Redefining the Acetabular Component Safe Zone for Posterior Approach Total Hip Arthroplasty.
Acetabular component orientation influences joint stability in total hip arthroplasty (THA). The purpose of this study was to evaluate the effect of cup orientation and other variables on hip dislocation risk and to define a posterior approach specific safe zone. A cohort of 1289 posterior approach primary THA cases was prospectively followed and component position measured radiographically. Cup malposition, with respect to the Lewinnek safe zone, was an independent risk factor for dislocation (OR1.88). Modifying the anteversion safe zone limits to 10-25° strongly predicted increased dislocation risk (OR2.69). No dislocations occurred within a zone defined by a circle centered at 41.4° abduction and 17.1° anteversion, radius 4.3°. Utilizing a posterior approach specific safe zone of 10-25° anteversion and 30-50° abduction may minimize THA dislocations. Level III.


Are there any cross-ethnic differences in menstrual profiles? A pilot comparative study on Australian and Chinese women with primary dysmenorrhea.
To explore and compare the features of menstruation, perception and management of menstrual pain between two cohorts of Australian and Chinese women. A pilot comparison study was carried out using modified valid menstrual questionnaires. The study included 120 Australian women and 122 Chinese women aged from 18 to 45 years with primary dysmenorrhea. Australian women rated menstrual pain as more intense than Chinese women (8.5 ± 1.5 on a 10-point pain scale vs 7.3 ± 1.8, P < 0.001), duration of pain was 36% longer (3.0 ± 2.5 vs 2.2 ± 0.9 days, P = 0.002) and menarche commenced earlier (12.7 ± 1.5 vs 14.2 ± 1.4 years, P < 0.001). The mean reported menstrual interval was also shorter (29.2 ± 5.3 vs 30.52 ± 3.7, P = 0.020) with heavier overall menstrual flow (P = 0.002) and fewer clots in menstrual blood (83% vs 95.8%, P = 0.001). There was no significant difference in duration of menstruation (5.2 ± 1.3 vs 5.4 ± 1.1 days; P = 0.180). Correlations were found between earlier menarche and increased intensity of menstrual pain (r = -0.16, P = 0.011), and between heavier menstrual flow and increased intensity of menstrual pain (r = 0.19, P = 0.003). Evidence from this pilot study suggested that the clinical menstrual presentations in the cohorts of Australian and Chinese women were different. Although the findings are preliminary, evaluating ethnic differences in menstruation and experimental menstrual pain models may not only provide some information about underlying mechanisms but may also predict or explain group differences.


PPARγ-Dependent and -Independent Inhibition of the HMGB1/TLR9 Pathway by Eicosapentaenoic Acid Attenuates Ischemic Brain Damage in Ovariectomized Rats.
High mobility group box 1 (HMGB1) elevation after cerebral ischemia activates inflammatory pathways via receptors such as the receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs) and leads to brain damage. Eicosapentaenoic acid (EPA), a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, attenuates postischemic inflammation and brain damage in male animals. However, postischemic HMGB1 signaling and the effects of EPA on ovariectomized (OVX(+)) rats remain unclear. We hypothesized that EPA attenuates brain damage in OVX(+) rats via the inhibition of HMGB1 signaling in a PPARγ-dependent manner. Seven-week-old female Sprague-Dawley rats were divided into 3 groups; nonovariectomized (OVX(-)) rats and EPA-treated and EPA-untreated OVX(+) rats before cerebral ischemia induction. Another set of EPA-treated OVX(+) rats was injected with the PPARγ inhibitor GW9662. OVX(+) decreased the messenger RNA level of PPARγ and increased that of HMGB1, RAGE, TLR9, and tumor necrosis factor alpha (TNFα) in parallel with ischemic brain damage. EPA restored the PPARγ expression, downregulated the HMGB1 signal-related molecules, and attenuated the ischemic brain damage. Neither OVX(+) nor EPA affected the expression of TLR2 or TLR4. Interestingly, GW9662 partially abrogated the EPA-induced neuroprotection and the downregulation of RAGE and TLR9. In contrast, GW9662 did not affect HMGB1 or TNFα. These results suggest that EPA exerts PPARγ-dependent and PPARγ-independent effects on postischemic HMGB1/TLR9 pathway. The cortical infarct volume exacerbated by OVX(+) is associated with the upregulation of the HMGB1/TLR9 pathway. Suppression of this pathway may help to limit ischemic brain damage in postmenopausal women.


Atopic Dermatitis Across Shades of Skin.
Atopic dermatitis (AD) is a chronic, heterogeneous inflammatory skin disease that is associated with immense patient burden globally. There is increasing appreciation of disparities among patients identified as having skin of color (SOC), which often refers to patients of non-White race or non-European ancestry, but can broadly include individuals from a number of different racial, ethnic, ancestral, and skin pigmentation groups based on definition. In this narrative review, we discuss key terminology as it relates to AD across shades of skin, including modern definitions of 'race', 'ethnicity', and 'SOC'. We then synthesize the current literature describing disparities in AD prevalence, disease recognition, and burden alongside current data regarding genetic and immunologic findings across SOC populations. In the context of these findings, we highlight key concomitant social determinants of health, including environmental factors, socioeconomic status, and access to care, for which race often serves as a proxy for true biological and genetic differences. Finally, we discuss future efforts to shift to a more inclusive understanding of AD to encompass all shades of skin, to ensure equitable representation of diverse populations in high impact research, and intensify efforts to address the critical upstream factors driving observed disparities.


Placement of Brånemark Mk IV implants in compromised and grafted bone: radiographic outcome of 61 sites in 27 patients with 3- to 7-year follow-ups.
Sites in which bone is reduced in quality or height create challenges in esthetic reconstruction and loading support, which leads to a higher risk of failure. The Mk IV system with a TiUnite surface was designed specifically for placement in soft bone. This paper describes postloading outcomes of 103 Mk IV implants, with a focus on bone preservation in compromised bone sites during early remodeling, stability after abutment connection, and a 3- to 7-year follow-up from implant placement. A series of 103 4-mm (diameter), ≤ 10-mm (length) Mk IV implants were placed in the maxillae of 25 females and 14 males. Twenty-three patients also received staged bone grafts, and two underwent socket augmentation as well as grafts. Areas of previous infection were prepared mechanically and chemically. To ensure primary implant stability, the size of the osteotomy and the number of entries were minimized. Following a delayed loading protocol, all patients were restored with fixed partial dentures. For analysis of bone stability, the marginal levels on the mesial and distal aspects of the implants were measured at 7x magnification by a radiologist not involved in the treatment. Three implants were lost, 1 implant was never loaded although it integrated, 14 implants were not available for follow-up after abutment correction, and 5 had poor-quality radiographs. The mean marginal bone loss between implant insertion and loading was 1.21 ± 0.86 mm (n = 80). The differences in bone-remodeling levels in grafted and nongrafted sites were not significant. Data are reported on 103 implants in 39 consecutive patients through abutment connection, with radiographic follow-up from 3 to 7 years postimplant placement on 27 patients. It is critical to ensure optimal three-dimensional orientation and minimize site preparation, particularly when placing implants in compromised bone. With bone of poor preoperative density using a customized site preparation technique, excellent short-term implant survival and long-term bone stability have been demonstrated. Further follow-up will determine whether the Mk IV implant is the optimal design for compromised bone, including associated soft tissue stability.


Cytokine regulation of tight junctions.
Epithelial and endothelial tight junctions act as a rate-limiting barrier between an organism and its environment. Continuing studies have highlighted the regulation of the tight junction barrier by cytokines. Elucidation of this interplay is vital for both the understanding of physiological tight junction regulation and the etiology of pathological conditions. This review will focus on recent advances in our understanding of the molecular mechanisms of tight junctions modulation by cytokines.


Mucinous metaplasia of the penis.
To determine the incidence of mucinous metaplasia occurring in the foreskin or glans penis and any associated clinical or histopathological features. Following the recognition of two index cases, 100 other foreskin specimens were retrieved from the histopathology archives at Southampton General Hospital. The haematoxylin and eosin-stained slides were examined by a single observer to detect the presence of mucin-producing cells in the surface epithelium. The absence of mucinous metaplasia in negative cases was confirmed with mucin histochemistry. In total, four cases of mucinous metaplasia were identified, three involving the foreskin and one involving the glans penis. The age range was 51-80 years. Three cases were associated with Zoon's balanitis and the fourth showed mild non-specific balanitis. All four cases showed positive staining with both diastase periodic acid-Schiff and alcian blue. No mucin-producing cells were identified in non-inflamed or minimally inflamed specimens. Mucinous metaplasia of the penis is an uncommon but under-recognized condition. It is seen in the elderly and appears to be a metaplastic change associated with severe chronic inflammation, and possibly more specifically with Zoon's balanitis. Our study identified a case affecting the glans penis, a site not previously recorded.


Topical Adoptive Transfer of Plasmacytoid Dendritic Cells for Corneal Wound Healing.
Plasmacytoid dendritic cells (pDCs) are crucial for corneal homeostasis through secretion of various anti-angiogenic molecules and growth factors. Due to its avascular nature, only a limited number of adoptively transferred cells home to the cornea, when administered systemically. In addition, local adoptive transfer of cells poses several challenges and the clinical application of commonly used techniques is limited. Herein, we detail a novel approach for local adoptive transfer of pDCs to the cornea for the treatment of corneal wounds. This approach utilizes a commonly used fibrin sealant as a means of transferring previously isolated cells locally on the cornea. The technique is simple, reproducible, and is accompanied with successful transfer and integration of a substantial number of the cells to the cornea. Application of this approach to transfer pDCs promotes corneal wound healing. Furthermore, this technique can be applied for adoptive transfer of any cell of interest to the cornea.


Rapid Progressive Osteonecrosis of the Humeral Head After Arthroscopic Rotator Cuff Surgery.
To verify the clinical features and the risk factors of rapid progressive osteonecrosis of the humeral head after arthroscopic rotator cuff surgery (ARCS). Data and medical records of 24 patients who had rapid progressive collapse of the humeral head after ARCS performed from October 2012 to March 2016 were retrospectively analyzed. Among them, 8 patients demonstrated no evidence of osteonecrosis of the humeral head preoperatively yet developed rapid progressive collapse of the humeral head within 12 months after ARCS. All patients were women with a mean age of 64.0 years (range, 52-74 years), and all of them had surgery on their dominant side. Sudden pain developed at a mean 4 months (range, 0-6 months) after index surgery. The rapid progressive collapse of the humeral head occurred within 12 months after index surgery. No clear risk factor or evidence supporting an association between ARCS and humeral head osteonecrosis was found. Although the cause of the rapid progressive humeral head osteonecrosis after ARCS still needs to be established, surgeons should be aware of the possible development of humeral head osteonecrosis after ARCS, especially in older women with dominant arm involvement. Level IV, prognostic case series.


