Treatment of hidradenitis supprurativa associated pain with nonsteroidal anti-inflammatory drugs, acetaminophen, celecoxib, gabapentin, pegabalin, duloxetine, and venlafaxine.
Hidradenitis Supprurativa is a painful dermatological condition. Although the pain of HS has unique aspects, the pain of HS pain shares common elements with essential pain, fibromyalgia, and pure neuropathic pain syndromes. Futhermore, depression plays an important role in the pain of HS. This paper reviews the potential for use of nonsteroidal anti-inflammatory drug (NSAIDS), acetaminophen, celecoxib, gabpentin, pregabalin, and the serotonin and norepinephrine reuptake inhibitors (SNRIs), duloxetine and venlafaxine, for treating HS related pain. No studies exist for pain control in HS. Initially, the pain of HS is treated medically e.g. oral rifampin and clindamycin or adalimumab to decrease inflammation, but an analysis of pain medications to treat the pain of HS merits its own discussion and treatment algorithm. First-line HS pain treatments include: topical analgesics and oral NSAIDs, such as celecoxib (Celebrex®), and acetaminophen. If these are inadequate, which is common, the less expensive gabapentin (Neurontin®) 400-1200 mg TID or the more expensive (Lyrica®) pregabalin 50-100mg BID can be added for synergistic effect. In my experience, HS patients prefer pregabalin, which induces less drowiness than gabapentin. If these combinations are inadequate, an SNRI can be added. Of SNRIs, duloxetine (Cymbalta®) 30-120 mg, given QD or divided BID, is most optimal. I have used gabapetin or pregabalin in combination with duloxtine effectively. Venlafaxine (Effexor®), 75 mg-375mg (divided into BID or TID dosing), or in extended release form Venlafaxine ER (Effexor ER®) (37.5mg-375mg daily) can be combined with pregalin or gabapetin. Venlafaxine's cardiovascular side effects and lesser effectiveness serves HS patients less well then duloxetine, in my experience. An advantage of duloxetine and venlafaxine is that they can be used to treat the depression often associated with HS. If prolonged use of opiates is required, patients should be referred to a pain specialist.


A feasibility and acceptability study of an adaptation of the Mindful Self-Compassion program for adult cancer patients.
Psychosocial interventions that mitigate psychosocial distress in cancer patients are important. The primary aim of this study was to examine the feasibility and acceptability of an adaptation of the Mindful Self-Compassion (MSC) program among adult cancer patients. A secondary aim was to examine pre-post-program changes in psychosocial wellbeing. The research design was a feasibility and acceptability study, with an examination of pre- to post-intervention changes in psychosocial measures. A study information pack was posted to 173 adult cancer patients 6 months-5 years post-diagnosis, with an invitation to attend an eight-week group-based adaptation of the MSC program. Thirty-two (19%) consented to the program, with 30 commencing. Twenty-seven completed the program (mean age: 62.93 years, SD 14.04; 17 [63%] female), attending a mean 6.93 (SD 1.11) group sessions. There were no significant differences in medico-demographic factors between program-completers and those who did not consent. However, there was a trend toward shorter time since diagnosis in the program-completers group. Program-completers rated the program highly regarding content, relevance to the concerns of cancer patients, and the likelihood of recommending the program to other cancer patients. Sixty-three percent perceived that their mental wellbeing had improved from pre- to post-program; none perceived a deterioration in mental wellbeing. Small-to-medium effects were observed for depressive symptoms, fear of cancer recurrence, stress, loneliness, body image satisfaction, mindfulness, and self-compassion. The MSC program appears feasible and acceptable to adults diagnosed with non-advanced cancer. The preliminary estimates of effect sizes in this sample suggest that participation in the program was associated with improvements in psychosocial wellbeing. Collectively, these findings suggest that there may be value in conducting an adequately powered randomized controlled trial to determine the efficacy of the MSC program in enhancing the psychosocial wellbeing of cancer patients.


Mechanisms of targeted therapy resistance in a pediatric glioma driven by ETV6-NTRK3 fusion.
Chromosomal rearrangements of the NTRK genes generate kinase fusions that are targetable oncogenic drivers in diverse adult and pediatric malignancies. Despite robust clinical response to targeted NTRK inhibition, the emergence of therapeutic resistance poses a formidable clinical challenge. Here we report the characterization of an ETV6-NTRK3 fusion-driven pediatric glioma that progressed through NTRK-targeted treatments with entrectinib and selitrectinib. Genetic analysis of multifocal recurrent/resistant lesions identified a previously uncharacterized NTRK3 p.G623A and a known p.G623E resistance mutation, in addition to other alterations of potential pathogenic impact. Functional studies using heterologous reconstitution model systems and patient-derived tumor cell lines establish that NTRK3G623A and NTRK3G623E mutated kinases exhibit reduced sensitivity to entrectinib and selitrectinib, as well as other NTRK inhibitors tested herein. In summary, this genetic analysis of multifocal recurrent/resistant glioma driven by ETV6-NTRK3 fusion captured a cross section of resistance-associated alterations that, based on in vitro analysis, likely contributed to resistance to targeted therapy and disease progression.


Variation in Preferences for Long-Acting Injectable Pre-Exposure Prophylaxis Among US Men Who Have Sex with Men: A Latent Class Analysis.
Cabotegravir long-acting injectable HIV pre-exposure prophylaxis (LA PrEP) is efficacious, with a good safety profile, and was approved by the US Food and Drug Administration in December 2021. Understanding variations in potential user preferences for LA PrEP may inform implementation and subsequently improve uptake and community-level effectiveness. HIV-negative, sexually active men who have sex with men (MSM) aged ≥15 years were recruited online for the 2019 American Men's Internet Survey, before LA PrEP approval. Respondents completed a discrete-choice experiment (DCE) with hypothetical LA PrEP attributes (out-of-pocket cost, perceived side effects, injection frequency, perceived stigma, service location). Latent class analysis segmented respondents into groups based on their preferences for the attributes presented, and relative importance of preference weights and willingness-to-pay were calculated. While the majority had never used daily oral PrEP, 73% of the 2489 respondents were very or somewhat likely to use LA PrEP. Three latent classes were identified from 2241 respondents in the DCE. The "side effects-averse" class was the largest group (64% of respondents) and placed 61% relative importance on side effects. The "ambivalent" class (20% of respondents) placed higher importance on stigma (17% of relative importance) than other classes. The "cost-conscious" class (16% of respondents) placed higher relative importance (62%) on cost compared with other attributes and classes. Perceived side effects were an important hypothetical barrier for LA PrEP uptake among a large proportion of potential MSM users. Minimizing out-of-pocket costs is likely to increase uptake and may be important to equitable access. Tailored communication strategies are recommended for the different groups of potential LA PrEP users.


Unveiling the role of miR-137-3p/miR-296-5p/SERPINA3 signaling in colorectal cancer progression: integrative analysis of gene expression profiles and in vitro studies.
Colorectal cancer (CRC) is a prevalent malignancy worldwide, with increasing incidence and mortality rates. Although treatment options have improved, CRC remains a leading cause of death due to metastasis. Early intervention can significantly improve patient outcomes, making it crucial to understand the molecular mechanisms underlying CRC metastasis. In this study, we performed bioinformatics analysis to identify potential genes associated with CRC metastasis. We downloaded and integrated gene expression datasets (GSE89393, GSE100243, and GSE144259) from GEO database. Differential expression analysis was conducted, followed by Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The hub gene SERPINA3 was selected for further in vitro functional studies. Additionally, the role of miR-137-3p/miR-296-5p/ Serpin family A member 3 (SERPINA3) in CRC cell function was investigated using in vitro assays. Analysis of the gene expression datasets revealed differentially expressed genes (DEGs) associated with CRC metastasis. GO analysis showed enrichment in biological processes such as blood coagulation regulation and wound healing. Cellular component analysis highlighted extracellular matrix components and secretory granules. Molecular function analysis identified activities such as serine-type endopeptidase inhibition and lipoprotein receptor binding. KEGG analysis revealed involvement in pathways related to complement and coagulation cascades, cholesterol metabolism, and immune responses. The common DEGs among the datasets were further investigated. We identified SERPINA3 as a hub gene associated with CRC metastasis. SERPINA3 exerted enhanced effects on migration, proliferation and epithelial-mesenchymal transition (EMT) and inhibitory effects on caspase-3/-9 activities in HT29 and SW620 cells. MiR-137-3p overexpression increased activities of caspase-3/-9, decreased migration and proliferation, and also repressed EMT in HT29 cells, which were obviously attenuated by SERPINA3 enforced overexpression. Consistently, SERPINA3 enforced overexpression also largely reversed miR-296-5p mimics-induced increased in activities of caspase-3/-9, decrease in migration, proliferation and EMT in HT29 cells. Through bioinformatics analysis, we identified potential genes associated with CRC metastasis. The functional studies focusing on SERPINA3/miR-137-3p/miR-296-5p further consolidated its role in regulating CRC progression. Our findings provide insights into novel mechanisms underlying CRC metastasis and might contribute to the development of effective treatment strategies. However, the role of SERPINA3/miR-137-3p/miR-296-5p signaling in CRC still requires further investigation.


Schimke immuno-osseous dysplasia: a clinicopathological correlation.
Schimke immuno-osseous dysplasia (SIOD) is a fatal autosomal recessive disorder caused by loss-of-function mutations in swi/snf-related matrix-associated actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1). Analysis of detailed autopsies to correlate clinical and pathological findings in two men severely affected with SIOD. As predicted by the clinical course, T cell deficiency in peripheral lymphoid organs, defective chondrogenesis, focal segmental glomerulosclerosis, cerebral ischaemic lesions and premature atherosclerosis were identified. Clinically unexpected findings included a paucity of B cells in the peripheral lymphoid organs, emperipolesis-like (penetration of one cell by another) abnormalities in the adenohypophysis, fatty infiltration of the cardiac right ventricular wall, pulmonary emphysema, testicular hypoplasia with atrophy and azospermia, and clustering of small cerebral vessels. A regulatory role for the SMARCAL1 protein in the proliferation of chondrocytes, lymphocytes and spermatozoa, as well as in the development or maintenance of cardiomyocytes and in vascular homoeostasis, is suggested. Additional clinical management guidelines are recommended as this study has shown that patients with SIOD may be at risk of pulmonary hypertension, combined immunodeficiency, subcortical ischaemic dementia and cardiac dysfunction.


