious mental illnesses, involving individuals or groups. Quasi-randomised trials were excluded. Data were extracted independently by at least two reviewers from included papers. Authors of trials were contacted for additional and missing data. Relative risks (RR) and 95% confidence intervals (CI) of homogeneous dichotomous data were calculated. A random effects model was used for heterogeneous dichotomous data. Where possible the numbers needed to treat (NNT) were also calculated. Weighted or standardised means were calculated for continuous data. Ten studies are included in this review. All studies of group education included family members. Compliance with medication was significantly improved in a single study using brief group intervention (at one year) but other studies produced equivocal or skewed data. Any kind of psychoeducational intervention significantly decreased relapse or readmission rates at nine to 18 months follow-up compared with standard care (RR 0.8 CI 0.7-0.9 NNT 9 CI 6-22). Several of the secondary outcomes (knowledge gains, mental state, global level of functioning, status of high expressed emotion family members) were measured using scales that are difficult to interpret. Generally, however, findings were consistent with the possibility that psychoeducation has a positive effect on a persons' well being. No impact was found on insight, medication related attitudes or on overall satisfaction with services of patients or relatives but these findings rested on very few studies. Health economic outcome was only measured in one study and data were skewed. It was not possible to analyse whether different duration or formats of psychoeducation influenced effectiveness. Evidence from trials suggests that psychoeducational approaches are useful as a part of the treatment programme for people with schizophrenia and related illness. That the interventions are brief and inexpensive should make them attractive to managers and policy makers. More well-designed, conducted and reported randomised studies investigating the efficacy of psychoeducation are needed.


Use of Buffers in Specific Contexts: Highly Trained Female Athletes, Extreme Environments and Combined Buffering Agents-A Narrative Review.
This narrative review evaluated the evidence for buffering agents (sodium bicarbonate, sodium citrate and beta-alanine), with specific consideration of three discrete scenarios: female athletes, extreme environments and combined buffering agents. Studies were screened according to exclusion and inclusion criteria and were analysed on three levels: (1) moderating variables (supplement dose and timing, and exercise test duration and intensity), (2) design factors (e.g., use of crossover or matched group study design, familiarisation trials) and (3) athlete-specific factors (recruitment of highly trained participants, buffering capacity and reported performance improvements). Only 19% of the included studies for the three buffering agents reported a performance benefit, and only 10% recruited highly trained athletes. This low transferability of research findings to athletes' real-world practices may be due to factors including the small number of sodium citrate studies in females (n = 2), no studies controlling for the menstrual cycle (MC) or menstrual status using methods described in recently established frameworks, and the limited number of beta-alanine studies using performance tests replicating real-world performance efforts (n = 3). We recommend further research into buffering agents in highly trained female athletes that control or account for the MC, studies that replicate the demands of athletes' heat and altitude camps, and investigations of highly trained athletes' use of combined buffering agents. In a practical context, we recommend developing evidence-based buffering protocols for individual athletes which feature co-supplementation with other evidence-based products, reduce the likelihood of side-effects, and optimise key moderating factors: supplement dose and timing, and exercise duration and intensity.


Development and validation of combined symptom-medication scores for allergic rhinitis.
Validated combined symptom-medication scores (CSMSs) are needed to investigate the effects of allergic rhinitis treatments. This study aimed to use real-life data from the MASK-air® app to generate and validate hypothesis- and data-driven CSMSs. We used MASK-air® data to assess the concurrent validity, test-retest reliability and responsiveness of one hypothesis-driven CSMS (modified CSMS: mCSMS), one mixed hypothesis- and data-driven score (mixed score), and several data-driven CSMSs. The latter were generated with MASK-air® data following cluster analysis and regression models or factor analysis. These CSMSs were compared with scales measuring (i) the impact of rhinitis on work productivity (visual analogue scale [VAS] of work of MASK-air® , and Work Productivity and Activity Impairment: Allergy Specific [WPAI-AS]), (ii) quality-of-life (EQ-5D VAS) and (iii) control of allergic diseases (Control of Allergic Rhinitis and Asthma Test [CARAT]). We assessed 317,176 days of MASK-air® use from 17,780 users aged 16-90 years, in 25 countries. The mCSMS and the factor analyses-based CSMSs displayed poorer validity and responsiveness compared to the remaining CSMSs. The latter displayed moderate-to-strong correlations with the tested comparators, high test-retest reliability and moderate-to-large responsiveness. Among data-driven CSMSs, a better performance was observed for cluster analyses-based CSMSs. High accuracy (capacity of discriminating different levels of rhinitis control) was observed for the latter (AUC-ROC = 0.904) and for the mixed CSMS (AUC-ROC = 0.820). The mixed CSMS and the cluster-based CSMSs presented medium-high validity, reliability and accuracy, rendering them as candidates for primary endpoints in future rhinitis trials.


A New Approach to Diagnose Parkinson's Disease Using a Structural Cooccurrence Matrix for a Similarity Analysis.
Parkinson's disease affects millions of people around the world and consequently various approaches have emerged to help diagnose this disease, among which we can highlight handwriting exams. Extracting features from handwriting exams is an important contribution of the computational field for the diagnosis of this disease. In this paper, we propose an approach that measures the similarity between the exam template and the handwritten trace of the patient following the exam template. This similarity was measured using the Structural Cooccurrence Matrix to calculate how close the handwritten trace of the patient is to the exam template. The proposed approach was evaluated using various exam templates and the handwritten traces of the patient. Each of these variations was used together with the Naïve Bayes, OPF, and SVM classifiers. In conclusion the proposed approach was proven to be better than the existing methods found in the literature and is therefore a promising tool for the diagnosis of Parkinson's disease.


Lengthened G1 phase indicates differentiation status in human embryonic stem cells.
The cell cycle in pluripotent stem cells is notable for the brevity of the G1 phase, permitting rapid proliferation and reducing the duration of differentiation signal sensitivity associated with the G1 phase. Changes in the length of G1 phase are understood to accompany the differentiation of human embryonic stem cells (hESCs), but the timing and extent of such changes are poorly defined. Understanding the early steps governing the differentiation of hESCs will facilitate better control over differentiation for regenerative medicine and drug discovery applications. Here we report the first use of real-time cell cycle reporters in hESCs. We coexpressed the chromatin-decorating H2B-GFP fusion protein and the fluorescence ubiquitination cell cycle indicator (FUCCI)-G1 fusion protein, a G1 phase-specific reporter, in hESCs to measure the cell cycle status in live cells. We found that FUCCI-G1 expression is weakly detected in undifferentiated hESCs, but rapidly increases upon differentiation. hESCs in the G1 phase display a reduction in undifferentiated colony-initiating cell function, underscoring the relationship between G1 phase residence and differentiation. Importantly, we demonstrate inter- and intracolony variation in response to chemicals that induce differentiation, implying extensive cell-cell variation in the threshold necessary to alter the G1 phase length. Finally, gain of differentiation markers appears to be coincident with G1 phase lengthening, with distinct G1 phase profiles associated with different markers of early hESC differentiation. Our data demonstrate the tight coupling of cell cycle changes to hESC differentiation, and highlight the cell cycle reporter system and assays we have implemented as a novel avenue for investigating pluripotency and differentiation.