Fusion of hC3d3 to hCGbeta enhances responsiveness in vitro of human peripheral immunocompetent cells upon the antigen primary challenge.
Contraceptive vaccines based on hCGbeta have not met clinical application because of poor immunogenicity. In the present study, the eukaryotic expression vectors pCI-gs-signal-6His-hCGbeta and pCI-gs-signal-6His-hCGbeta-hC3d3 were constructed, and transfected into CHO cells with aid of Lipofectaine 2000 reagent to gain the secretory recombinant protein. Isolated B cells from human peripheral blood, combined B cells with T cells, and PBMC were treated in vitro, respectively, with 1 nM, 10 nM, 100 nM hCGbeta, hCGbeta-hC3d3 or PWM for 12 days. Immunoglobulin (Ig) and anti-hCG antibody levels in the supernatant were measured by an indirect enzyme-linked immunosorbent assay (ELISA). The expressions of CD80/CD86 on B cells, and CD154/CD25 on T cells, were analyzed by flow cytometry (FCM), and IL-2 production was assayed by ELISA. It was found that the Ig levels in the B-cell supernatants, the combined B with T cells, and PBMC treated with 100 nM hCGbeta-C3d3 fusion protein were 4-fold, 10-fold and 10.9-fold more, respectively, than that of hCGbeta. The anti-hCG antibody could be produced in the combined B cells with T cells, as well as PBMC challenged with 100 nM hCGbeta-C3d3, but no anti-hCG antibody was produced in the challenge with hCGbeta. The hCGbeta-hC3d3 fusion protein enhanced the expression of CD80 and CD86 on B cells, especially CD86 (P<0.05), and significantly increased the expression of CD154 and CD25 molecules on T cells compared to that of hCGbeta (P<0.05). The hCGbeta-hC3d3 promoted human PBMC producing more IL-2 than hCGbeta. These findings indicate that the fusion of hC3d3 to hCGbeta, as a means of harnessing the adjuvant potential of the innate immune system, may contribute to a more efficient humoral immune response, and might provide a potential application of protein vaccine strategies in humans in the future.


Crohn's disease in children and adolescents: is inadequate weight gain a valid indication for surgery?
Seventy children and adolescents hospitalized for Crohn's disease at the University of Michigan Medical Center between 1966 and 1976 are reviewed. Thirty-three of these children were managed medically and 37 underwent a total of 60 operative procedures. There were 33 bowel resections, 7 appendectomies, 4 abscess drainages, 3 bowel bypasses, and 13 miscellaneous operative procedures. The total operative mortality was 1.7%, and there were 10 complications, all of which were successfully managed. Among the 26 children undergoing bowel resections, 22 were below the third percentile for weight preoperatively. Nearly two-thirds of these gained weight to the 35th percentile following resection. The remainder of the children had a variety of growth and symptomatic responses to surgery. Resection aimed at complete removal of diseased bowel can be expected to yield substantial weight gain in children with Crohn's disease.


Body fat-lowering effect of conjugated linoleic acid is not due to increased lipolysis.
The ability of conjugated linoleic acid (CLA) to reduce adiposity may be due to changes in energy expenditure and/or direct effects on adipocyte lipid metabolism. The aim of the present work was to analyse if CLA supplementation modifies lipolytic activity in adipose tissue from hamsters fed on high-fat diet. Hamsters were divided into two groups and fed on diets supplemented with either 0.5% linoleic acid (control) or 0.5% trans-10,cis-12 CLA. After 6 weeks, animals were fasted overnight and adipose tissues were dissected and weighed. Adipocytes were isolated by collagenase digestion and incubated in Krebs-Ringer bicarbonate buffer with or without several agents acting at different levels of the lipolytic cascade. Adipocyte diameters were measured by microscopy. Adipose tissue DNA content was assessed by spectrophotometry. Animals fed on CLA diet showed significantly reduced adipose tissue mass. No differences between both groups was found for basal lipolysis, lipolytic effects of isoproterenol, forskolin, dibutyryl-cAMP and isobutylmethylxanthine, and pD2 for isoproterenol. A similar total DNA amount was found in adipose tissue of both groups, showing that CLA diet had no effect on total cell number per fat pad. Although DNA content per gram tissue, an indirect reverse index of cell size, was significantly increased in CLA fed hamsters, microscopy did not reveal differences in medium mature adipocyte diameter, nor in cell size distribution between both groups. These results suggest that adipose tissue size reduction induced by trans-10,cis-12 CLA intake is not due to changes in lipolysis. Reduced preadipocyte differentiation into mature adipocytes may account for this fat-lowering effect.


Combined Borderline Acetabular Dysplasia and Increased Femoral Anteversion Is Associated With Worse Outcomes in Female Patients Undergoing Hip Arthroscopy for Femoroacetabular Impingement.
To determine the relationship of increased femoral anteversion and borderline acetabular dysplasia on the outcomes of hip arthroscopy for femoroacetabular impingement in a female cohort of patients. This is a retrospective study of female patients undergoing hip arthroscopy for femoroacetabular impingement. All patients had preoperative radiographs and computed tomography scans from which lateral center edge angle (LCEA) and femoral anteversion were measured. Patient outcome was quantified by preoperative and postoperative International Hip Outcome Tool 12-item instrument (iHOT-12). All patients had follow-up at 2 to 4 years postoperatively. Published values for minimum clinically important difference, substantial clinical benefit (SCB), patient acceptable symptomatic state (PASS), and a normal or abnormal hip were used to determine outcome as well as the final score and delta of the iHOT-12. There were 243 female patients included in the cohort (83% follow-up) who had iHOT-12 scores at 2- to 4-year follow-up (mean 36.9 months). Female patients with combined LCEA ≤25° and femoral anteversion >20° had lower final IHOT-12 scores (P = .001) and delta iHOT-12 (P = .010) and were less likely to achieve a normal hip (P = .013), minimum clinically important difference (P = .018), SCB (P < .001), or PASS (P < .001) and more likely to have an abnormal hip (P = .002). In addition, patients with an LCEA ≤25° and normal femoral version were less likely to achieve a normal hip (P = .013), SCB (P < .001), and PASS (P < .001) compared with those with normal acetabular coverage (all P < .05). There was no difference in these outcome measures between the groups with an LCEA >25° with or without increased femoral version. Female patients with femoral anteversion >20° and borderline acetabular dysplasia did poorly after hip arthroscopy. However, those with increased femoral anteversion and normal acetabular coverage had outcomes similar to control hips. Level IV, case series.


Development of a ¹³C-optimized 1.5-mm high temperature superconducting NMR probe.
We report a 1.5-mm NMR probe based on high temperature superconductors operating at 14.1T optimized for (13)C detection. The probe has a total sample volume of about 35 microliters (μL) with an active volume of 20 μL and provides exceptional mass sensitivity for (13)C detection. The probe also has excellent (1)H sensitivity and employs a (2)H lock; (15)N irradiation capability can be added in the future. The coils are cooled to about 20K using a standard Agilent cryogenic refrigeration system, and the sample temperature is regulated near room temperature. The coil design considerations are discussed in detail. This probe is ideal for directly detected (13)C NMR experiments for natural products chemistry and metabolomics applications, for which 35 μL is an optimal sample volume. The outstanding (13)C sensitivity of this probe allowed us to directly determine the (13)C connectivity on 1.1mg of natural abundance histidine using an INADEQUATE experiment. We demonstrated the utility of this probe for (13)C-based metabolomics using a synthetic mixture of common natural abundance metabolites whose concentrations ranged from 1 to 5mM (40-200 nmol).


The combination of RPA-CRISPR/Cas12a and Leptospira IgM RDT enhances the early detection of leptospirosis.
Lack of available sensitive point-of-care testing is one of the primary obstacles to the rapid diagnosis of leptospirosis. The purpose of this study was to test the performance of two point-of-care tests, a clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 12a (CRISPR/Cas12a) fluorescence-based diagnostic assay (FBDA), a Leptospira immunoglobulin M (IgM) rapid diagnostic test (RDT), and the two tests combined. For the diagnosis of 171 clinical samples, a recombinase polymerase amplification (RPA)-CRISPR/Cas12a FBDA for whole blood and Leptospira IgM RDT (Medical Science Public Health, Thailand) for serum were used. The confirmed cases were determined by using any positive qPCR, microscopic agglutination test (MAT), and culture results. Diagnostic accuracy was assessed on the first day of enrollment and stratified by the day after symptom onset. The overall sensitivity of the Leptospira IgM RDT and RPA-CRISPR/Cas12a FBDA was 55.66% and 60.38%, respectively. When the two tests were combined, the sensitivity rose to 84.91%. The specificity of each test was 63.08% and 100%, respectively, and 63.08% when combined. The sensitivity of the Leptospira IgM RDT rose on days 4-6 after the onset of fever, while the RPA-CRISPR/Cas12a FBDA continued to decrease. When the two tests were combined, the sensitivity was over 80% at different days post-onset of fever. The combination of Leptospira IgM RDT and RPA-CRISPR/Cas12 FBDA exhibited significant sensitivity for the detection of leptospires at various days after the onset of fever, thereby reducing the likelihood of misdiagnosis. The combination of these assays may be suitable for early leptospirosis screening in situations with limited resources.


Evaluation of toxicity profile of kratom (Mitragyna speciosa Korth) decoction in rats.
Mitragyna speciosa Korth also known as kratom, is an herbal drug preparation for its therapeutic properties and opioid-replacement therapy. Kratom is consumed in a brewed decoction form in Malaysia and to date, no studies have characterized its chemical and toxicity profile. Thus, this study aims to evaluate kratom decoction's safety and toxicity profile after 28 days of treatment. Mitragynine content was quantified in kratom decoction and used as a marker to determine the concentration. Male and female Sprague Dawley rats were orally treated with vehicle or kratom decoction (10, 50 or 150 mg/kg) and two satellite groups were treated with vehicle and kratom decoction (150 mg/kg). Blood and organs were collected for hematology, biochemical and histopathology analysis at the end of treatment. No mortality was found after 28 days of treatment and no significant changes in body weight and hematology profile, except for low platelet count. High amounts of uric acid, AST, ALT and alkaline phosphatase were found in the biochemical analysis. Histological investigation of the heart and lungs detected no alterations except for the kidney, liver and brain tissues. In conclusion, repeated administration of kratom decoction provided some evidence of toxicity in the kidney and liver with no occurrence of mortality.