Ammonia Levels Do Not Guide Clinical Management of Patients With Hepatic Encephalopathy Caused by Cirrhosis.
Ammonia appears to play a major role in the pathophysiology of hepatic encephalopathy (HE), but its role in guiding management is unclear. We aimed to understand the impact of ammonia levels on inpatient HE management, hypothesizing that patients with elevated ammonia levels would receive more aggressive lactulose therapy than patients with normal ammonia or no ammonia level drawn. We examined patients with cirrhosis older than 18 years admitted for management of HE from 2005 to 2015. We additionally used propensity matching to control for confounding by the severity of underlying disease. Patients with an ammonia level taken at time of HE diagnosis were further separated into those with normal or elevated ammonia levels. The primary endpoint was the total lactulose (mL) amount (or dose) given in the first 48 hours of HE management. One thousand two hundred two admissions with HE were identified. Ammonia levels were drawn in 551 (46%) patients; 328 patients (60%) had an abnormal ammonia level (>72 μmol/L). There were no significant differences in the Child-Pugh score, MELD, or Charlson Comorbidity Index in those with and without ammonia levels drawn. The average total lactulose dose over 48 hours was 167 and 171 mL in the no ammonia vs ammonia groups, respectively (P = 0.42). The average lactulose dose in patients with an elevated ammonia level was 161 mL, identical to the lactulose dose in patients with a normal ammonia level. There was no correlation between lactulose dose and ammonia level (R = 0.0026). Inpatient management of HE with lactulose was not influenced by either the presence or level of ammonia level, suggesting that ammonia levels do not guide therapy in clinical practice.


CD1a on Langerhans cells controls inflammatory skin disease.
CD1a is a lipid-presenting molecule that is abundantly expressed on Langerhans cells. However, the in vivo role of CD1a has remained unclear, principally because CD1a is lacking in mice. Through the use of mice with transgenic expression of CD1a, we found that the plant-derived lipid urushiol triggered CD1a-dependent skin inflammation driven by CD4(+) helper T cells that produced the cytokines IL-17 and IL-22 (TH17 cells). Human subjects with poison-ivy dermatitis had a similar cytokine signature following CD1a-mediated recognition of urushiol. Among various urushiol congeners, we identified diunsaturated pentadecylcatechol (C15:2) as the dominant antigen for CD1a-restricted T cells. We determined the crystal structure of the CD1a-urushiol (C15:2) complex, demonstrating the molecular basis of urushiol interaction with the antigen-binding cleft of CD1a. In a mouse model and in patients with psoriasis, CD1a amplified inflammatory responses that were mediated by TH17 cells that reacted to self lipid antigens. Treatment with blocking antibodies to CD1a alleviated skin inflammation. Thus, we propose CD1a as a potential therapeutic target in inflammatory skin diseases.


Nanobody-loaded nanobubbles targeting the G250 antigen with ultrasound/photoacoustic/fluorescence multimodal imaging capabilities for specifically enhanced imaging of RCC.
Clinicians have attempted to discover a noninvasive, easy-to-perform, and accurate method to distinguish benign and malignant renal masses. The targeted nanobubbles (NBs) we constructed that target the specific membrane antigen of renal cell carcinoma (RCC), G250, and contain indocyanine green (ICG) provide multimodal enhanced imaging capability in ultrasound/photoacoustic/fluorescence for RCC which may possibly solve this problem. In this study, we encapsulated ICG in the lipid shell of the NBs by mechanical oscillation, then anti-G250 nanobodies (AGN) were coupled to the surfaces by the biotin-streptavidin bridge method, and the nanobubble named AGN/ICG-NB was completely constructed. The average particle diameter of the prepared AGN/ICG-NBs was (427.2 ± 4.50) nm, and the zeta potential was (-13.33 ± 1.01) mV. Immunofluorescence and flow cytometry confirmed the specific binding capability of AGN/ICG-NBs to G250-positive cells. In vitro imaging experiments confirmed the multimodal imaging capability of AGN/ICG-NBs, and the in vivo imaging experiments demonstrated the specifically enhanced ability of AGN/ICG-NBs for ultrasound/photoacoustic/fluorescence imaging of human-derived RCC tumors. The biosafety of AGN/ICG-NB was verified by CCK-8 assay, organ H&E staining and blood biochemical indices. In conclusion, the targeted nanobubbles we prepared with ultrasound/photoacoustic/fluorescence multimodal imaging capabilities provide a potentially feasible approach to address the need for early diagnosis and differential diagnosis of renal masses.


In Vitro Evaluation of Probiotic Properties of Lactic Acid Bacteria Isolated from Some Traditionally Fermented Ethiopian Food Products.
Probiotics are live microorganisms which when consumed in large number together with a food promote the health of the consumer. The aim of this study was to evaluate in vitro probiotic properties of lactic acid bacteria (LAB) isolated from traditional Ethiopian fermented Teff injera dough, Ergo, and Kocho products. A total of 90 LAB were isolated, of which 4 (4.44%) isolates showed 45.35-97.11% and 38.40-90.49% survival rates at pH values (2, 2.5, and 3) for 3 and 6 h, in that order. The four acid-tolerant isolates were found tolerant to 0.3% bile salt for 24 h with 91.37 to 97.22% rate of survival. The acid-and-bile salt-tolerant LAB isolates were found inhibiting some food-borne test pathogenic bacteria to varying degrees. All acid-and-bile-tolerant isolates displayed varying sensitivity to different antibiotics. The in vitro adherence to stainless steel plates of the 4 screened probiotic LAB isolates were ranged from 32.75 to 36.30% adhesion rate. The four efficient probiotic LAB isolates that belonged to Lactobacillus species were identified to the strain level using 16S rDNA gene sequence comparisons and, namely, were Lactobacillus plantarum strain CIP 103151, Lactobacillus paracasei subsp. tolerans strain NBRC 15906, Lactobacillus paracasei strain NBRC 15889, and Lactobacillus plantarum strain JCM 1149. The four Lactobacillus strains were found to be potentially useful to produce probiotic products.


A complete set of maize individual chromosome additions to the oat genome.
All 10 chromosomes of maize (Zea mays, 2n = 2x = 20) were recovered as single additions to the haploid complement of oat (Avena sativa, 2n = 6x = 42) among F(1) plants generated from crosses involving three different lines of maize to eight different lines of oat. In vitro rescue culture of more than 4,300 immature F(1) embryos resulted in a germination frequency of 11% with recovery of 379 F(1) plantlets (8.7%) of moderately vigorous growth. Some F(1) plants were sectored with distinct chromosome constitutions among tillers of the same plant and also between root and shoot cells. Meiotic restitution facilitated development of un-reduced gametes in the F(1). Self-pollination of these partially fertile F(1) plants resulted in disomic additions (2n = 6x + 2 = 44) for maize chromosomes 1, 2, 3, 4, 6, 7, and 9. Maize chromosome 8 was recovered as a monosomic addition (2n = 6x + 1 = 43). Monosomic additions for maize chromosomes 5 and 10 to a haploid complement of oat (n = 3x + 1 = 22) were recovered several times among the F(1) plants. Although partially fertile, these chromosome 5 and 10 addition plants have not yet transmitted the added maize chromosome to F(2) offspring. We discuss the development and general utility of this set of oat-maize addition lines as a novel tool for maize genomics and genetics.


Children's Command of Four Inflectional Constructions in Arabic: Differences and Development With Age.
This study examines whether differences in acquisition exist among the inflectional constructions of number, gender, possessive pronouns, and tense. Moreover, the study investigates whether these inflectional patterns develop with age. The participants were 1,020 Arabic-speaking kindergartners from K2 and K3. Children were assessed in morphological tasks, which targeted four different morphological inflectional constructions both in real words and pseudowords: gender, number-plural, possessive pronouns, and tense. Findings reveal the differences between all inflectional constructions. In other words, children demonstrated higher performance in gender construction, followed by construction of numbers and possessive pronouns, while the lowest performance is shown among tense construction. In addition, the results indicate that all inflectional constructions develop with age, that is, there was higher performance in K3 than in K2 in all inflection constructions. This study contributes to our knowledge about early language development by showing that the acquisition of gender and number-plurals is faster and more advanced than the acquisition of possessive pronouns or tense. The implications of these results are discussed, especially the need to develop children's inflectional forms such as possessive pronouns and tense, which may eventually also impact narrative understanding and production.


[Antimony accumulation in agricultural food crops].
A study was made of the antimony content in some farm products of plant and animal origin in the zones of wastes of antimony factories and those having nothing to do with antimony processing. The content of antimony was discovered to be elevated in all foods obtained in the zone where antimony factories are located, especially in vegetables with ground fruit. A high antimony content was detected in milk. The content of antimony in a "standard" diet calculated on the basis of maximally allowable concentrations of the metal in foods and in analogous diets containing products of plant and animal origin grown in the Fergana and Chuisk valleys was 0.405, 8.585 and 1.702, respectively. The high proportion of vegetables and fruit in the local diets makes them, apart from milk and dairy products, the main sources of antimony supply to the human body.


[Experimental model of canine oleic acid-induced acute lung injury: establishment of a working model].
There are several experimental model of acute lung injury induced by oleic acid (OA); however, there are few studies that show how this injury develops. This study seeks to detail the x-ray, hemodynamic, gasometrical, gravimetrical, macroscopic and microscopic alterations developed in an experimental model of canine OA-induced acute lung injury (ALI). Twelve dogs were divided in 2 study groups: Group I (n=6): Control group without ALI. Group II (n=6); OA-induced ALI. All dogs were submitted to X-ray, hemodynamic and gasometric evaluation before ALI induction, and later every 15 minutes during 150 minutes. At the end of the study, the animals were euthanatized and were evaluated the changes gravimetric, macroscopic and microscopic in injured lungs. All the animals survived through the study. In group II, 100% of the animals developed x-ray (p < 0.003 Wilcoxon), hemodynamic, gasometrical and gravimetric (p < 0.5 ANOVA, Tukey), macroscopically and microscopically (p < 0.001 Wilcoxon) ALI. The OA-induced ALI is a model in which dogs develop X-ray, hemodynamic, gasometrical, gravimetrical, macroscopically and microscopically injuries of the exudative phase that lung with ALI injury presents.


Sexual dimorphism in renal production of prostanoids in spontaneously hypertensive rats.
Male spontaneously hypertensive rats (SHR) have higher blood pressure, blunted pressure-natriuresis relationship, and accelerated progression of renal injury compared with female SHR. Renal medullary prostanoids mediate vascular tone, salt and water balance, and renin release and, as a result, are involved in the maintenance of renal blood flow and the pathogenesis of hypertension. The aim of this study was to determine whether a gender difference exists in prostanoid production in SHR and whether sex steroids influence prostaglandin (PG) production. Thirteen-week-old intact and gonadectomized male and female SHR rats were placed in metabolic cages for 24-hour urine collection. Prostanoid excretion was determined using enzyme immunoassay. Kidneys were isolated and separated into outer and inner medulla for Western blot analysis. Female SHR had enhanced urinary excretion of PG E2 (PGE2) metabolites and thromboxane B2, an indicator of renal thromboxane production, compared with male SHR. There were no gender differences in excretion of systemic thromboxane or prostacyclin. Correspondingly, female SHR had enhanced microsomal PGE2 synthase protein expression in the renal inner medulla and greater cyclooxygenase-2 (COX-2) expression in the outer medulla. Orchidectomy was associated with increased PGE2 metabolite excretion and microsomal PGE synthase protein expression. Thromboxane B2 excretion was not affected by gonadectomy in either male or female SHR. Protein expressions of COX and cytoplasmic PGE2 synthase in the renal medulla were unchanged by gonadectomy in both sexes. These results demonstrate a sexual dimorphism in renal production of prostanoids in SHR and that PGE production is testosterone sensitive and estrogen insensitive.


Applying best practices from digital control systems to BMI implementation.
Many brain-machine interface (BMI) algorithms, such as the population vector decoder, must estimate neural spike rates before transforming this information into an external output signal. Often, rate estimation is performed via the selection of a bin width corresponding to the effective sampling rate of the decoding algorithm. Here, we implement real-time rate estimation by extending prior work on the optimization of Gaussian filters for offline rate estimation. We show that higher sampling rates result in improved spike rate estimation. We further show that the choice of sampling rate need not dictate the number of parameters which must be used in an autoregressive decoding algorithm. Multiple studies in other neural signal processing contexts suggest that BMI performance could be improved substantially via careful choice of smoothing filter, discrete-time decoder representation, and sampling rate. Together, these ensure minimal deviation from the behavior of the modeled continuous-time systems.


Intervention and alcoholism.
It is difficult for some alcoholics to admit their illness and recognize their need for help. From experience a process called intervention has evolved. Basically it consists of a well planned and rehearsed scenario, devoid of coercion and criticism, in which the alcoholic can find no acceptable alternative to treatment. He is given every opportunity to begin his recovery with dignity.


Pre- and postsynaptic neuromuscular junction abnormalities in musk myasthenia.
Autoantibodies to muscle-specific kinase (MuSK) can cause myasthenia gravis (MG). The pathophysiological mechanism remains unknown. We report in vitro electrophysiological and histological studies of the neuromuscular junction in a MuSK MG patient. Low levels of presynaptic acetylcholine release and small miniature endplate potentials were found. This combination of pre- and postsynaptic abnormalities was supported by histology, revealing partially denervated postsynaptic areas, and some degeneration of postsynaptic folds. Results suggest that anti-MuSK antibodies reduce the stability of muscle-nerve contact.


Immunotoxins against CD19 and CD22 are effective in killing precursor-B acute lymphoblastic leukemia cells in vitro.
Monoclonal antibodies (Mabs) conjugated to toxins or their subunits (immunotoxins or ITs) are undergoing clinical testing in adults with a variety of malignancies. The potential impact of this form of therapy in pediatric precursor B-lineage acute lymphoblastic leukemia (pre-B ALL) has yet to be determined. Mabs directed against the cell surface antigens, CD19 and CD22 conjugated to deglycosylated ricin A chain (dgRTA) have been tested in patients with non-Hodgkin's lymphoma (NHL), but not in patients with pre-B ALL. Because of the encouraging performance of these ITs in phase I trials, we evaluated the specific cytotoxicity of anti-CD19 (HD37-dgRTA) and anti-CD22 (RFB4-dgRTA) ITs or their combination (Combotox) on patient-derived pre-B ALL cells maintained in vitro on a stromal feeder layer. After 48 h in culture, cytotoxicity to tumor cells was determined by flow cytometry using propidium iodide (PI) and fluorescein isothiocyanate (FITC)-conjugated anti-CD10, 19, and 22. Both RFB4-dgRTA and HD37-dgRTA induced a statistically significant reduction in the number of viable leukemic cells, and Combotox was even more effective. Our results demonstrate that these ITs are specifically cytotoxic to primary pre-B ALL cells and that they should be further evaluated for the therapy of B-lineage ALL.


HER catalytic activity and regulation of a transition metal atom-anchored BC3 monolayer: a first-principles study.
An atomic-level understanding of the hydrogen evolution reaction (HER) on a transition metal (TM) atom-anchored 2D monolayer is vital to explore highly efficient catalysts for hydrogen production. Here, the catalytic activities and modulation of TM atom (Ti, Fe, Cu, Zn, Mo, Ag, Au)-doped BC3 monolayers are investigated by first-principles calculations. Au@BC3 and Fe@BC3 are proven to be potentially excellent HER catalysts. Partial oxidation engineering on Zn@BC3 could improve its performance. Au@BC3 and Ti, Cu and Mo-anchored BC3 with the support of a NbB2 (0001) surface are expected to replace Pt due to the Gibbs free energy changes extremely close to zero. It is revealed that the catalytic activity of the adsorption site is highly related to the degree of charge transfer between the adsorption site and substrate.


[Peculiarities of surgical interventions in the nasopharynx of patients presenting with lymphoid tissue hypertrophy and exudative otitis media].
A total of 118 patients presenting with exudative otitis media and lymphoid tissue hypertrophy in the nasopharynx were examined and treated. A classification of different variants of lymphoid tissue hypertrophy and pharyngeal tonsil hypertrophy was developed and used as a basis to plan the strategy of surgical interventions in the nasopharynx.


Inducing effect of cortisone and insulin on the activity of beta-galactosidase in the E. coli strains K12.
Individual and combined effects of cortisone and insulin on the synthesis of beta-galactosidase in the strains E. coli K 12 200 PS/Flac and M-308 and the possiblity of cortisone uptake by the bacterial cell under different temperature conditions were investigated in their dynamics. When insulin and cortisone are applied simultaneously in doses showing individually the greatest stimulative effect on the synthesis of beat-galactosidase, no summation of the effect of the hormones occurs in the strain E. coli 200 PS/Flac in the presence of IPTG while in the strain E. coli ML-308 simultaneous application of insulin and cortisone induces a negligible increase in the activity of beta-galactosidase. Tests for the incorporation of [3H] cortisone into the strains E. coli 200 PS/Flac and ML-308 have shown that the hormone is taken up by the bacterial cell immediately after its addition to the incubation medium, reaching its maximum after 5 min of incubation and maintaining the same level in the subsequent 30 min. The incorporation of [3H] cortisone at a temperature of 37degrees C is markedly higher than at 4degrees C. Preliminary incubation of the cultures with unlabelled cortisone and insulin resulted in a decrease in the uptake of [3H] cortisone by the bacterial cell.


Atmospheric nitrogen deposition impacts on the structure and function of forest mycorrhizal communities: A review.
Humans have dramatically increased atmospheric nitrogen (N) deposition globally. At the coarsest resolution, N deposition is correlated with shifts from ectomycorrhizal (EcM) to arbuscular mycorrhizal (AM) tree dominance. At finer resolution, ectomycorrhizal fungal (EcMF) and arbuscular mycorrhizal fungal (AMF) communities respond strongly to long-term N deposition with the disappearance of key taxa. Conifer-associated EcMF are more sensitive than other EcMF, with current estimates of critical loads at 5-6 kg ha-1 yr-1 for the former and 10-20 kg ha-1 yr-1 for the latter. Where loads are exceeded, strong plant-soil and microbe-soil feedbacks may slow recovery rates after abatement of N deposition. Critical loads for AMF and tropical EcMF require additional study. In general, the responses of EcMF to N deposition are better understood than those of AMF because of methodological tractability. Functional consequences of EcMF community change are linked to decreases by fungi with medium-distance exploration strategies, hydrophobic walls, proteolytic capacity, and perhaps peroxidases for acquiring N from soil organic matter. These functional losses may contribute to declines in forest floor decomposition under N deposition. For AMF, limited capacity to directly access complexed organic N may reduce functional consequences, but research is needed to test this hypothesis. Mycorrhizal biomass often declines with N deposition, but the relative contributions of alternate mechanisms for this decline (lower C supply, higher C cost, physiological stress by N) have not been quantified. Furthermore, fungal biomass and functional responses to N inputs probably depend on ecosystem P status, yet how N deposition-induced P limitation interacts with belowground C flux and mycorrhizal community structure and function is still unclear. Current 'omic analyses indicate potential functional differences among fungal lineages and should be integrated with studies of physiology, host nutrition, growth and health, fungal and plant community structure, and ecosystem processes.


Noradrenergic transmission in depression: under- or overfunction?
The pros and cons of the noradrenaline hypothesis of depression are examined and a critical assessment is made of the recent theory that antidepressants act by reducing the sensitivity of postsynaptic beta-adrenergic receptors, implying that depressed patients suffer from a overfunction and not underfunction of cerebral noradrenergic systems. The evidence that the latter are in some way involved in depression, although very probably other transmitter systems are also involved in this disease, is considered quite convincing. On the other hand, the subsensitivity of postsynaptic receptors occurring after antidepressive treatment is seen as a counterregulatory mechanism responding to an increased noradrenaline concentration in the synaptic cleft rather than as the cause of the antidepressant effect. It is stressed that it is the intensity of noradrenergic synaptic transmission that matters, i.e. the functional activity of integral system and not that of the pre-or postsynaptic parts alone. A model of the sequential occurrence of events influencing noradrenergic transmission during treatment with an uptake inhibitor is suggested which could explain both the latency of onset of the therapeutic response and the fact that some patients do not respond to the treatment.


Bilateral diffuse melanocytic uveal tumors associated with systemic malignant neoplasms. A recently recognized syndrome.
Four cases of the simultaneous occurrence of bilateral diffuse melanocytic uveal tumors were studied by us. In each case, the patient had an associated systemic malignant neoplasm diagnosed by biopsy or at autopsy. There was no evidence of metastatic melanoma in any patient. Clinically, the patients experienced rapid loss of vision, and cataracts were usually present. Multiple pigmented and nonpigmented placoid iridic and choroidal nodules, as well as serous retinal detachment, frequently were noted. Histopathologically, the uveal tracts of both eyes were diffusely infiltrated by preponderantly benign-appearing nevoid or spindle-shaped cells. Areas of necrosis within the tumors and scleral involvement were commonly seen. We believe this constellation of findings constitutes a new syndrome in which there is a bilateral, diffuse proliferation of melanocytic cells throughout the uvea in association with a systemic malignant neoplasm.


Metachronous mature teratoma in the corpus callosum occurring 12 years after a pineal germinoma.
The authors report a metachronous germ cell tumor with different histological type occurring 12 years after resection of a pineal germinoma. Histological examination of the original tumor revealed germinoma without any other component of germ cell tumor, and the patient underwent chemotherapy followed by 24 Gy of localized irradiation. Twelve years later, follow-up MR imaging showed a round mass in the genu of the corpus callosum. Two courses of chemotherapy were administered, but the tumor size remained stable. A second operation was performed and this second tumor was completely removed. The histological diagnosis was mature teratoma. The second tumor was considered as a metachronous mature teratoma rather than a recurrence of the original germinoma. To the authors' knowledge, this combination of metachronous germ cell tumor has not previously been reported in the literature.