Stratifying risk of acute kidney injury in pre and post cardiac surgery patients using a novel biomarker-based algorithm and clinical risk score.
Acute kidney injury (AKI) following cardiac surgery significantly increases morbidity and mortality risks. Improving existing clinical methods of identifying patients at risk of perioperative AKI may advance management and treatment options. This study investigated whether a combination of biomarkers and clinical factors pre and post cardiac surgery could stratify patients at risk of developing AKI. Patients (n = 401) consecutively scheduled for elective cardiac surgery were prospectively studied. Clinical data was recorded and blood samples were tested for 31 biomarkers. Areas under receiver operating characteristic (AUROCs) were generated for biomarkers pre and postoperatively to stratify patients at risk of AKI. Preoperatively sTNFR1 had the highest predictive ability to identify risk of developing AKI postoperatively (AUROC 0.748). Postoperatively a combination of H-FABP, midkine and sTNFR2 had the highest predictive ability to identify AKI risk (AUROC 0.836). Preoperative clinical risk factors included patient age, body mass index and diabetes. Perioperative factors included cardio pulmonary bypass, cross-clamp and operation times, intra-aortic balloon pump, blood products and resternotomy. Combining biomarker risk score (BRS) with clinical risk score (CRS) enabled pre and postoperative assignment of patients to AKI risk categories. Combining BRS with CRS will allow better management of cardiac patients at risk of developing AKI.


The influence of congenital and developmental cataract surgery on the ocular surface in a six-month follow-up prospective clinical study.
The purpose of this study was to identify changes in tear film function and meibomian gland function in children after congenital/developmental cataract surgery. This study enrolled 16 eyes of 16 congenital/developmental cataract patients (mean age: 8.05 ± 1.43 years) who underwent cataract surgery and 16 eyes of 16 normal volunteers (mean age: 8.31 ± 2.18 years). Clinical assessments were conducted preoperatively and at 1 week, 1, 3 and 6 months postoperatively. Symptom questionnaires, non-invasive tear film break-up time, tear meniscus height, corneal fluorescein staining, lid margin abnormality, meibomian gland expressibility, and meibography were assessed. The ocular symptom score was significantly higher in congenital/developmental cataract patients compared to normal controls during the 5 visits (P = 0.009). And the average non-invasive tear film break-up time was significantly lower in congenital/developmental cataract patients compared to normal controls (P = 0.017). The first non-invasive tear film break-up time and average non-invasive tear film break-up time were lowest at 1 month postoperatively compared to baseline levels (P = 0.008 and P = 0.012, respectively). The lid margin score of the upper eyelid was significantly higher in congenital/developmental cataract patients compared to normal controls at 1 week postoperatively (P = 0.027). The meibum expressibility score decreased significantly during the 5 visits (P = 0.024). No significant difference was observed in meibomian gland tortuosity, meibomian gland width, meibomian gland area and meibomian gland length between the congenital/developmental group and normal controls preoperatively and at 6 months postoperatively (P > 0.05). Tear film stability and meibomian gland function are worsened transiently after congenital/developmental cataract surgery without accompanying meibomian gland morphological changes.


Determination of selected polychlorinated biphenyls in soil by miniaturised ultrasonic solvent extraction and gas chromatography-mass-selective detection.
Miniaturised ultrasonic solvent extraction procedure was developed for the determination of selected polychlorinated biphenyls (PCBs) in soil samples by gas chromatography-mass-selective detection by using 2(3) factorial experimental design. Recoveries of PCBs from fortified soil samples are over 90% for three different fortification levels between 40 and 120 microg kg(-1), and relative standard deviations of the recoveries are below 7%. The limits of detection (LODs) ranged from 0.003 to 0.006 microg kg(-1). The performance of the proposed method was compared to traditional shake flask extraction method on the spiked real soil sample and extraction methods showed comparable efficiencies. Proposed miniaturised ultrasonic solvent extraction offers several advantages, i.e., reducing sample requirement for measurement of target compound, less solvent consumption and reducing the costs associated with solvent purchase and waste disposal.


Ultrastructural characteristics and lysozyme content in hypergranular and variant type of acute promyelocytic leukaemia.
We investigated the electronmicroscopic (EM) features and cellular lysozyme (LZ) content in 16 cases of acute promyelocytic leukaemia (APL): 11 cases of the hypergranular form (M3) and five cases of the microgranular variant (M3-V). The main EM features in all cases were: irregular, folded or bilobed nuclei, many cytoplasmic granules, distended rough endoplasmic reticulum (RER) cisternae which, in some cases, presented as stellate forms (more frequent in M3-V), and bundles of cytoplasmic microfilaments. Many Auer rods were present in M3 cases and few in M3-V; most of these disclosed parallel tubular arrays (PTA) with a varied periodicity ranging from 13 to 26 nm. There was a significant difference between M3 and M3-V (P<0.0001) in both the number of granules per cell section (62.9 +/- 34.5 v 38.0 +/- 23.6) and in the granule section area (0.044 +/- 0.033 v 0.026 +/- 0.015 microm2). In some cases, mainly in M3-V, we found cells with large granules containing PTA which probably represent poorly developed Auer rods. Intracellular LZ content assayed by a post-embedding immunogold method, showed high granular LZ density (in the range of that found in M4 and M5) in M3 cells and very low granular LZ content in M3-V. This study adds new objective parameters for the diagnosis of these two types of APL and provides new information on their LZ pattern of expression.


Tourette syndrome: associated symptoms and most disabling features.
Four hundred forty-six patients with Tourette Syndrome (TS) and/or their parents completed a 52-item self-report survey about vocal and motor tics, and the frequency of associated co-morbid conditions of aggression, obsessions and compulsions, attentional problems, sleep disturbance, mood disturbance, anxiety, and self-mutilative behaviours which have been frequently reported in the literature on TS. Respondents also responded to an open-ended question regarding the most disabling aspects of TS. Results were analyzed within two age groups; under 18 years of age (N = 245) and 18 years of age or older (N = 177). Tics and associated conditions were the most frequently reported disabling aspect by both age groups. Subjects under age 18, however, reported significantly more frequent problems with hyperactivity, temper control, aggressive behaviours and sleepwalking than adults with TS.


Inhibition of NK cell-induced cytolysis by thiocarbamide antithyroid drugs.
The thiocarbamide antithyroid drugs, methimazole and propylthiouracil, suppressed natural killer (NK) cell-induced cytolysis in vitro (determined by the release of 51Cr-chromate from labelled target cells) in a dose-dependent manner. Parallel experiments demonstrated a similar reduction in NK cell luminol chemiluminescence during activation by K562 tumour cells. It would appear, therefore, that an association may exist between NK cell-induced cytolysis and the peroxidase/oxygenase activity of these lymphocytes.


A 'periodic table' for protein structures.
Current structural genomics programs aim systematically to determine the structures of all proteins coded in both human and other genomes, providing a complete picture of the number and variety of protein structures that exist. In the past, estimates have been made on the basis of the incomplete sample of structures currently known. These estimates have varied greatly (between 1,000 and 10,000; see for example refs 1 and 2), partly because of limited sample size but also owing to the difficulties of distinguishing one structure from another. This distinction is usually topological, based on the fold of the protein; however, in strict topological terms (neglecting to consider intra-chain cross-links), protein chains are open strings and hence are all identical. To avoid this trivial result, topologies are determined by considering secondary links in the form of intra-chain hydrogen bonds (secondary structure) and tertiary links formed by the packing of secondary structures. However, small additions to or loss of structure can make large changes to these perceived topologies and such subjective solutions are neither robust nor amenable to automation. Here I formalize both secondary and tertiary links to allow the rigorous and automatic definition of protein topology.


[Technical principles of incisional hernia surgery].
Many publications are available on the best surgical techniques and treatment of incisional hernias with reports of experiences and randomized clinical studies at the two extremes of the evidence scale. The ultimate proof of the best operative technique has, however, not yet been achieved. In practically no other field of surgery are the variability and the resulting potential aims of surgery so great. The aim of surgery is to provide patients with the optimal recommendation out of a catalogue of possibilities from a holistic perspective. This article describes the surgical techniques using meshes for strengthening (in combination with an anatomical reconstruction) and for replacement of the abdominal wall (with bridging of the defect).


High-temperature tribological performance of stir-cast and heat-treated EV31A magnesium alloy: Experiments and predictions.
The temperature effect on the wear behaviour of EV31A Mg alloy during dry sliding wear was investigated. Wear tests were carried out at 50, 100, 150, 200, and 250 °C using a standard load of 10 N and a sliding distance of 1000 m. Weight loss method was used to calculate the wear rate. Optical microscopy was used to examine the microstructure of the EV31A alloy. FE-SEM with EDS analysis was used to investigate the wear morphology, and XRD analysis was performed both before and after the wear test. A high wear coefficient (K) value (more than 10-4) indicates extreme wear for EV31A in all the scenarios. T4 EV31A had a maximum wear rate of 20.2 mg at 150 °C. The as-cast EV31A alloy exhibits an excellent wear rate at the price of mechanical properties under all test scenarios. Wear resistance is improved by Nd and Zr oxides, although Mg and Gd oxides have little effect. Zn has no effect on the wear behaviour of the EV31A. In as-cast, T4, and T6 heat-treated conditions, the EV31A alloy exhibits delamination (abrasive wear), oxide development (corrosive wear), and delamination mixed with plastic deformation (adhesive wear). A Three-layered ANN and adapted Fine Gaussian SVM predicted tribological characteristics. In ANN prediction, the maximum R2 was 0.99 for CoF and 0.89 for wear rate, respectively. Despite the fact that the study's normal load is constant, machine learning models allow to deduce that temperature and normal load are the main influential parameters in CoF and wear rate, respectively.