Single-organoid analysis reveals clinically relevant treatment-resistant and invasive subclones in pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases, characterized by a treatment-resistant and invasive nature. In line with these inherent aggressive characteristics, only a subset of patients shows a clinical response to the standard of care therapies, thereby highlighting the need for a more personalized treatment approach. In this study, we comprehensively unraveled the intra-patient response heterogeneity and intrinsic aggressive nature of PDAC on bulk and single-organoid resolution. We leveraged a fully characterized PDAC organoid panel (N = 8) and matched our artificial intelligence-driven, live-cell organoid image analysis with retrospective clinical patient response. In line with the clinical outcomes, we identified patient-specific sensitivities to the standard of care therapies (gemcitabine-paclitaxel and FOLFIRINOX) using a growth rate-based and normalized drug response metric. Moreover, the single-organoid analysis was able to detect resistant as well as invasive PDAC organoid clones, which was orchestrates on a patient, therapy, drug, concentration and time-specific level. Furthermore, our in vitro organoid analysis indicated a correlation with the matched patient progression-free survival (PFS) compared to the current, conventional drug response readouts. This work not only provides valuable insights on the response complexity in PDAC, but it also highlights the potential applications (extendable to other tumor types) and clinical translatability of our approach in drug discovery and the emerging era of personalized medicine.


Improvement in Parkinson disease by subthalamic nucleus stimulation based on electrode placement: effects of reimplantation.
The misplacement of electrodes is a possible explanation for suboptimal response to bilateral subthalamic nucleus (STN) stimulation in patients with Parkinson disease. To evaluate whether reimplantation of electrodes in the STN can produce improvement in patients with poor results from surgery and with suspected electrode misplacement based on imaging findings. Prospective follow-up study. Academic research. A 1-year postoperative study was undertaken in 7 consecutive patients with Parkinson disease who, despite bilateral STN stimulation, experienced persistent motor disability and who were operated on for reimplantation a median of 16.9 months later. The primary outcome was measured as the change in the Unified Parkinson Disease Rating Scale (UPDRS) motor score 1 year after reimplantation. The secondary outcome was measured as the extent of pharmacologic and electrical treatments required and the threshold at which the first stimulation-induced adverse effect appeared. The distances between the electrode contacts used for chronic stimulation and the STN theoretical effective target, defined as the mean position of the clinically efficient contact from 193 previously implanted electrodes, were compared. Except for a single patient, all patients displayed improvement following reimplantation. Under off-medication (ie, the patient is taking no medication) condition, STN stimulation improved the basal state UPDRS motor score by 26.7% before reimplantation and by 59.4% at 1 year after reimplantation. The median off-medication Schwab and England score improved from 51% to 76%. The median levodopa equivalent daily dose was reduced from 1202 mg to 534 mg. The stimulation varibles changed from a mean of 2.6 V/73.0 micros/163.0 Hz to 2.8 V/60. 0 micros/ 140.0 Hz. The mean threshold of the first stimulation-induced adverse effect increased from 2.6 to 4.4 V. The mean distance between the contacts used for chronic stimulation and the theoretical effective target decreased from 5.4 to 2.0 mm. This distance correlated inversely with the percentage improvement in theUPDRS motor score. Patients demonstrating poor response to STN stimulation as a result of electrode misplacement can benefit from reimplantation in the STN closer to the theoretical target.


Peritonitis in peritoneal dialysis patients from a hospital in Lima, Peru.
In order to determine the rate and factors related to peritonitis in peritoneal dialysis (PD) patients treated at a hospital in Lima, Peru; a retrospective single-cohort study was conducted during the period 2014-2016. All patients diagnosed with chronic renal disease from the PD program at the Cayetano Heredia Hospital were included. The incidence rate of peritonitis was estimated and a bivariate analysis was performed to assess related factors. A total of 73 patients were included. The incidence rate of peritonitis was 0.60 episodes per patient per year; 46.7% of the cultures were positive and the most common isolated germ was S. aureus. Lower albumin and hematocrit values were found to be related to peritonitis. In this study, the incidence rate of peritonitis and negative cultures were found to be higher than the internationally estimated rate.


A proposed reference method for plasminogen activators that enables calculation of enzyme activities in SI units.
A method has been developed for accurately and precisely measuring the activity of a range of plasminogen activators (PAs) used as thrombolytic agents, including streptokinase, tissue plasminogen activator (tPA) and variants, and urokinase (uPA), both single and two chain forms. Plasminogen activation is monitored in a transparent, solid fibrin matrix but uses chromogenic substrate hydrolysis, rather than changes in fibrin, to quantitate the activity of PAs. The method has been tested in two recent international collaborative studies involving tPA and streptokinase where it has been shown to perform very well. Furthermore, the method is based on sound enzymological principles and once correction for the competitive inhibition of fibrin(ogen) is made, the generation of plasmin can be determined in molar terms and hence the activity of PAs can be expressed and compared in SI units (rate of increase in molar concentration of plasmin) as well as International Units. The assay is also arranged in such a way to reflect the behavior of PAs in vivo during thrombolytic therapy and it is shown that the specific activity of streptokinase and tPA in this system reflects plasmin generation capacity of these thrombolytics for doses given in infusions for treatment of myocardial infarction. The method would make a suitable reference method for PAs and provides a rigorous means of studying and modeling the enzymology of fibrinolysis and will be helpful in the rational design of third generation thrombolytic agents.


Retinal polyol and myo-inositol in galactosemic dogs given an aldose-reductase inhibitor.
Galactitol and myo-inositol concentrations were measured in retinas, erythrocytes, and skeletal muscle of experimentally galactosemic dogs receiving a placebo or the aldose reductase inhibitor, sorbinil, for 5 yr. The concentration of galactitol was increased more than 30-fold in the retina and other tissues by galactosemia, and the increase was inhibited 90-96% in all tissues by sorbinil. The concentration of free myo-inositol was greater than normal in retinas of galactosemic dogs, and its concentration was not altered by the aldose-reductase inhibitor. The myo-inositol concentration likewise was greater than normal in the retinas of dogs that were diabetic for 2-4 months. The marked inhibition of polyol production and accumulation in the retina of sorbinil-treated galactosemic dogs was not associated with a comparable inhibition of retinopathy.


Biosynthesis of the thiamin pyrimidine: the reconstitution of a remarkable rearrangement reaction.
The conversion of 5-aminoimidazole ribonucleotide (AIR) into 4-amino-2-methyl-5-hydroxymethylpyrimidine (HMP) is a fascinating reaction on the thiamin biosynthetic pathway in bacteria and is probably the most complex unresolved rearrangement in primary metabolism. We have successfully reconstituted this reaction in a cell-free system. The E. coli thiC gene product and an additional unidentified E. coli protein are required for the reaction. In addition, SAM and nicotinamide cofactors are required for full activity. Labeling studies to determine the origin of most of the atoms in the pyrimidine are described. Based on these studies, a new mechanism for HMP formation is proposed.


Stochastic, real-space, imaginary-time evaluation of third-order Feynman-Goldstone diagrams.
A new, alternative set of interpretation rules of Feynman-Goldstone diagrams for many-body perturbation theory is proposed, which translates diagrams into algebraic expressions suitable for direct Monte Carlo integrations. A vertex of a diagram is associated with a Coulomb interaction (rather than a two-electron integral) and an edge with the trace of a Green's function in real space and imaginary time. With these, 12 diagrams of third-order many-body perturbation (MP3) theory are converted into 20-dimensional integrals, which are then evaluated by a Monte Carlo method. It uses redundant walkers for convergence acceleration and a weight function for importance sampling in conjunction with the Metropolis algorithm. The resulting Monte Carlo MP3 method has low-rank polynomial size dependence of the operation cost, a negligible memory cost, and a naturally parallel computational kernel, while reproducing the correct correlation energies of small molecules within a few mEh after 10(6) Monte Carlo steps.


Indigenous community participation: how does it relate to student centered learning and embrace primary health care philosophies?
The health and well-being of Indigenous Australians has been identified as a critical problem with high levels of chronic illness, morbidity and mortality compared to other Australian population groups. However, as health professionals we continue to discuss and theorise components of Indigenous health addressing issues in a piecemeal way. The concept of primary health care has been shown to have an independent effect on improving the health status of populations and having the ability to reduce health inequalities. Countries with well developed primary care systems have healthier populations and reduced health care costs (Macinko et al., 2003, p. 407). Primary health care combined with a community holistic approach and the defined use of student centered learning in Indigenous education has the potential to provide optimal health care and thus be an effective way to improve Indigenous Community health (McMurray, 2003, p. 296).


UV and VUV-induced fragmentation of tin-oxo cage ions.
Photoresist materials are being optimized for the recently introduced Extreme Ultraviolet (EUV) photolithographic technology. Organometallic compounds are potential candidates for replacing the ubiquitous polymer-based chemically amplified resists. Tin (Sn) has a particularly large absorption cross section for EUV light (13.5 nm, 92 eV), which could lead to a lower required EUV dose for achieving the desired solubility change (improved sensitivity). However, the fundamental interaction between organometallic materials and higher energy photons is poorly understood. In this work, we exposed n-butyltin-oxo cage dications (M2+) in the gas phase to photons in the energy range 4-35 eV to explore their fundamental photoreactivity. Photoproducts were detected using mass spectrometry. Homolytic cleavage of tin-carbon bonds was observed for all photon energies above the onset of electronic absorption at ∼5 eV (∼250 nm), leading to photoproducts which have lost one or more of the attached butyl groups (Bu). Above 12 eV (<103 nm), dissociative photoionization occurred for the dication (M2+), competing with the neutral loss channels. The photoionization threshold is lowered by approximately 2 eV when one counterion (triflate, OTf- or tosylate, OTs-) is attached to the tin-oxo cage (MOTf+ and MOTs+). This threshold is expected to be even lower if each tin-oxo cage is attached to two counterions, as is the case in a solid film of tin-oxo cages. Addition of counterions also affected the fragmentation pathways; photoexcitation of (MX)+ (X = counterion, OTf or OTs) always led to formation of (MX-2Bu)+ rather than (MX-Bu)+. MOTs+ was much more reactive than MOTf+ in terms of reaction products per absorbed photon. A possible explanation for this is proposed, which involves the counterion reacting with the initially formed tin-based radical.