[Morphofunctional research on the interrenal gland of the frog Rana temporaria following arginine vasotocin administration].
Studies have been made of the effect of injections of hypothalamic nonapeptide neurohormone, arginine vasotocin, on functional condition of the interrenal gland in mature frogs. In unoperated, sham-operated and in animals 10 days after hypophysectomy, single and especially three subsequent injections of arginine vasotocin (5 x 10(-9) M per 1 kg of the body weight) result in evident activation of glandular cells of the interrenal gland which is manifested in the increase of the volume of their nuclei and cytoplasmic area, as well as in the dilatation of the blood vessels. Activation of the interrenal gland in hypophysectomized frogs, which lack endogenous ACTH, indicate the direct para-adenohypophyseal influences of nonapeptide hypothalamic hormones on the activity of glandular cells in the peripheral endocrine glands, in particular, the interrenal gland of the grass frog.


Curing bacteria of antibiotic resistance: reverse antibiotics, a novel class of antibiotics in nature.
By screening cultures of soil bacteria, we re-discovered an old antibiotic (nybomycin) as an antibiotic with a novel feature. Nybomycin is active against quinolone-resistant Staphylococcus aureus strains with mutated gyrA genes but not against those with intact gyrA genes against which quinolone antibiotics are effective. Nybomycin-resistant mutant strains were generated from a quinolone-resistant, nybomycin-susceptible, vancomycin-intermediate S. aureus (VISA) strain Mu 50. The mutants, occurring at an extremely low rate (<1 × 10(-11)/generation), were found to have their gyrA genes back-mutated and to have lost quinolone resistance. Here we describe nybomycin as the first member of a novel class of antibiotics designated 'reverse antibiotics'.


Achieving Minimum Standards for Infection Prevention and Control in Sierra Leone: Urgent Need for a Quantum Leap in Progress in the COVID-19 Era!
Good Infection prevention and control (IPC) is vital for tackling antimicrobial resistance and limiting health care-associated infections. We compared IPC performance before (2019) and during the COVID-19 (2021) era at the national IPC unit and all regional (4) and district hospitals (8) in Sierra Leone. Cross-sectional assessments using standardized World Health Organizations IPC checklists. IPC performance scores were graded as inadequate = 0-25%, basic = 25.1-50%, intermediate = 50.1-75%, and advanced = 75.1-100%. Overall performance improved from 'basic' to 'intermediate' at the national IPC unit (41% in 2019 to 58% in 2021) and at regional hospitals (37% in 2019 to 54% in 2021) but remained 'basic' at district hospitals (37% in 2019 to 50% in 2021). Priority gaps at the national IPC unit included lack of: a dedicated IPC budget, monitoring the effectiveness of IPC trainings and health care-associated infection surveillance. Gaps at hospitals included no assessment of hospital staffing needs, inadequate infrastructure for IPC and lack of a well-defined monitoring plan with clear goals, targets and activities. Although there is encouraging progress in IPC performance, it is slower than desired in light of the COVID-19 pandemic. There is urgent need to mobilize political will, leadership and resources and make a quantum leap forward.


Review of Loteprednol Etabonate 0.5%/Tobramycin 0.3% in the Treatment of Blepharokeratoconjunctivitis.
Use of a combination corticosteroid and antibiotic in a single formulation is common in the treatment of ocular inflammatory conditions for which corticosteroid therapy is indicated and there exists a risk of superficial bacterial infection. Loteprednol etabonate (LE) is a corticosteroid engineered to maintain potent anti-inflammatory activity while minimizing the risk of undesirable class effects of corticosteroids, such as elevated intraocular pressure and cataract. Tobramycin is a broad-spectrum aminoglycoside antibiotic that is considered generally safe and well tolerated. An ophthalmic suspension combining LE 0.5% and tobramycin 0.3% (LE/T) is approved in the US and several other countries. Use of a combination therapy increases convenience, which may promote patient adherence. A systematic literature review was conducted to examine the efficacy and safety of LE/T for ocular inflammatory conditions within the scope of its labeled indications. Results of published studies indicate that LE/T is effective in the treatment of blepharokeratoconjunctivitis in adults, with similar efficacy as dexamethasone 0.1%/tobramycin 0.3%, but is associated with a lower risk of clinically significant increases in intraocular pressure as demonstrated in both efficacy and safety studies and studies with healthy volunteers. Furthermore, studies in children with blepharitis or blepharoconjunctivitis indicate LE/T was well tolerated in this population, although efficacy vs vehicle was not demonstrated, potentially due to improvements in all groups overall and/or limited sample size. Separately, tobramycin demonstrated potent in vitro activity against most bacterial species associated with blepharitis. In conclusion, published data demonstrate the utility of LE/T for the treatment of the various clinical manifestations of blepharokeratoconjunctivitis in adults.


Bio-based poly (γ-glutamic acid) hydrogels reinforced with bacterial cellulose nanofibers exhibiting superior mechanical properties and cytocompatibility.
Natural polymer hydrogels are expected to be promising biomaterial because of its excellent biocompatibility and biodegradability, but they are soft and easily broken. Herein, the poly (γ-glutamic acid) (γ-PGA)/bacterial cellulose (BC) composite hydrogels with excellent mechanical properties were constructed by introducing bacterial cellulose. The γ-PGA/BC composite hydrogels were obtained by the covalent cross-linking of γ-PGA in the BC nanofibers suspensions. The γ-PGA/BC composite hydrogels exhibited excellent strength and toughness due to the more effective energy dissipation of hydrogen bonds network among BC nanofibers and γ-PGA hydrogel matrix and BC also acts as an enhancer. The compressive fracture strength and toughness of the γ-PGA/BC composite hydrogels could reach up to 5.72 MPa and 0.42 MJ/m3 respectively. Additionally, the tensile strength of γ-PGA/BC composite hydrogels were improved 8.16 times compared with γ-PGA single network hydrogels. More significantly, BC could disperse evenly in the γ-PGA hydrogels because of the hydrophilic nature of γ-PGA and BC nanofillers, which led to good interface compatibility. The result of cytotoxicity tests indicated that γ-PGA/BC composite hydrogels present excellent cytocompatibility, which suggested that the γ-PGA/BC composite hydrogels could serve as promising materials for many biomaterial related applications.


Performance of the pooled cohort equations in cancer survivors: the Atherosclerosis Risk in Communities study.
Cancer survivors may have elevated atherosclerotic cardiovascular disease (ASCVD) risk. Therefore, we tested how accurately the American College of Cardiology/American Heart Association 2013 pooled cohort equations (PCEs) predict 10-year ASCVD risk in cancer survivors. To estimate the calibration and discrimination of the PCEs in cancer survivors compared to non-cancer participants in the Atherosclerosis Risk in Communities (ARIC) study. We evaluated the PCEs' performance among 1244 cancer survivors and 3849 cancer-free participants who were free of ASCVD at the start of follow-up. Each cancer survivor was incidence-density matched with up to five controls by age, race, sex, and study center. Follow-up began at the first study visit at least 1 year after the diagnosis date of the cancer survivor and finished at the ASCVD event, death, or end of follow-up. Calibration and discrimination were assessed and compared between cancer survivors and cancer-free participants. Cancer survivors had higher PCE-predicted risk, at 26.1%, compared with 23.1% for cancer-free participants. There were 110 ASCVD events in cancer survivors and 332 ASCVD events in cancer-free participants. The PCEs overestimated ASCVD risk in cancer survivors and cancer-free participants by 45.6% and 47.4%, respectively, with poor discrimination in both groups (C-statistic for cancer survivors = 0.623; for cancer-free participants, C = 0.671). The PCEs overestimated ASCVD risk in all participants. The performance of the PCEs was similar in cancer survivors and cancer-free participants. Our findings suggest that ASCVD risk prediction tools tailored to survivors of adult cancers may not be needed.


Sphingosine Kinase 1 is Associated With Immune Cell-Related Gene Expressions in Human Breast Cancer.
Although previous experiments have implicated sphingosine-1-phosphate (S1P) as a links between immune reactions and cancer progression, the exact mechanism of this interaction has not comprehensively studied in clinical human samples. This study sought to evaluate the S1P regulation by sphingosine kinase 1 (SPHK1), an S1P-producing enzyme, in the immunity/immuno-reactivity of clinical human breast cancer surgical specimens. S1P levels were examined in tumor, peritumoral, and normal human breast samples using mass spectrometry. Genomics Data Commons data portal of The Cancer Genome Atlas cohort was used to assess the expression of S1P-related and immune-related genes. S1P levels were significantly higher in tumor samples compared to peritumoral (P < 0.05) or normal human breast samples (P < 0.001). SPHK1 gene expression was elevated in tumoral samples compared to normal breast samples (P < 0.01). Furthermore, the elevated expression of SPHK1 in breast cancer tissue was associated with an increased expression of the different kinds of immune-related genes, such as CD68, CD163, CD4, and FOXP3 (forkhead box P3), in HER2-negative breast cancer. Network analysis showed the central role of SPHK1 in the interaction of S1P signaling and expression of immune cell-related proteins. We demonstrated that S1P is mainly produced by tumor tissue, rather than peritumoral tissue, in breast cancer patients. Our data revealed the involvement of S1P signaling in the regulation of immune-related genes, suggesting the links between S1P and complicated immune-cancer interactions in breast cancer patients.


Geostatistical spatial projection of geophysical parameters for practical aquifer mapping.
Dense data acquisition for 3-D high-resolution aquifer mapping through heliborne transient electromagnetic (HTEM) survey is continually not possible due to various technical and administrative constraints. Consequently, we apply ground geophysical surveys at possibly closer spacing to collect the sub-surface information in the no-fly area, which provides only a regional aquifer picture. In the area near Patna of Northern India, an extent of 18% was covered under the HTEM survey, and the rest was surveyed by ground geophysical methods. Both data are integrated using the theory of regionalized variables. The parameters of multi-aquifers i.e., top of the first aquifer, top of the separating clay layer, top and the bottom of second aquifer, are estimated together with their respective resistivities. The estimations are made at an interval of 250 m, practically an appropriate distance at which dense data generation was carried out using the HTEM survey. The integrated approach generates the data in the no-fly area with the same spatial density as the flown area. With this, we achieved the goal of completing the 3-D aquifer mapping of the entire area with dense data at high spatial resolution. This is a unique finding to manage the handicapped situation in this HTEM surveys, and an aide to overcome such constraints with cost-effectiveness.