Measuring Biofouling Potential in SWRO Plants with a Flow-Cytometry-Based Bacterial Growth Potential Method.
Measuring the bacterial growth potential of seawater reverse osmosis (SWRO) feed water is an issue that is receiving growing attention. This study developed and demonstrated the applicability of the flow-cytometry (FCM)-based bacterial growth potential (BGP) method to assess the biofouling potential in SWRO systems using natural microbial consortium. This method is relatively fast (2-3 days) compared to conventional bioassays. The effect of the potential introduction of nutrients during measurement has been studied thoroughly to achieve the lowest measure value of about 45,000 cells/mL, which is equivalent to about (10 µg-C glucose/L). The BGP method was applied in two full-scale SWRO plants that included (i) dissolved air flotation (DAF) and ultra-filtration (UF); (ii) dual-media filtration (DMF) and cartridge filter (CF), which were compared with the cleaning frequency of the plants. A significant reduction (54%) in BGP was observed through DAF-UF as pre-treatment (with 0.5 mg Fe3+/L), while there was a 40% reduction by DMF-CF (with 0.8 mg Fe3+/L). In terms of the absolute number, the SWRO feed water after DAF-UF supports 1.5 × 106 cells/mL, which is 1.25 times higher than after DMF-CF. This corresponds to the higher cleaning-in-place (CIP) frequency of SWRO with DAF-UF compared to DMF-CF as pre-treatment, indicating that the BGP method has an added value in monitoring the biofouling potential in SWRO systems.


Evaluation of bishexadecyltrimethyl ammonium palladium tetrachloride based dual functional colloidal carrier as an antimicrobial and anticancer agent.
We have developed a dual function carrier using bishexadecyltrimethyl ammonium palladium tetrachloride, which has anticancer as well as antibacterial activity, using a ligand insertion method with a simple and easy work procedure. The complex is prepared by a simple and cost effective method using hexadecyltrimethyl ammonium chloride and palladium chloride under controlled stoichiometry. Herein, we report the aggregation (self assembly) of the metallosurfactant having palladium as a counter ion, in aqueous medium along with its binding affinity with bovine serum albumin. The palladium surfactant has exhibited excellent antimicrobial efficacy against fungus and bacteria (both Gram-positive and Gram-negative bacteria). Cytotoxicity of palladium surfactant against cancerous (Human leukemia HL-60, pancreatic MIA-Pa-Ca-2 and prostate cancer PC-3) and healthy cells (fR2 human breast epithelial cells) was also evaluated using MTT assay. The present dual functional moiety shows a low IC50 value and has potential to be used as an anticancer agent. Our dual function carrier which itself possesses antimicrobial and anticancer activity represents a simple and effective system and can also be utilized as a drug carrier in the future.


TP53INP1 exerts neuroprotection under ageing and Parkinson's disease-related stress condition.
TP53INP1 is a stress-induced protein, which acts as a dual positive regulator of transcription and of autophagy and whose deficiency has been linked with cancer and metabolic syndrome. Here, we addressed the unexplored role of TP53INP1 and of its Drosophila homolog dDOR in the maintenance of neuronal homeostasis under chronic stress, focusing on dopamine (DA) neurons under normal ageing- and Parkinson's disease (PD)-related context. Trp53inp1-/- mice displayed additional loss of DA neurons in the substantia nigra compared to wild-type (WT) mice, both with ageing and in a PD model based on targeted overexpression of α-synuclein. Nigral Trp53inp1 expression of WT mice was not significantly modified with ageing but was markedly increased in the PD model. Trp53inp2 expression showed similar evolution and did not differ between WT and Trp53inp1-/- mice. In Drosophila, pan-neuronal dDOR overexpression improved survival under paraquat exposure and mitigated the progressive locomotor decline and the loss of DA neurons caused by the human α-synuclein A30P variant. dDOR overexpression in DA neurons also rescued the locomotor deficit in flies with RNAi-induced downregulation of dPINK1 or dParkin. Live imaging, confocal and electron microscopy in fat bodies, neurons, and indirect flight muscles showed that dDOR acts as a positive regulator of basal autophagy and mitophagy independently of the PINK1-mediated pathway. Analyses in a mammalian cell model confirmed that modulating TP53INP1 levels does not impact mitochondrial stress-induced PINK1/Parkin-dependent mitophagy. These data provide the first evidence for a neuroprotective role of TP53INP1/dDOR and highlight its involvement in the regulation of autophagy and mitophagy in neurons.


Body mass index in screening for adiposity in children and adolescents: systematic evaluation using receiver operating characteristic curves.
Body mass index (BMI) has been recommended for use in adolescent screening programs to select subjects with excess body fat for appropriate interventions. No systematic evaluation of MBI in screening for high degrees of adiposity was available when these recommendations were formulated. The purpose of this paper was to evaluated the screening performance of BMI using appropriate epidemiologic methods. Percentage body fat (TBF%) was measured by dual-energy X-ray absorptiometry DXA) in a convenience sample of 230 (119 males, 111 females) health Australian volunteers aged 4-20 y inclusive. Receiver operating characteristic (ROC) curves were prepared for detecting TBF% at or beyond the 85th percentile, using BMI as the screening test. Screening performance was slightly better for girls than for boys, but the differences were not significant. Reasonable true-positive (0.71, 95% CI: 0.53, 0.85) and low false-positive (0.05, 95% CI: 0.02, 0.09) rates were observed at the 85th percentile cutpoint for BMI. At the 95th percentile cutpoint for BMI, both true-positive (0.29, 95% CI: 0.15, 0.47) and false-positive (0.01, 95% CI: 0.00, 0.03) rates were lower. Screening for excess adiposity by using an appropriate percentile cutoff for BMI gives acceptable performance. ROC curves facilitate design of screening programs by allowing an explicit tradeoff between true-positive and false-positive rates. Although large sample sizes are required for precise estimates, the cutoff points that have been recommended appear to offer a reasonable compromise between true-and false-positive rates.


Aquaporin proteins in murine trophectoderm mediate transepithelial water movements during cavitation.
Mammalian blastocyst formation is dependent on establishment of trophectoderm (TE) ion and fluid transport mechanisms. We have examined the expression and function of aquaporin (AQP) water channels during murine preimplantation development. AQP 3, 8, and 9 proteins demonstrated cell margin-associated staining starting at the 8-cell (AQP 9) or compacted morula (AQP 3 and 8) stages. In blastocysts, AQP 3 and 8 were detected in the basolateral membrane domains of the trophectoderm, while AQP3 was also observed in cell margins of all inner cell mass (ICM) cells. In contrast, AQP 9 was predominantly observed within the apical membrane domains of the TE. Murine blastocysts exposed to hyperosmotic culture media (1800 mOsm; 10% glycerol) demonstrated a rapid volume decrease followed by recovery to approximately 80% of initial volume over 5 min. Treatment of blastocysts with p-chloromercuriphenylsulfonic acid (pCMPS, > or =100 microM) for 5 min significantly impaired (P < 0.05) volume recovery, indicating the involvement of AQPs in fluid transport across the TE. Blastocysts exposure to an 1800-mOsm sucrose/KSOMaa solution did not demonstrate volume recovery as observed following treatment with glycerol containing medium, indicating glycerol permeability via AQPs 3 and 9. These findings support the hypothesis that aquaporins mediate trans-trophectodermal water movements during cavitation.


Kidney flow and function in hypertension: protective effects of pycnogenol in hypertensive participants--a controlled study.
This study evaluated the effects of Pycnogenol as an adjunct to angiotensin-converting enzyme (ACE)-inhibitor ramipril treatment of hypertensive patients presenting with early signs of renal function problems. One group of 26 patients was medicated with 10 mg ramipril per day only; a second group of 29 patients took Pycnogenol in addition to the ACE inhibitor over a period of 6 months. At trial end, a lowered systolic and diastolic blood pressure was found in both groups, with a significant further reduction of diastolic pressure in the group given Pycnogenol in addition to ramipril. The major aim of this study was the investigation of kidney-protective effects of Pycnogenol. Urinary albumin decreased from 87 +/- 23 to 64 +/- 16 mg/d with ramipril only. Additional Pycnogenol lowered albumin significantly better from 91 +/- 25 to 39 +/- 13 mg/day (P < .05). In both groups, serum creatinine was lowered; however, only in the combination treatment group did the effect reached statistical significance. In both groups, CRP levels decreased from 2.1 to 1.8 with ramipril and from 2.2 to 1.1 with the ramipril-Pycnogenol combination; the latter reached statistical significance. Kidney cortical flow velocity was investigated by Doppler color duplex ultrasonography. Both systolic and diastolic flow velocities increased significantly after 6 months medication with ramipril. The addition of Pycnogenol to the regimen statistically significantly further enhanced kidney cortical flow velocities, by 8% for diastolic flow and 12% for systolic flow, relative to values found for the group taking ramipril only. The protective effects of Pycnogenol for initial kidney damage found in this study warrant further research with a larger number of patients and over a longer period of time.


Localization of an origin of DNA replication within the TRS/IRS repeated region of the herpes simplex virus type 1 genome.
An assay has been developed and used to locate an origin of DNA replication on the herpes simplex virus type 1 (HSV-1) genome. Baby hamster kidney cells were transfected with circular plasmid molecules containing cloned copies of HSV-1 DNA fragments, and helper functions were provided by superinfection with wild-type HSV-1. The presence of an HSV-1 origin of replication within a plasmid enabled amplification of the vector DNA sequences, which was detected by the incorporation of [32P]orthophosphate. By screening various HSV-1 DNA fragments it was possible to identify a 995-bp fragment that maps entirely within the reiterated sequences flanking the short unique region of the viral genome and contains all the cis-acting signals necessary to function as an origin of viral DNA replication. The products of plasmid replication were shown to be high mol. wt. DNA molecules consisting of tandem duplications of the complete plasmid, suggesting that replication was occurring by a rolling-circle mechanism.


Sociodemographic correlates of food habits among school adolescents (12-15 year) in North Gaza Strip.
There is little information about meal patterns and food consumption of adolescents in Palestine. The objective of this study was to describe the association between sociodemographic factors and food intake, and meal patterns among Palestinian school adolescents (12-15 year) in North Gaza Strip. A cross-sectional study was conducted in 2002 comprising 944 subjects in 10 schools in Gaza city, Jabalia village and Jabalia refugee camp. Self-administered questionnaires were filled in by students and parents to obtain data on frequency of meals, food intake and sociodemographic characteristics. High household socioeconomic status (SES) was associated with the increased number of meals and the increased intakes of many nutritious foods such as; animal food items, fruits and vegetables and dairy foods. The percentage of adolescents having breakfast daily of high and low SES was 74.5% vs 55% in boys and 65.6% vs 45% in girls. The percentage of girls with refugee status who had lunch was higher (90.2%) compared to the local citizen girls (83.9%), (p = 0.03). Girls were less likely to skip daily lunch (OR = 0.55, 95% CI = 0.36-0.87, p = 0.01) compared to boys. Risk of skipping lunch was three times higher among adolescents living in the village compared to Gaza well-off area (OR = 3.3, 95% CI = 1.72-6.31, p < 0.001). Adolescents who were having lunch daily were less likely to skip breakfast or dinner. Only 11.6% of boys and 16.2% of girls consumed fruits daily. In multivariate analysis, SES was positively associated with food frequency intake scores in both genders. Boys from the refugee camp and the village had a significant higher consumption of fruits and vegetables than boys from high and low income area in Gaza City, while it was the opposite in girls. Meal skipping is common, particularly among those of low SES and the intakes of many nutritious foods such as animal food items, fruits and vegetables and dairy foods seem to be low among adolescents of low SES. The results of this study could be used as an important base-line for future monitoring of the nutritional situation of adolescents.


The Impact of Monetary Poverty Alleviation Programs on Children's and Adolescents' Mental Health: A Systematic Review and Meta-Analysis Across Low-, Middle-, and High-Income Countries.
Poverty alleviation programs, such as cash transfers and monetary grants, may not only lift people out of poverty but, some argue, may improve mental health as well. However, to date, the impact of such programs on children and adolescents' mental health is unclear. We carried out a systematic review and meta-analysis of poverty alleviation interventions providing monetary support and reporting mental health outcomes in 0-19 year olds in low-, middle-, and high-income countries. We searched 11 databases for research published between January 1, 1990 and June 1, 2020 and included interventions offering unconditional and/or conditional monetary support and reporting mental health outcomes. After screening 7,733 unique articles, we included 14 papers (16,750 children and adolescents at follow-up) in our narrative summary. We meta-analyzed data on internalizing symptoms from 8 papers (13,538 children and adolescents analyzed). This indicated a small but significant reduction in adolescents' internalizing problems postintervention compared to control (odds ratio 0.72, 95% confidence interval 0.59-0.88, p < .01; I2 = 67%, τ2 = 0.05, p < .01). Our narrative synthesis provides further support for the overall effectiveness of cash programs but also notes that monetary support alone may not be sufficient in extreme risk settings and that imposing conditions may be actively harmful for the mental health of adolescent girls. We provide causal evidence that monetary interventions reduce internalizing symptoms of adolescents experiencing poverty. We recommend that future programming thoughtfully considers whether to apply conditions as part of their interventions and highlight the importance of providing additional comprehensive support for children and adolescents living in extreme risk settings.


Examining the Traits-Desires-Intentions-Behavior (TDIB) model for fertility planning in women living with HIV in Ontario, Canada.
The objective of this study was to determine the predictors of fertility behavior (i.e., trying to become pregnant) in a large representative sample of women living with HIV of reproductive age in Ontario, Canada. The Traits-Desires-Intentions-Behavior model was used to examine the key predictors of reproductive decision making and behavior. A total of 320 women living with HIV were included in the current analysis. The women living with HIV were between the ages of 18 and 52 (mean=37.23, SD=7.53), 56.4% had at least one child living in the home, over 40% identified as being of African ethnicity, and the average time since HIV diagnosis was 10.49 years (SD=5.71). In hierarchical multilevel analysis, perceived family support for trying to become pregnant, living in a large metropolitan city (i.e., Toronto), women's fertility desires, and fertility intentions were associated with fertility behavior (χ(2)9=59.97, p<0.001). As only 10.6% of participants reported engaging in fertility-related behavior, while 57.5% intended a pregnancy in the future, identifying barriers to fertility and discrepancies between intentions and behaviors can support policy programs and assist health care providers to better facilitate the fertility goals of women living with HIV.


Role of Alpelisib in the Treatment of PIK3CA-Mutated Breast Cancer: Patient Selection and Clinical Perspectives.
The PI3K/AKT/mTOR pathway has long been known to play a major role in the growth and survival of cancer cells. Breast tumors often harbor PIK3CA gene alterations, which therefore constitute a rational drug target. However, it has taken many years to demonstrate clinically-relevant efficacy of PI3K inhibition and eventually attain regulatory approvals. As data on PI3K inhibitors continue to mature, this review updates and summarizes the current state of the science, including the prognostic role of PIK3CA alterations in breast cancer; the evolution of PI3K inhibitors; the clinical utility of the first-in-class oral selective PI3Kα inhibitor, alpelisib; PIK3CA mutation detection techniques; and adverse effect management. PIK3CA-mutated breast carcinomas predict survival benefit from PI3K inhibitor therapy. The pan-PI3K inhibitor, buparlisib and the beta-isoform-sparing PI3K inhibitor, taselisib, met efficacy endpoints in clinical trials, but pictilisib did not; moreover, poor tolerability of these three drugs abrogated further clinical trials. Alpelisib is better tolerated, with a more manageable toxicity profile; the principal adverse events, hyperglycemia, rash and diarrhea, can be mitigated by intensive monitoring and timely intervention, thereby enabling patients to remain adherent to clinically beneficial treatment. Alpelisib plus endocrine therapy shows promising efficacy for treating postmenopausal women with HR+/HER2- advanced breast cancer. Available evidence supporting using alpelisib after disease progression on first-line endocrine therapy with or without CDK4/6 inhibitors justifies PIK3CA mutation testing upon diagnosing HR+/HER2- advanced breast cancer, which can be done using either tumor tissue or circulating tumor DNA. With appropriate toxicity management and patient selection using validated testing methods, all eligible patients can potentially benefit from this new treatment. Further clinical trials to assess combinations of hormone therapy with PI3K, AKT, mTOR, or CDK 4/6 inhibitors, or studies in men and women with other breast subtypes are ongoing.


Metagenomics reveals sediment microbial community response to Deepwater Horizon oil spill.
The Deepwater Horizon (DWH) oil spill in the spring of 2010 resulted in an input of ∼4.1 million barrels of oil to the Gulf of Mexico; >22% of this oil is unaccounted for, with unknown environmental consequences. Here we investigated the impact of oil deposition on microbial communities in surface sediments collected at 64 sites by targeted sequencing of 16S rRNA genes, shotgun metagenomic sequencing of 14 of these samples and mineralization experiments using (14)C-labeled model substrates. The 16S rRNA gene data indicated that the most heavily oil-impacted sediments were enriched in an uncultured Gammaproteobacterium and a Colwellia species, both of which were highly similar to sequences in the DWH deep-sea hydrocarbon plume. The primary drivers in structuring the microbial community were nitrogen and hydrocarbons. Annotation of unassembled metagenomic data revealed the most abundant hydrocarbon degradation pathway encoded genes involved in degrading aliphatic and simple aromatics via butane monooxygenase. The activity of key hydrocarbon degradation pathways by sediment microbes was confirmed by determining the mineralization of (14)C-labeled model substrates in the following order: propylene glycol, dodecane, toluene and phenanthrene. Further, analysis of metagenomic sequence data revealed an increase in abundance of genes involved in denitrification pathways in samples that exceeded the Environmental Protection Agency (EPA)'s benchmarks for polycyclic aromatic hydrocarbons (PAHs) compared with those that did not. Importantly, these data demonstrate that the indigenous sediment microbiota contributed an important ecosystem service for remediation of oil in the Gulf. However, PAHs were more recalcitrant to degradation, and their persistence could have deleterious impacts on the sediment ecosystem.


Abdominal Hodgkin's disease in a child.
We describe a girl with Hodgkin's disease limited to the abdomen. She had severe hypochromic, microcytic anemia with increased iron deposition in the liver. Abdominal Hodgkin's disease should be considered in the differential diagnosis of a child with hypochromic anemia, systemic symptoms, and lack of peripheral adenopathy.


An in vivo examination of rat brain during sepsis with 31P-NMR spectroscopy.
Neurological symptoms including lethargy, obtundation, and confusion are early and common findings in patients with sepsis. The etiology of the mental status changes that occur during severe infection is not known. We investigated the effects of sepsis on the levels of high-energy phosphates to determine whether decreased energy metabolism was a factor in the depressed neurological state. The time course of changes in brain pH and brain high-energy phosphate metabolites during an Escherichia coli infusion was determined from sequential phosphorus-31 nuclear magnetic resonance (31P-NMR) spectra of ketamine-xylazine-anesthetized rats. A second group of rats received 0.9% saline infusion and served as a control group. Despite severe obtundation and near loss of righting reflex, the rats in the septic group had no significant differences in the brain pH, the ratio of phosphocreatine (PCr) to beta-adenosine 5'-triphosphate (beta-ATP), or in the ratio of PCr to Pi. The only significant decrease in brain high-energy phosphates or pH occurred terminally in the septic rat group and corresponded with a rapidly falling arterial blood pressure. We conclude that the severe neurological depression that is characteristic of sepsis is not due to decreased levels of brain high-energy phosphates or brain acidosis.


Disruption of the joint synchrony of luteinizing hormone, testosterone, and androstenedione secretion in adolescents with polycystic ovarian syndrome.
The present study explores the postulate that the polycystic ovarian syndrome (PCOS) is marked by failure of physiological feedforward and feedback signaling between pituitary LH and ovarian androgens. To this end, we appraised the 3-fold simultaneous overnight release of LH (assayed by high precision immunofluorometry), testosterone (RIA), and androstenedione (RIA) in 12 an- or oligoovulatory adolescents with PCOS (mean +/- SEM age, 16.4 +/- 0.47 yr) and 10 eumenorrheic girls (age, 16.5 +/- 0.45 yr). Gynecological (postmenarchal) ages (years) were also comparable at 4.8 +/- 0.39 (PCOS) and 4.0 +/- 3.6 (control; P = NS). Body mass index and fasting serum insulin and estradiol concentrations were indistinguishable in the two study cohorts. Mean overnight serum concentrations of LH (assayed by both immunofluorometry and Leydig cell bioassay), testosterone, androstenedione, and 17alpha-hydroxyprogesterone were each elevated significantly in patients with PCOS (all P </= 0.027). The bivariate cross-approximate entropy (cross-ApEn) statistic was used as a sensitive barometer of altered within-axis feedback. This scale-invariant metric is designed to quantitate the joint synchrony of putatively linked (neurohormone) time series in a lag-independent pattern-sensitive manner. Here, we applied cross-ApEn to the coupled release of LH and testosterone, LH and androstenedione, and testosterone and androstenedione. Statistical comparisons of the two adolescent study cohorts unveiled consistently elevated cross-ApEn in patients with PCOS, denoting disruption of the pairwise synchrony of LH and testosterone (P = 0.0055), LH and androstenedione (P = 0.0076), and testosterone and androstenedione (P = 0.014) secretion. As an analytically distinct technique to monitor coordinate hormone release, we also applied cross-correlation analysis with variable lag. This appraisal revealed that adolescents with PCOS further exhibit 1) loss of rapid feedforward coupling between LH and testosterone output, 2) erosion of the time-lagged positive linkages between LH and androstenedione secretion, and 3) attenuation of the coordinate relationship between testosterone and androstenedione release. In summary, based on complementary, but independent, statistical tools, the present two-variable analyses unmask vivid deterioration of the joint synchrony of LH-testosterone, LH-androstenedione, and testosterone-androstenedione secretion in adolescents with PCOS. The multiplicity of the bihormonal coupling defects points to impaired feedforward and feedback signaling interfaces among the hypothalamus, pituitary gland, and ovary. Disruption of interandrogen synchrony also identifies pathophysiological dissociation of testosterone and androstenedione cosecretion. Whether presumptive failure of integrative hypothalamo-pituitary-gonadal control emerges prepubertally in girls at risk for PCOS or persists in adults with PCOS is not known.