A rare case of non-small cell lung cancer metastasizing to the pituitary gland: detection with (18)F-FDG PET-CT.
Metastases to the pituitary gland are rare. We here present a case of a 52-year-old man with non-small cell lung cancer where pituitary metastasis was detected on staging F-FDG PET-CT, characterized with MRI and confirmed at histopathology. By demonstrating such rare site of metastasis, F-FDG PET-CT can have significant impact on management of cancer patients.


Effects of n-3 PUFA supplementation on plasma soluble adhesion molecules: a meta-analysis of randomized controlled trials.
Previous studies indicate that oral supplementation with n-3 PUFA protects against atherosclerotic disease by inhibiting inflammatory processes, which underlie atherosclerosis and are reflected by the plasma concentrations of soluble adhesion molecules. However, consistent results were not obtained among studies. The objective was to assess the effects of n-3 PUFA supplementation on plasma concentrations of soluble adhesion molecules. We conducted a meta-analysis of randomized controlled trials identified from PubMed, Embase, the Cochrane Library, and reference lists of relevant articles and reviews. Eighteen studies were included. n-3 PUFA supplementation reduced plasma concentrations of soluble intercellular adhesion molecule-1 [sICAM-1; weighted mean difference (WMD): -5.17; 95% CI: -10.07, -0.27; P = 0.04] but had no significant effects on soluble vascular cell adhesion molecule-1 (WMD: -5.90; 95% CI: -17.63, 5.84; P = 0.32), soluble P-selectin (WMD: -1.53; 95% CI: -4.33, 1.28; P = 0.29), or soluble E-selectin (WMD: 0.46; 95% CI: -1.54, 2.46; P = 0.65). Subgroup analysis stratified by the subjects' health status showed that n-3 PUFA supplementation reduced sICAM-1 concentrations in healthy subjects (WMD: -8.87; 95% CI: -15.20, -2.53; P = 0.006; heterogeneity test: I² = 0%, P = 0.76) and in subjects with dyslipidemia (WMD: -15.31; 95% CI: -26.82, -3.81; P = 0.009; heterogeneity test: I² = 26%, P = 0.26). n-3 PUFA supplementation can reduce plasma concentrations of sICAM-1. The effect is identified in both healthy subjects and subjects with dyslipidemia, which supports the hypothesis that n-3 PUFA can be supplemented as a primary or secondary means for preventing the development as well as the progression of atherosclerosis.


The role of loops 3 and 4 in the interdomains and intersubunits communication of E. coli cAMP receptor protein.
Cyclic AMP serves as an intracellular messenger in cells and regulates a variety of biological functions by transmitting information through proteins. These proteins of different functions all consist of a cAMP-binding motif, and the structure of this motif is highly conserved with an exception of the loop 3 and 4. In current study, cAMP receptor protein was employed as a model system to investigate the function of the two loops. The results indicated that the loop 3 involves in the intersubunits communication of CRP, whereas the loop 4 involves in cAMP binding and interdomains communication.


Value of (18)F-FDG-PET/CT in patients with fever of unknown origin and unexplained prolonged inflammatory syndrome: a single centre analysis experience.
The aim of our study was to evaluate the diagnostic contribution of (18)F-fluoro-deoxyglucose ((18)F-FDG)-positron emission tomography (PET)/computed tomography (CT) in patients with fever of unknown origin (FUO) or unexplained prolonged inflammatory syndrome (UPIS) in real life. We performed a retrospective study including 14 patients with FUO or UPIS hospitalised in our institution (Strasbourg University Hospital, France) between January 2005 and July 2006. (18)F-FDG-PET/CT was considered helpful when abnormal results allowed an accurate diagnosis. (18)F-FDG-PET/CT was helpful in half the patients (7/14) for final diagnosis. A diagnosis was reached in 87.5% of the patients (7/8) with an abnormal (18)F-FDG-PET/CT but only in 50% of the patients (3/6) with a normal (18)F-FDG-PET/CT. Conventional chest and abdominal CT was performed in 13 patients before ordering (18)F-FDG-PET/CT. We considered that (18)F-FDG-PET/CT was essential to establish the final diagnosis in only 23% of the patients (3/13) since neither chest nor abdominal CT identified abnormalities consistent with the final diagnosis. However, among the three patients, two were diagnosed with large vessel vasculitis and one patient with local prosthetic infection. Our study supports the potential interest of (18)F-FDG-PET/CT in the diagnostic workup of FUO and UPIS as it helped establish a fine diagnosis in half of the cases. However, (18)F-FDG-PET/CT appeared to be essential to the final diagnosis in only 23% of the cases. In our opinion, this protocol should be performed as a second level test, especially when conventional CT is normal or is unable to discriminate between active and silent lesions.


HER2 chimeric antigen receptor T cell immunotherapy is an effective treatment for diffuse intrinsic pontine glioma.
Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMG) of the thalamus and spinal cord are rare but devastating high-grade glial tumors of childhood with no curative treatment. Despite aggressive treatment attempts the prognosis has remained poor. Chimeric antigen receptor (CAR) T cell therapy has been identified as a promising new approach in the treatment of DMG tumors; however, additional targets are urgently required given known tumor heterogeneity and the prospect of antigen escape of this cancer. Using cell surface mass spectrometry, we detected high HER2 cell surface protein across a panel of patient-derived DIPG cells, thereby identifying an existing CAR T cell therapy for use in DIPG. Primary human T cells were transduced to express a second-generation HER2 CAR and interrogated for efficacy against patient-derived DIPG cells. HER2 CAR T cells demonstrated potent and antigen-specific cytotoxicity and cytokine secretion when co-cultured with patient-derived DIPG cells. Furthermore, HER2 CAR T cells provided a significant regression in intracranial DIPG xenograft tumors. HER2 CAR T cells are already in clinic development and are well tolerated in pediatric patients. Here we provide strong preclinical evidence for the inclusion of DIPG patients in future pediatric CNS tumor HER2 CAR T cell clinical trials.


Clinical and radiological outcomes of arachnoid-preseving suboccipital decompression for adult chiari I malformation with and without syringomyelia.
To share our experience related to clinic and radiologic outcomes of patients with Chiari I malformation. This retrospective study evaluated surgical outcome of 48 patients who underwent posterior fossa decompression and duraplasty with arachnoid-preservation technique February 2010 and February 2019. Clinic and radiologic outcomes at long-term follow-up were provided. Surgery led to satisfactory outcomes in both clinic and radiologic measures. The majority of patients (66.7%) in the follow-up period informed us that their symptoms significantly improved. In 14 patients (29.2%), the symptoms were gone totally and no complaining was reported to us. Syringomyelia was encountered in 21 patients (43.7%) on pre-operative MRI. During long-term, significant improvement (syrinx segments were remarkably reduced in diameter) in syrinx size was noted in 16 of the 21 patients (76.1%). In 5 of the 21 patients (23.8), complete improvement, that is, syrinxes were totally collapsed, was seen. Surgery-related complications occurred in a total of 5 patients (10.4%). In our experience, we found decompressive craniectomy wide enough with duraplasty without arachnoid opening is safe and successful in patients with CIM. Complication rate is low and arachnoid preserving technique should be performed by experienced neurosurgeons.


Adipose-derived stromal/stem cells are verified to be potential seed candidates for bio-root regeneration in three-dimensional culture.
Bio-root regeneration is a promising treatment for tooth loss. It has been reported that dental-derived stem cells are effective seed cells for bio-root construction, but further applications are limited by their few sources. Human adipose tissues have a wide range of sources and numerous studies have confirmed the ability of adipose-derived stromal/stem cells (ASCs) in regenerative medicine. In the current study, the odontogenic capacities of ASCs were compared with dental-derived stem cells including dental follicle cells (DFCs), and stem cells from human exfoliated deciduous teeth (SHEDs). The biological characteristics of ASCs, DFCs, and SHEDs were explored in vitro. Two-dimensional (2D) and three-dimensional (3D) cultures were compared in vitro. Odontogenic characteristics of porcine-treated dentin matrix (pTDM) induced cells under a 3D microenvironment in vitro were compared. The complexes (cell/pTDM) were transplanted subcutaneously into nude mice to verify regenerative potential. RNA sequencing (RNA-seq) was used to explore molecular mechanisms of different seed cells in bio-root regeneration. 3D culture was more efficient in constructing bio-root complexes. ASCs exhibited good biological characteristics similar to dental-derived stem cells in vitro. Besides, pTDM induced ASCs presented odontogenic ability similar to dental-derived stem cells. Furthermore, 3D cultured ASCs/pTDM complex promoted regeneration of dentin-like, pulp-like, and periodontal fiber-like tissues in vivo. Analysis indicated that PI3K-Akt, VEGF signaling pathways may play key roles in the process of inducing ASCs odontogenic differentiation by pTDM. ASCs are potential seed cells for pTDM-induced bio-root regeneration, providing a basis for further research and application.


Pharmacist recommendations for carbapenem de-escalation in urinary tract infection within an antimicrobial stewardship program.
Carbapenem antibiotics are considered the treatment of choice for serious extended-spectrum beta-lactamase-producing Gram-negative bacteria infections. Our objectives were to analyze the results of carbapenem de-escalation therapy in complicated urinary tract infections (UTIs) attended in a third-level Spanish hospital and to evaluate the impact of pharmacist recommendation in this practice, the outcomes obtained, and associated factors. This prospective observational study of carbapenem prescriptions and de-escalation performance was conducted in a third-level hospital between August 1 2013 and July 31, 2014. Data were gathered on carbapenem treatment duration, de-escalation, length of hospital stay, mortality rate, and associated re-admissions. De-escalation, which was only ordered for patients with positive cultures, was conducted in 49.7% of the 163 patients with complicated UTI. More than half (69.1%) of pharmacist interventions were accepted. De-escalation reduced the median hospital stay by five days (p=0.030). Crude hospital mortality was lower in the de-escalation group (7.4% vs. 29.3%, p<0.001), although their exposure to carbapenems was lower (4 vs 6 days, p<0.001). Factors associated with de-escalation were ICU stay for at least 48h, pharmacist recommendation and ESBL or AmpC producing Enterobacteriaceae. Factors associated with in-hospital mortality were age, previous admission and duration of hospital stay, but not pharmacist recommendation. Otherwise, carbapenem de-escalation was associated as a protective factor against in-hospital mortality. Carbapenem de-escalation in accordance with pharmacist recommendation proved to be a safe approach in complicated UTI, reducing the hospital stay of patients without affecting the re-admission rate.