[Therapy of patients with severe anorexia (summary of a report on a research project)].
From 1981 to 1983 a special project on anorexia nervosa was granted within "Sonderforschungsbereich 115" (Hamburg--West Germany). We want to give a review of those aspects of our studies which led us to a therapeutic concept for severely affected inpatients. Starting in the diagnostic field with problems of motivation and alexithymia we turn to psychodynamic subgroups, mention the studies of endocrinology, the Self-structure and the father-types, continue with epidemiologic studies as a device of interpreting pathologic phenomena. Concerning our therapeutic investigations--basing on a long-term follow-up--we report on therapeutic elements, results, follow-up and a hierarchy in prognostic factors of our in-patient treatment. In a critical survey of the results we finally discuss therapeutic recommendations.


Clinicopathological features of primary jejunoileal tumors.
Tumors of the small bowel are rare, accounting for about 3-6% of all gastrointestinal neoplasms, though they cover more than 90% of the intestinal surface. However, diagnosis and treatment are difficult and present an ongoing challenge for both gastrointestinal surgeons and gastroenterologists. The aim of this study was to investigate the clinical features of small bowel tumors. Between November 1994 and November 2007, 81 patients underwent treatments for primary tumors in the jejuno-ileal region at the Department of Surgery, Kangnam St. Mary's Hospital, the Catholic University of Korea. A retrospective review of the patients' characteristics and variable tumor factors was performed. The mean age of the patients was 53.2 years with 48 men and 33 women. The most common symptom was abdominal pain (59.3%), followed by bleeding (22.2%) and an abdominal mass (6.2%). We found that the patients with ileal tumors complained mainly of abdominal pain (72.9%) whereas the patients with jejunal tumors presented with gastrointestinal bleeding (36.4%) (P = 0.048). Seventy-six of the 81 patients (93.8%) had malignant tumors, including 40 (49.4%) gastrointestinal stromal tumors, 26 (32.1%) lymphomas and 5 (6.2%) adenocarcinomas. No postoperative mortalities were observed. The overall 5-year survival rate of the patients with malignant small bowel tumors was 31.8%. Because the clinical features of a primary tumor of the small bowel are obscure and its diagnosis is difficult, maintaining a high degree of suspicion and recognizing the possibility of a primary small bowel tumor are important.


Spinal column shortening for tethered cord syndrome associated with myelomeningocele, lumbosacral lipoma, and lipomyelomeningocele in children and young adults.
OBJECTIVE Tethered cord syndrome is the clinical manifestation of an abnormal stretch on the spinal cord, presumably causing mechanical injury, a compromised blood supply, and altered spinal cord metabolism. Tethered cord release is the standard treatment for tethered cord syndrome. However, direct untethering of the spinal cord carries potential risks, such as new neurological deficits from spinal cord injury, a CSF leak from opening the dura, and retethering of the spinal cord from normal scar formation after surgery. To avoid these risks, the authors applied spinal column shortening to children and transitional adults with primary and secondary tethered cord syndrome and report treatment outcomes. The authors' aim with this study was to determine the safety and efficacy of spinal column shortening for tethered cord syndrome by analyzing their experience with this surgical technique. METHODS The authors retrospectively reviewed the demographic and procedural data of children and young adults who had undergone spinal column shortening for primary or secondary tethered cord syndrome. RESULTS Seven patients with tethered cord syndrome caused by myelomeningocele, lipomyelomeningocele, and transitional spinal lipoma were treated with spinal column shortening. One patient with less than 24 months of follow-up was excluded from further analysis. There were 3 males and 4 females; the average age at the time was surgery was 16 years (range 8-30 years). Clinical presentations for our patients included pain (in 5 patients), weakness (in 4 patients), and bowel/bladder dysfunction (in 4 patients). Spinal column osteotomy was most commonly performed at the L-1 level, with fusion between T-12 and L-2 using a pedicle screw-rod construct. Pedicle subtraction osteotomy was performed in 6 patients, and vertebral column resection was performed in 1 patient. The average follow-up period was 31 months (range 26-37 months). Computed tomography-based radiographic outcomes showed solid fusion and no instrumentation failure in all cases by the most recent follow-up. Five of 7 patients (71%) reported improvement in preoperative symptoms during the follow-up period. The mean differences in initial and most recent Scoliosis Research Society Outcomes Questionnaire and Oswestry Disability Index scores were 0.26 and -13%, respectively; minimum clinically important difference in SRS-22 and ODI were assumed to be 0.4% and -12.8%, respectively. CONCLUSIONS Spinal column shortening seems to represent a safe and efficacious alternative to traditional untethering of the spinal cord for tethered cord syndrome.


Ionic channels of Paramecium: from genetics and electrophysiology to biochemistry.
This paper reviews the combined genetical, electrophysiological and biochemical analysis of excitation that has been carried out in Paramecium. Paramecium cells display graded Ca++ action potentials in response to a variety of stimuli. These action potentials regulate the orientation of the ciliary beat hence the cell's swimming behaviour. A large array of mutants displaying altered behaviour have been isolated and mapped to over 20 loci. Detailed electrophysiological analyses have been carried out on several classes of mutants revealing defects in specific ion channels in some cases. Mutants have proven very useful to analyze channel properties, to unravel interactions between channels and to discover the function of these channels in a variety of cellular processes. Some important channels are located in the ciliary membranes and cilia as well as ciliary membranes can now be purified in high purity and reasonable yield. These fractions have been used recently in a variety of biochemical approaches to gain insight into the molecular components of the excitation machinery. Specific alterations in some minor membrane proteins have been found in two mutants as well as a specific defect in sphingolipids in a third mutant. Those alterations had to be distinguished from large scale variations in membrane proteins and lipids that occur in this organism in response to modifications in growth conditions. Several other recent biochemical developments are reviewed and the advantages as well as the difficulties of the genetic approach to the molecular study of biological processes are discussed.


Marine omega-3 fatty acid intake and survival of stage III colon cancer according to tumor molecular markers in NCCTG Phase III trial N0147 (Alliance).
Marine omega-3 polyunsaturated fatty acids (MO3PUFAs) have anticancer properties and may improve colon cancer survival. However, it remains unknown whether the benefit differs by tumor molecular subtype. We examined data from a phase III randomized trial of FOLFOX or FOLFOX + cetuximab among 1,735 stage III colon cancer patients who completed a dietary questionnaire at enrollment. Multivariable hazard ratios and 95% confidence intervals (CIs) were calculated for the association between MO3PUFA and disease-free survival (DFS) and overall survival according to KRAS and BRAFV600E mutations and DNA mismatch repair (MMR) status. Higher MO3PUFA intake was associated with improved 3-year DFS for KRAS wild-type tumors (77% vs. 73%; HR: 0.84; 95% CI: 0.67-1.05) but not KRAS-mutant tumors (64% vs. 70%; HR: 1.30; 95% CI: 0.97-1.73; Pinteraction = 0.02). Similar heterogeneity was found by MMR (Pinteraction = 0.14): higher MO3PUFA was associated with better 3-year DFS for tumors with deficient MMR (72% vs. 67%) but not proficient MMR (72% vs. 72%). No heterogeneity was found by BRAFV600E mutation. Similar findings were obtained for overall survival. In conclusion, we found a suggestive beneficial association between higher MO3PUFA intake and improved survival among stage III colon cancer patients with wild-type KRAS and deficient MMR. Given the relatively small number of cases with tumor molecular assessments, further studies, preferably through pooled analyses of multiples cohorts, are needed to validate our findings.


Localization of phosphorylated SMAD proteins in granulosa cells, oocytes and oviduct of female mice.
SMAD signaling is essential for follicular development. The distribution of activated (phosphorylated) SMADs during folliculogenesis has not been described in detail. The present results indicate that oocytes from preantral and antral follicles contain the mRNA for the receptor regulated Smads (-1, -2, -3, -5 and -9), Smad4 (co-SMAD), and Smad6 and Smad7 (inhibitory SMADs). Levels of Smad5, Smad6 and Smad7 mRNA decreased in fully-grown oocytes compared to growing oocytes. Immunostaining for pSMAD1/5/9, pSMAD2 and pSMAD3 was evident in oocytes from primordial, primary, secondary and antral follicles. We also observed substantial staining for pSMADs in intact fully-grown oocytes from antral follicles. In granulosa cells, immunostaining for both pSMAD2/3 and pSMAD1/5/9 was apparent in preantral granulosa cells from primordial to secondary follicles. In antral follicles, immunostaining for pSMADs became more intense in the cumulus cells surrounding the oocyte. Immunostaining for pSMAD2 and pSMAD1/5/9 was also apparent in the epithelium lining of the oviduct. Clearly, oocytes, preantral granulosa cells, cumulus cells and the epithelium of the oviduct are major targets of SMAD-mediated pathways in female reproductive tissues. The finding that pSMAD pathways are active in oocytes raises new questions regarding the role of TGF-beta superfamily members in directly promoting oocyte development. The extent to which defects in pSMAD signaling in oocytes or the oviduct contribute to infertility in humans or animals remains an open question.