Conversion to Once-Daily Tacrolimus Results in Increased p38MAPK Phosphorylation in T Lymphocytes of Kidney Transplant Recipients.
The once-daily formulation of tacrolimus (TAC(OD)) has been developed to overcome adherence problems. Conversion from the twice-daily TAC (TAC(BID)) formulation to TAC(OD) on a 1:1 basis, however, often leads to a decrease of TAC predose concentrations, which averages ∼15%. Switching between the two TAC formulations may thus influence drug efficacy and necessitates therapeutic drug monitoring. As an additional tool in transplantation diagnostics, phospho-specific flow cytometry was used to study the biological effects of conversion on p38MAPK phosphorylation, a kinase involved in T-lymphocyte activation. Stable renal transplant recipients (n = 12), at least 1 year after their transplantation, were converted from TAC(BID) to TAC(OD) on 1:1 mg for mg base. Comedication consisted of mycophenolate mofetil (n = 10) and prednisolone (n = 3). TAC whole-blood predose concentrations were determined by immunoassay before and 3 months after conversion. P38MAPK phosphorylation was measured in T lymphocytes by whole-blood phospho-specific flow cytometry. Three months after conversion, no significant decreases in TAC predose concentrations (C0) were found (P = 0.54), whereas p38MAPK phosphorylation increased with 11.4% (P < 0.05) in CD4 and with 15.6% (P < 0.05) in CD8 T lymphocytes. The TAC C0 during treatment with TAC(BID) correlated inversely with p38MAPK phosphorylation in T lymphocytes (rs = -0.638; P < 0.05). These results suggest that the measurement of p38MAPK phosphorylation status in T lymphocytes is a sensitive method to determine the biological effects of TAC before and after conversion from TAC(BID) to TAC(OD). This method could be a more sensitive tool for therapeutic drug monitoring of TAC.


Evaluation of Racial Microaggressions Experienced During Medical School Training and the Effect on Medical Student Education and Burnout: A Validation Study.
Microaggressions in the learning environment have been documented at various levels of medical training. However, there is lack of data detailing the prevalence and effects of racial microaggressions in medical school. This limits interventions that might improve the learning environment for underrepresented minority medical students (URMMS). This study describes the creation and validation of a survey instrument characterizing the experience of microaggressions in medical school and their impact on medical student education and burnout. An anonymous survey instrument was adapted for medical students from the validated Racial and Ethnic Microaggressions Scale (REMS) and distributed to the national listservs of the Student National Medical Association (SNMA), Latino Medical Student Association (LMSA), and the Asian Pacific American Medical Student Association. Responses were categorized into two cohorts: under-represented minority (URM) and non-URM based on self-reported race or ethnicity. A total of 217 responses were collected from medical students across the United States, with 148 (68.2%) students identifying as URM. URM respondents were significantly (p < 0.05) more likely to report experiencing race-related microaggressions during medical school (55% vs 31%), and to report that these microaggressions contributed to feelings of burnout (62% vs 29%) and compromised learning (64% vs 49%). URM students were significantly less likely to feel that adequate resources were available to address microaggressions (26% vs 39%, p < 0.05). Our results suggest that microaggressions experienced by URMMS can be evaluated using an adapted REMS. Additionally, the experience of microaggressions negatively impact the learning environment, and students feel the availability of sufficient resources to address microaggressions and their effects are lacking. Further research is needed to evaluate microaggressions and their impact on a larger scale. This should be followed by interventions to minimize the frequency and impact of these microaggressions.


Saccular Aneurysm of the Internal Jugular Vein in an Adult Patient and Its Surgical Treatment.
Congenital jugular vein aneurysm in an adult patient is a rare condition. A 17-year-old patient presented to the authors' clinic with left neck swelling. The clinical and radiological findings were appropriate with the internal jugular vein aneurysm. The authors detailed their experience in the surgical treatment of this true saccular aneurysm. Jugular venous aneurysm is a rare benign venous pathology and it can be easily confused with other neck pathologies. Its surgical excision can be sometimes difficult and troublesome than expected.


[Errors in medical care rendered by military treatment and prevention institutions (according to the data of forensic medical expertise].
The authors discuss one of the important aspects of military medicolegal laboratory activities connected with the quality control of medical care rendered in the military treatment-and-prophylactic institutions in the nineties of the XX century. The example of medical care defects (MCD) permitted to reveal their nature, causes and sites of origin at pre-hospital (PHS) and hospital (HS) stages. Despite some decrease in the total number of MCD revealed HS defects prevail (more than 75%); the organizational defects at PHS and diagnostic defects at HS are predominant. The main MCD causes are inadequate qualification of medical workers, defects in organization of treatment-and-diagnostic process and inadequate examination of patients.


Differential effects of homocysteine on porcine endothelial and vascular smooth muscle cells.
High concentrations of homocysteine damage endothelial cells and lower concentrations increase vascular smooth muscle cell (VSMC) growth. This study investigated the effects of various concentrations of homocysteine on endothelial cells (VECs) and VSMCs in terms of cell survival, proliferation, and function. VECs and VSMCs from porcine thoracic aorta were studied. These cells were exposed to homocysteine in concentrations of 20 microM, 400 microM, and 1 mM every 8 h for 24 h, and its effect on cell survival, proliferation, and function were studied using methylthiazoletetrazolium assay, [3H]-thymidine incorporation test, and 6-keto-prostaglandin F1alpha enzyme-linked immunosorbent assay for VECs, and platelet-derived growth factor (PDGF) enzyme-linked immunosorbent assay for VSMCs, respectively. In VECs, 20 microM of homocysteine reduced the viable cell count to 95 +/- 31%, 400 microM reduced it to 89 +/- 35%, 1,000 microM reduced it to *58 +/- 29% (control = 100 +/- 30%, n = 18, *p < 0.05). In VSMCs, 20 microM of homocysteine slightly increased the viable cell count to 106 +/- 30%, but there was no statistical significance; 400 microM of homocysteine reduced the viable cell count to *74 +/- 29%, 1,000 microM to *50 +/- 24% (control = 100 +/- 28%, n = 18, *p < 0.05). In VECs, 20 microM of homocysteine reduced [3H]-thymidine uptake by 98 +/- 14%, 400 microM reduced it by *82 +/- 17%, 1,000 microM reduced it by *66 +/- 17% (control = 100 +/- 12, n = 6, *p < 0.05), respectively. But in VSMCs, 20 microM of homocysteine significantly increased [3H]-thymidine uptake (*131 +/- 16%), and thereafter, homocysteine decreased VSMCs [3H]-thymidine uptake, 400 microM by *24 +/- 7%, 1,000 microM by *29 +/- 10% (control = 100 +/- 16, n = 6, *p < 0.05), respectively. Homocysteine decreased VEC prostacyclin secretion in a dose-dependent manner, 20 microM by 105 +/- 0.65 pg/100 microl, 400 microM by *100 +/- 2.37 pg/100 microl, 1,000 microM by *93 +/- 2.54 pg/100 microl (control = 107 +/- 1.26 pg/100 microl, n = 6, *p = 0.007). In VSMCs, 20 microM of homocysteine slightly increased PDGF secretion by 62.2 +/- 20.7 pg/100 microl, but there was little statistical significance (p = 0.13); 400 microM of homocysteine reduced PDGF secretion by *28.9 +/- 10.7 pg/100 microl, and 1,000 microM reduced it by *21.3 +/- 4.7 pg/100 microl (control = 54.5 +/- 9.3 pg/100 microl, n = 6, *p < 0.05). High concentrations of homocysteine damaged both VECs and VSMCs with respect to cell survival, proliferation, and function. By increasing exposure to homocysteine, it was shown that physiologic high concentrations of homocysteine enhanced VSMC proliferation.


Discriminating somatic evoked potentials using a pairwise procedure.
Generally, investigators use only the magnitude spectra of a signal for processing or for discriminant analysis, with the phase information discarded. However, it is not difficult to generate two different time domain signals having identical magnitude spectra in the frequency domain. Thus the phase information should not be neglected. This paper presents the results of a simulation study of a discriminant analysis procedure for paired variables, e.g. magnitude and phase pairs. The procedure is then applied to discriminating somatic evoked potentials from normal and damaged spinal cords with excellent results.


Risk factors for bovine tuberculosis in New Zealand cattle farms and their relationship with possum control strategies.
This paper reports the investigation of farm-level risk factors for confirmed bovine tuberculosis (TB), based on a retrospective cohort study of a population of cattle in the lower North Island of New Zealand. Data were obtained from the TB testing surveillance programme operational in this area since the mid-1970s and comprised 190,665 cattle-years at risk from July 1980 to June 2004 (inclusive). A mixed-effects Poisson regression model was used to investigate the influence of farm-level covariates on the number of cattle confirmed with TB throughout the study period. This model was interpreted in context of depopulation strategies for the wildlife reservoir for TB, the brushtail possum Trichosurus vulpecula, that were applied in this area. The model showed that, despite intensification of possum control strategies over time, proximity to forest parks (a principal possum habitat in this area) remained a significant predictor of the number of confirmed cases of TB detected per farm per year. Our analyses showed a significant, three-fold increase in TB risk in dairy cattle relative to beef conditional on the size of local possum habitat, and confirmed the positive influence of cattle population size and the presence of previous infection status as a determinant of the number of confirmed TB cases per farm per year.


Detection of microhemorrhage in posterior reversible encephalopathy syndrome using susceptibility-weighted imaging.
PRES-related vasogenic edema is potentially reversible while hemorrhage occurs in only 15.2%-17.3% of patients. However, the true incidence of hemorrhage could be higher when SWI is considered. Thus, we set out to determine the incidence of MH, SAH, and IPH in PRES by using SWI and to particularly evaluate whether such MHs are reversible. Thirty-one patients with PRES and SWI were included, 17 having follow-up SWI. Two neuroradiologists reviewed SWI, FLAIR, DWI, and CE-T1WI. The presence and number of MHs (<5 mm) on SWI, SAH, and IPH (>5 mm) were recorded at presentation and follow-up. We evaluated associations between the presence of MH on SWI and DWI lesions, SAH, IPH, contrast enhancement, and MR imaging severity. Hemorrhage was present in 20/31 patients (64.5%), with MHs on SWI in 18/31 (58.1%) at presentation and in 11/17 (64.7%) at follow-up. SAH was present in 3/31 on SWI and 4/31 on FLAIR, while 2/31 had IPH. At follow-up, no patients had acquired new MHs; 2/5 MHs in 1 patient resolved. Four patients with available SWI before PRES developed MHs after PRES onset. No association was found between the presence of MHs on SWI and DWI, SAH, IPH, enhancement, and MR imaging severity (all P > .05). SWI showed a higher rate of MH than previously described, underscoring the potential of SWI in evaluating PRES. Such MHs typically persist and may develop after PRES onset. However, the clinical relevance of MHs in PRES is yet to be determined. We propose that MHs in PRES relate to endothelial cell dysfunction.