The role of nocturnal polysomnography in assessing children with Chiari type I malformation.
To evaluate nocturnal polysomnogram findings in children with suspected symptomatic Chiari type I malformation, correlate them with clinical and magnetic resonance imaging data and to determine if this information has value in clinical decision making process. A retrospective review identified 24 children with type I Chiari malformation, presumed symptomatic who had undergone neurological assessment, cranial magnetic resonance imaging and nocturnal polysomnography. Perimedullary subarachnoid space effacement on the magnetic resonance studies and the magnitude of cerebellar tonsillar descent in relation to the McRae line were correlated with frequency of obstructive or central sleep apnea, number of cortical arousals and evidence of impaired vocal mobility on laryngoscopy. The Wilcoxon rank sum test was applied for continuous variables and the Fisher exact test for categorical variables. The median age of the subjects was 6 years. The findings from 16/24 subjects with perimedullary subarachnoid space effacement (effaced group) were compared with those of 8/24 in the non-effaced group. The central apnea index [1.5 (IQR 1-3.5) versus 0.5 (IQR 0-1.5)] and cortical arousal index [12 (IQR 10-19) versus 8 (IQR 6.5-9)] were significantly higher in the effaced group than in the non-effaced group (p=0.0376 and 0.0036 respectively). Greater descent of tonsils as measured by distance from the McRae line to the tonsil tip was associated with significantly higher central apnea index, total arousal index and respiratory event related arousals. Measurements of clivus-canal angle, Klauss index and pB-C2 line did not correlate with abnormalities on polysomnography. The central apnea and arousal indices derived from the nocturnal polysomnogram correlate well with magnetic resonance imaging findings of subarachnoid space effacement and degree of tonsillar herniation. In children with Chiari type I malformation, the nocturnal polysomnogram findings provides important information that aids in the decision making process about proceeding with surgical decompression.


[Laparoscopy in urgent abdominal surgery].
The use of videolaparoscopic methods for the treatment of penetrating stomach and duodenal ulcers, acute cholecystitis, acute pancreatitis, acute appendicitis, intestinal obstruction, acute gynecological diseases and abdominal trauma is analyzed. Laparoscopic methods at urgent abdominal surgery improves the quality of diagnosis and treatment, decrease the rate of postoperative complications and lethality, reduce the hospital stay.


Central nervous system toxicity and cerebrospinal fluid pharmacokinetics of intraventricular 3-[(4-amino-2-methyl-5-pyrimidinyl)ethyl]-1-(2-chloroethyl)-1-nitro soureas and other nitrosoureas in beagles.
The central nervous system toxicity and cerebrospinal fluid (CSF) pharmacokinetics of 3-[(4-amino-2-methyl-5-pyrimidinyl)ethyl]-1-(2-chloroethyl)-1- nitrosoureas, a (ACNU) were determined in beagles and compared to those for three other nitrosoureas, 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea, 1,3-bis(2-chloroethyl)-1-nitrosourea, and chlorozotocin. Of the four drugs, ACNU was tolerated best and at doses of 0.2 to 0.8 mg/week for 8 consecutive weeks. We found that the average half-time for CSF elimination of ACNU was 18 min (range, 12 to 38 min). This value exceeded the known rate of ACNU decomposition in aqueous solution (28 to 29 min), implying that the disappearance of ACNU from CSF was due to hydrolytic decomposition and cellular entry and/or transcapillary loss across central nervous system capillaries. The drug exposure integral (C X t) of ACNU in the CSF after a "toxic dose low" of 0.8 mg in the dogs would achieve the equivalent of in vitro cell kills in excess of 3 logs for rat 9L and human glioma 126 cells. As a potential therapeutic agent for meningeal neoplasia, the major limiting factor may be that the CSF elimination of ACNU is rapid compared to its equilibration time from ventricle to spinal- and cerebral convexity-subarachnoid space. Based on these results, we have instituted clinical Phase I trials of intra-CSF ACNU.


Genomic Epidemiology of Carbapenem-Resistant Klebsiella in Qatar: Emergence and Dissemination of Hypervirulent Klebsiella pneumoniae Sequence Type 383 Strains.
The emergence of carbapenem-resistant, hypervirulent Klebsiella pneumoniae is a new threat to health care. We studied the molecular epidemiology of carbapenem-resistant Klebsiella pneumoniae isolates in Qatar using whole-genome sequence data. We also characterized the prevalence and genetic basis of hypervirulent phenotypes and established the virulence potential using a Galleria mellonella model. Of 100 Klebsiella isolates studied, NDM and OXA-48 were the most common carbapenemases. Core genome single-nucleotide polymorphism (SNP) analysis indicated the presence of diverse sequence types and clonal lineages; isolates belonging to Klebsiella quasipneumoniae subsp. quasipneumoniae sequence type 196 (ST196) and ST1416 may be disseminated among several health care centers. Ten K. pneumoniae isolates carried rmpA and/or truncated rmpA2, and 2 isolates belonged to KL2, indicating low prevalence of classical hypervirulent isolates. Isolates carrying both carbapenem resistance and hypervirulence genes were confined mainly to ST231 and ST383 isolates. One ST383 isolate was further investigated by MinION sequencing, and the assembled genome indicated that blaNDM was located on an IncHI1B-type plasmid (pFQ61_ST383_NDM-5) which coharbored several virulence factors, including the regulator of the mucoid phenotype (rmpA), the regulator of mucoid phenotype 2 (rmpA2), and aerobactin (iucABCD and iutA), likely resulting from recombination events. Comparative genomics indicated that this hybrid plasmid may be present in two additional Qatari ST383 isolates. Carbapenem-resistant, hypervirulent K. pneumoniae ST383 isolates pose an emerging threat to global health due to their simultaneous hypervirulence and multidrug resistance.


Rapid and reversible secretion changes during uncoupling of rat insulin-producing cells.
To determine whether insulin secretion is affected by a blockage of gap junctions between B cells, we have studied the secretion of rat pancreatic islets of Langerhans, primary dispersed islet cells, and cells of the RINm5F line, during short-term exposure to heptanol. Within minutes, this alkanol blocked gap junctions between the B cells of intact islets and abolished their normal secretory response to glucose. These two changes were rapidly and fully reversible after return of the islets to control medium. We further found that heptanol had no significant effect on the glucose-stimulated secretion of single B cells but inhibited that of B cell pairs. In the clone of RINm5F cells, whose junctional coupling and D-glyceraldehyde-induced stimulation of insulin release by aggregated cells were also inhibited by heptanol, this alkanol did not perturb intracellular pH and Ca2+ and the most distal steps of the secretion pathway. In summary, a gap junction blocker affected the secretion of insulin-producing cells by a mechanism which is dependent on cell contact and is not associated with detectable pleiotropic perturbations of the cell secretory machinery. The data provide evidence for the involvement of junctional coupling in the control of insulin secretion.


Phenotypic Analysis of Dominant Mutant Effects in Mice.
Dominant effects of a mutation may show up at any time during a mutational analysis, including during the early stages of an embryonic stem (ES) cell gene targeting experiment. Here, we discuss the mechanisms of dominant and semidominant effects and how they might appear if they show up in heterozygous ES cells, in ES cell chimeras, or in heterozygous progeny of chimeras. Similarly, dominant effects may be seen in mice heterozygous for CRISPR-Cas-targeted, -induced, or spontaneous mutations. If the dominant effects prevent the germline transmission of ES cells or cause fertility problems in heterozygotes, they can severely limit further analysis of the mutation. Ways to circumvent such reproductive problems are presented. The special case of imprinted genes, which may be functionally hemizygous and present a different phenotype when inherited from the mother than when inherited from the father, is discussed.


The small, methionine-rich chloroplast heat-shock protein protects photosystem II electron transport during heat stress.
Evidence suggests that the small chloroplast heat-shock protein (Hsp) is involved in plant thermotolerance but its site of action is unknown. Functional disruption of this Hsp using anti-Hsp antibodies or addition of purified Hsp to chloroplasts indicated that (a) this Hsp protects thermolabile photosystem II and, consequently, whole-chain electron transport during heat stress; and (b) this Hsp completely accounted for heat acclimation of electron transport in pre-heat-stressed plants. Therefore, this Hsp is a major adaptation to acute heat stress in plants.


Dynamics of elliptical galaxies.
Elliptical galaxies were once thought to be similar in their structure and dynamics to rotationally flattened bodies like stars. The discovery that elliptical galaxies rotate much more slowly than a fluid body with the same shape has led to a qualitative change in our understanding of the dynamics of these systems. It is now believed that elliptical galaxies are fully triaxial in shape. Self-consistent triaxial equilibria have been constructed and appear to be long-lived; they are made possible by the existence of conserved quantities, or integrals of motion, for galactic potentials without rotational symmetry. Many self-consistent equilibria are unstable; the nonexistence of elliptical galaxies with axis ratios more extreme than 3:1 is probably the result of such an instability. There is evidence for strong central mass concentrations, perhaps massive black holes, at the centers of some nearby galaxies. Recent observations suggest that many elliptical galaxies formed through the merger of two or more spiral galaxies.


Effectiveness of ambulation to prevent venous thromboembolism in patients admitted to hospital: a systematic review.
Patient ambulation is frequently recommended to help prevent venous thromboembolism during hospital admission. Our objective was to synthesize the evidence for ambulation as a prophylaxis for venous thromboembolism in hospital. We conducted a systematic review. We searched MEDLINE, Embase, Scopus, Web of Science and Cochrane Central Register of Controlled Trials indexed from their inception through April 2020 for studies of adult patients admitted to hospital, in which ambulation or mobilization alone or concomitant with prophylaxis was indicated for prevention of venous thromboembolism. We searched ClinicalTrials.gov for unpublished trials. We included randomized controlled trials (RCTs) and observational studies. Two reviewers independently screened articles and assessed risk of bias using 2 validated tools. We scored studies on quality of reporting, internal and external validity and study power; combined scores determined the overall quality. Eighteen articles met the inclusion criteria: 8 retrospective and 2 prospective cohorts, 7 RCTs and 1 secondary analysis of an RCT. The intervention (ambulation or mobilized) groups varied across studies. Five studies examined exercise as a therapeutic prophylaxis for thrombosis and 9 described an ambulation protocol. Five studies attempted to quantify amount and duration of patient ambulation and 3 reported ambulation distance. In the 5 studies rated as good or excellent statistical quality, findings were mixed. Incidence of venous thromboembolism was lowest when pharmacologic anticoagulants were added as part of the prescribed prophylaxis regimen. We did not find high-quality evidence supporting ambulation alone as an effective prophylaxis for venous thromboembolism. Ambulation should not be considered an adequate prophylaxis for venous thromboembolism, nor as an adequate reason to discontinue pharmacologic prophylaxis for venous thromboembolism during a patient's hospital admission.


Color-selecting reflectors inspired from biological periodic multilayer structures.
We propose a semi-infinite 1-D photonic crystal approach for designing artificial reflectors which aim to reproduce color changes with the angle of incidence found in biological periodic multilayer templates. We show that both the dominant reflected wavelength and the photonic bandgap can be predicted and that these predictions agree with exact calculations of reflectance spectra for a finite multilayer structure. In order to help the designer, the concept of spectral richness of angle-tuned color-selecting reflectors is introduced and color changes with angle are displayed in a chromaticity diagram. The usefulness of the photonic crystal approach is demonstrated by modelling a biological template (found in the cuticle of Chrysochora vittata beetle) and by designing a bio-inspired artificial reflector which reproduces the visual aspect of the template. The bioinspired novel aspect of the design relies on the strong unbalance between the thicknesses of the two layers forming the unit cell.