Anterior Cruciate Ligament Reconstruction Using Autologous Hamstrings Augmented With the Ligament Augmentation and Reconstruction System Versus Hamstrings Alone: A Comparative Cohort Study.
Few studies have reported the return-to-sports (RTS) rate in patients after augmentation of autologous anterior cruciate ligament reconstruction (ACLR) with the Ligament Augmentation and Reconstruction System (LARS). The purpose of this study was to compare postoperative outcomes in patients who underwent ACLR with single-bundle 4-strand hamstring autograft either without augmentation (HA-ACLR group) or with LARS augmentation (AUG-ACLR group). It was hypothesized that clinical outcomes and RTS rates would be better in the AUG-ACLR group at the 1-year follow-up, with similar outcomes in both cohorts by 2 years. Cohort study; Level of evidence, 3. Patients who underwent ACLR between April 2014 and December 2017 were included in the current comparative study if they were skeletally mature and had 1- and 2-year follow-up outcomes; patients with concomitant meniscal surgery were also included. Included were 66 patients with AUG-ACLR (mean age, 26.8 years; 67% male) and 130 patients with HA-ACLR (mean age, 27.5 years; 61% male). Subjective outcome measures included the International Knee Documentation Committee Subjective Knee Evaluation Form, Knee injury and Osteoarthritis Outcome Score, Lysholm scale, Tegner activity scale, and the Noyes sports activity rating scale. Objective measures included knee laxity, maximal isokinetic knee flexion and extension strength, and the results of 4 functional hop tests. There were no significant differences between the study groups in age, sex distribution, body mass index, time to surgery, or number of concurrent meniscal surgeries. At the 1-year follow-up, the AUG-ACLR group had a significantly higher Tegner score (P = .001) and rates of RTS (P = .029) and return to preinjury level of sport (P = .003) compared with the HA-ACLR group. At the 2-year follow-up, there were no differences in these measures between groups. There were no between-group differences in other subjective outcomes, knee laxity, or strength and hop test results at either postoperative time point. There were also no differences in rerupture rates or other complications between the groups. Patients with AUG-ACLR had higher 1-year postoperative Tegner scores and rates of RTS and preoperative sport level compared with the HA-ACLR group. The 2-year rerupture rate for the AUG-ACLR group was low, and no intra-articular inflammatory complications were noted.


Critical illness myopathy serum fractions affect membrane excitability and intracellular calcium release in mammalian skeletal muscle.
The pathogenesis of myopathies occurring in critically ill patients (critical illness myopathy, CIM) is poorly understood. Both local and systemic responses to sepsis and other severe insults to the body are presumed to be involved but the precise mechanisms by which muscle function is impaired are far from clear. To elucidate such mechanisms we investigated the effects of blood serum fractions (5 kDa to 100 kDa molecular weight cut-off, MWCO) from patients with CIM and from control persons on membrane and contractile functions in intact mammalian single skeletal muscle fibres and chemically skinned fibre bundles. In intact fibres, resting membrane potentials were less negative when exposed to CIM serum fractions compared with control serum fractions. Half-width and maximum rise time of action potentials (AP) were smaller in CIM serum low MWCO fractions vs. control serum. Peak amplitudes of fast inward sodium currents (I(Na)) were increased by low MWCO-CIM fractions compared with control sera fractions. Additionally, voltage dependent inactivation of I(Na) was shifted towards more positive potentials by high MWCO fractions of CIM sera. In skinned fibres, pCa-force relations were similar in CIM and control serum fractions but peak force of Ca2+ induced force transients was decreased by low MWCO-CIM vs. control serum fractions. Our results (i) provide the first evidence that serum from CIM patients affects membrane excitability and the excitation-contraction coupling process at the level of the sarcoplasmic reticulum Ca2+ release of mammalian muscle fibres and (ii) also show that even control serum fractions "per se" alter the response to important physiological membrane and contractility parameters compared with physiological saline.


Lactate induced excitotoxicity in hippocampal slice cultures.
During the initial minutes of cerebral ischemia, lactic acid accumulates and acidifies brain pH to 6.0-6.7. Glutamate is also released during ischemia that activates glutamate receptors and induces excitotoxicity. While glutamate excitotoxicity is well established to induce ischemic injury, a role of lactic acidosis in ischemic brain damage is poorly understood. This study analyzes acidosis neurotoxicity in hippocampal slice cultures in the presence or absence of lactate. At pH 6.7, neuronal loss was similar whether or not lactate was present. At pH 6.4, neuronal loss was significantly greater in the presence of lactate suggesting that lactate potentiates the acidosis toxicity. At pH 6.4 in the presence of lactate, NMDA or non-NMDA receptor antagonists reduced neuronal loss, while in the absence of lactate, NMDA or non-NMDA receptor antagonists had little effect. [3H]-Glutamate uptake was inhibited by acidic pH, and the amount of inhibition was significantly greater in the presence of lactate. These findings suggest that lactate plays a role in acidosis neurotoxicity by inducing excitotoxicity. Lactic acidosis and excitotoxicity have been previously thought to be independent events during ischemia. This study suggests that during ischemia, lactic acidosis contributes to excitotoxic neuronal loss.


A modified stepping-stone model of population structure in red drum, Sciaenops ocellatus (Sciaenidae), from the northern Gulf of Mexico.
Genetic studies of population or 'stock' structure in exploited marine fishes typically are designed to determine whether geographic boundaries useful for conservation and management planning are identifiable. Implicit in many such studies is the notion that subpopulations or stocks, if they exist, have fixed territories with little or no gene exchange between them. Herein, we review our long-term genetic studies of red drum (Sciaenops ocellatus), an estuarine-dependent sciaenid fish in the Gulf of Mexico and western Atlantic Ocean. Significant differences in frequencies of mitochondrial DNA haplotypes and of alleles at nuclear-encoded microsatellites occur among red drum sampled across the northern Gulf of Mexico. The spatial distribution of the genetic variation, however, follows a pattern of isolation-by-distance consistent with the hypothesis that gene flow occurs among subpopulations and is an inverse (and continuous) function of geographic distance. However, successful reproduction and recruitment of red drum depend on estuarine habitats that have geographically discrete boundaries. We hypothesize that population structure in red drum follows a modified one-dimensional, linear stepping-stone model where gene exchange occurs primarily (but not exclusively) between adjacent bays and estuaries distributed linearly along the coastline. Gene flow does occur among estuaries that are not adjacent but probabilities of gene exchange decrease as a function of geographic distance. Implications of our hypothesis are discussed in terms of inferences drawn from patterns of isolation-by-distance and relative to conservation and management of estuarine-dependent species like red drum. Based on estimates of the ratio of genetic effective population size and census size in red drum, observed patterns of gene flow in red drum may play a significant role in recruitment.


Discovery of a polyesterase from Deinococcus maricopensis and comparison to the benchmark LCCICCG suggests high potential for semi-crystalline post-consumer PET degradation.
Plastic pollution remains a significant environmental challenge, with conventional waste management strategies proving insufficient in addressing the problem. Enzymatic degradation has emerged as a promising alternative, with LCCICCG, an engineered metagenome-derived cutinase, being the most effective in degrading polyethylene terephthalate (PET), the most commonly produced and discarded polyester. However, more efficient PET-hydrolases are needed for the upscaling of a PET-waste biorefinery. In this regard, the study reports the characterization of a novel, phylogenetically distinct, thermophilic polyesterase from Deinococcus maricopensis (DmPETase) and its comparison to LCCICCG. DmPETase is capable of degrading various synthetic polymers, including PET, polyurethane, as well as four semi-crystalline aliphatic polyesters. DmPETase was found to be comparable to LCCICCG at 50 °C in degrading semi-crystalline sections of post-consumer PET bottles, but it appeared to be less sensitive to crystallinity degree increase. This property makes DmPETase a new template for protein engineering endeavors to create an efficient biocatalyst to be integrated into the bio-recycling process of PET waste, without the need for amorphization of the materials.


Transcriptional suppression of cytokine-induced iNOS gene expression by IL-13 through IRF-1/ISRE signaling.
IL-13 has been reported as one of the major down-regulators of iNOS expression in various tissues and cells. The molecular mechanism of iNOS suppression by IL-13 remains unclear, especially at the transcriptional stage. In this study, we found that IL-13 inhibited the expression of iNOS mRNA, protein, and NO product in a concentration-dependent manner for cytokine-stimulated rat hepatocytes. The most effective dose for IL-13 inhibitory effect is approximately 5 ng/ml. IL-13 also decreased the rat iNOS transcriptional activity by promoter analysis, but had no effect on iNOS mRNA stability. By using TranSignal Protein/DNA Combo Array, we identified cytokine-stimulated IRF-1/ISRE binding that was decreased by the addition of IL-13. Gel shift assay confirmed that IL-13 reduced the IRF-1/ISRE binding at nucleotides -913 to -923 of the rat iNOS promoter. Western blot revealed that IL-13 diminished the relative amount of IRF-1 protein translocated to the nucleus. Our data demonstrate that IL-13 down-regulates the cytokine-induced iNOS transcription by decreasing iNOS specific IRF-1/ISRE binding activity.


Climate Change and Water Scarcity: The Case of Saudi Arabia.
Climate change is expected to bring increases in average global temperatures (1.4°C-5.8°C [34.52°F-42.44°F] by 2100) and precipitation levels to varying degrees around the globe. The availability and quality of water will be severely affected, and public health threats from the lack of this valuable resource will be great unless water-scarce nations are able to adapt. Saudi Arabia provides a good example of how the climate and unsustainable human activity go hand in hand in creating stress on and depleting water resources, and an example for adaptation and mitigation. A search of the English literature addressing climate change, water scarcity, human health, and related topics was conducted using online resources and databases accessed through the University at Albany, State University of New York library web page. Water scarcity, which encompasses both water availability and water quality, is an important indicator of health. Beyond drinking, water supply is intimately linked to food security, sanitation, and hygiene, which are primary contributors to the global burden of disease. Poor and disadvantaged populations are the ones who will suffer most from the negative effects of climate change on water supply and associated human health issues. Examples of adaptation and mitigation measures that can help reduce the strain on conventional water resources (surface waters and fossil aquifers or groundwater) include desalination, wastewater recycling and reuse, and outsourcing food items or "virtual water trade." These are strategies being used by Saudi Arabia, a country that is water poor primarily due to decades of irresponsible irrigation practices. The human and environmental health risks associated with these adaptation measures are examined. Finally, strategies to protect human health through international collaboration and the importance of these efforts are discussed. International, multidisciplinary cooperation and collaboration will be needed to promote global water security and to protect human health, particularly in low-income countries that do not have the resources necessary to adapt on their own.


Outcome after very early treatment of dense congenital unilateral cataract.
To evaluate whether very early treatment for congenital unilateral cataract results in better long-term functional outcomes, grating acuity, contrast sensitivity, recognition acuity, and random-dot stereoacuity were evaluated in two groups of children. Grating acuity and contrast sensitivity data were obtained with standard forced-choice protocols. Stereoacuity data were obtained both in a forced-choice laboratory protocol and by the Randot test. Immediately after treatment, both the very early (1 to 6 weeks; n = 8) and early (2 to 8 months; n = 6) treatment groups showed a 0.3 log unit grating acuity deficit in the aphakic eye. Grating acuity in the early group showed some improvement with age but reached a plateau of 0.75 logMAR at 18 to 24 months; the very early group showed more improvement and reached a plateau of 0.22 logMAR at 37 to 48 months. At 5 to 8 years of age, aphakic eyes of the very early group had significantly better contrast sensitivity and recognition acuity than the aphakic eyes of the early group. Overall, grating acuity deficits during years 2 through 5 were significantly correlated with contrast sensitivity and recognition acuity outcomes measured at 5 to 8 years of age. No deficits in grating acuity, contrast sensitivity, or recognition acuity were found for phakic fellow eyes in either group. Three children in the very early treatment group (37.5%) were orthotropic and demonstrated gross random-dot stereopsis; one child in the early group was orthotropic but none of these children demonstrated random-dot stereopsis. These results suggest that treatment initiated at 1 to 6 weeks of age maximizes the opportunity for normal or near-normal visual development of a congenitally cataractous eye with little or no risk to the phakic fellow eye.


An ICI 182,780-sensitive, membrane-related estrogen receptor contributes to estrogenic neuroprotective actions against amyloid-beta toxicity.
Although estrogen (E2)-related neuroprotection has been repeatedly demonstrated in different models, the involvement of non-classical estrogen receptors (ERs) in this activity remains unclear. Using SN56 murine cholinergic cell line from the basal forebrain, we present evidence indicating that an ER associated with the plasma membrane participates in estrogen-dependent reduction of neuronal death induced by amyloid-beta peptide (Abeta) toxicity. Exposure to either E2 or estradiol-horseradish peroxidase (E-HRP) for 15 min significantly reduced Abeta-induced cell death. This effect was decreased by the ER antagonist ICI 182,780 as well as by MC-20 antibody directed to a region neighboring the ligand-binding domain of ERa. Using MC-20 antibody in unpermeabilized SN56 cells, we detected a protein at the plasma membrane region. The binding of impermeant forms of E2, E-HRP, and E-BSA-FITC to specific sites of SN56 plasma membrane was blocked by pre-incubation with E2, ICI 182,780, and MC-20 antibody in a concentration-dependent manner. Thus, a membrane-related ER that shares some structural homologies with ERalpha may participate in estrogen-mediated neuroprotection.


Energy depletion and opportunistic microbial colonisation in white syndrome lesions from corals across the Indo-Pacific.
Corals are dependent upon lipids as energy reserves to mount a metabolic response to biotic and abiotic challenges. This study profiled lipids, fatty acids, and microbial communities of healthy and white syndrome (WS) diseased colonies of Acropora hyacinthus sampled from reefs in Western Australia, the Great Barrier Reef, and Palmyra Atoll. Total lipid levels varied significantly among locations, though a consistent stepwise decrease from healthy tissues from healthy colonies (HH) to healthy tissue on WS-diseased colonies (HD; i.e. preceding the lesion boundary) to diseased tissue on diseased colonies (DD; i.e. lesion front) was observed, demonstrating a reduction in energy reserves. Lipids in HH tissues were comprised of high energy lipid classes, while HD and DD tissues contained greater proportions of structural lipids. Bacterial profiling through 16S rRNA gene sequencing and histology showed no bacterial taxa linked to WS causation. However, the relative abundance of Rhodobacteraceae-affiliated sequences increased in DD tissues, suggesting opportunistic proliferation of these taxa. While the cause of WS remains inconclusive, this study demonstrates that the lipid profiles of HD tissues was more similar to DD tissues than to HH tissues, reflecting a colony-wide systemic effect and provides insight into the metabolic immune response of WS-infected Indo-Pacific corals.


Effects of bench step exercise on arterial stiffness in post-menopausal women: contribution of IGF-1 bioactivity and nitric oxide production.
To examine the effect of bench step exercise on arterial pulse wave velocity (PWV) and the associated contribution of insulin-like growth factor (IGF)-1 bioactivity and nitric oxide (NO). Twenty-six elderly (post-menopausal) women were randomly allocated to a bench step exercise group or a control group. The participants in the bench step exercise group practiced a 12-week home-based bench step exercise for 10-20min, 3 times daily (i.e., for a total of 140min/week at the intensity level of lactate threshold (LT)). In addition to conventional risk factors of atherosclerosis, PWV, IGF-1/IGF binding protein (IGFBP)-3 molar ratio (an index for IGF-1 bioactivity), and urinary nitrite/nitrate (NO(x)) excretion were measured before and after the intervention. BMI, systolic blood pressure, fasting plasma glucose, low-density lipoprotein cholesterol, LT, and PWV were significantly improved in the bench step exercise group. A significant positive correlation between changes in PWV and IGF-1/IGFBP-3 molar ratio, and a significant negative correlation between changes in IGF-1/IGFBP-3 molar ratio and urinary NO(x) excretion were found in the bench step exercise group. The bench step exercise leads to improvements in not only the classical risk factors of atherosclerosis but also the arterial stiffness in elderly women, partly through NO production via IGF-1 bioactivity.


Long-term prognosis of patients with severe radiation enteritis.
One hundred thirty-six patients (median age 59 years) presented with intestinal complications of previous radiotherapy. Seventy-eight had bleeding or stricture and 58 had perforation or fistula. One hundred twenty-four patients survived for more than 3 months and were followed for a median of 4.5 years. Sixty-eight patients were free of symptoms, whereas 16 experienced operation-related complications. Twelve patients had continuing symptoms of radiation enteritis, and new radiation-induced complications developed in 28. Sixteen of 51 patients with perforation or fistula had new complications compared with 12 of 73 patients with bleeding of stricture (p = 0.05). Overall, 57 patients died during the study. Thirteen died from radiation-induced complications and 27, from recurrent malignancy. Radiation deaths occurred in the postoperative period but had no impact on long-term survival. Life expectancy was poorer in patients presenting with perforation or fistula compared with bleeding or stricture, the main reason being significantly more recurrences among patients with fistulas (p less than 0.05).


The balance between NRTI discrimination and excision drives the susceptibility of HIV-1 RT mutants K65R, M184V and K65r+M184V.
The HIV-1 reverse transcriptase (RT) resistance mutations K65R and M184V occur individually and in combination, and can contribute to decreased treatment responses in patients. In order to understand how these mutations interact with one another to confer drug resistance, the susceptibilities and underlying resistance mechanisms of these mutants to nucleoside RT inhibitors (NRTIs) were determined. Virus carrying K65R have reduced susceptibility to most NRTIs, but retain full susceptibility to zidovudine (AZT). M184V mutants have reduced susceptibility to lamivudine (3TC), emtricitabine (FTC) and didanosine (ddl), and contribute to reduced susceptibility to abacavir; however, they remain fully susceptible to tenofovir (TFV), AZT and stavudine (d4T). In cell culture, the K65R+M184V virus showed slightly increased susceptibility to TFV, AZT and d4T compared with K65R alone, but showed further decreases in susceptibility to 3TC, FTC, ddl and abacavir. There are two major biochemical mechanisms of resistance: altered NRTI binding/incorporation and altered NRTI excision after incorporation. For most NRTIs, the primary mechanism of resistance by K65R, M184V and K65R+M184V mutant RTs is to disrupt the NRTI-binding/incorporation steps. In the case of AZT, however, decreased binding/incorporation by K65R and K65R+M184V was counteracted by decreased AZT excision resulting in wild-type susceptibility. For TFV, decreased excision by K65R and K65R+M184V may partially counteract the K65R-driven decrease in incorporation relative to wild-type resulting in only low levels of TFV resistance. The K65R-mediated effect on decreasing NRTI excision was stronger than for M184V. These studies show that both mechanisms of resistance (binding/incorporation and excision) must be considered when defining resistance mechanisms.


System for Observing Play and Leisure Activity in Youth: A Systematic Review of US and Canadian Studies.
The System of Observing Play and Leisure Activity in Youth (SOPLAY) has assisted in providing valid and reliable data of youth physical activity and characteristics specific to environmental contexts. The review aimed to examine empirical research that employed the SOPLAY instrument to measure physical activity in leisure-based activity environments in North American countries. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A systematic search was conducted with an exhaustive process using 10 electronic databases to locate peer-reviewed studies implementing SOPLAY that were published between 2000 and 2021. A total of 60 studies were included in the review. Most studies (n = 35) reported physical activity findings related to contextual characteristics measured using SOPLAY. Interestingly, a few of the studies (n = 8) found the provision of equipment and supervision, particularly adult supervision, significantly increased child physical activity observed. This review provides information relative to the group-level physical activity observed across multiple contexts (ie, playgrounds, parks, recreation centers) using a validated direct observation instrument.


Ileus and small bowel obstruction after radical cystectomy for bladder cancer: Analysis from the Nationwide Inpatient Sample.
To investigate prevalence and predictors of postoperative small bowel obstruction (SBO) and ileus in a large cohort of bladder cancer (BCa) patients treated with radical cystectomy (RC). All patients within the Nationwide Inpatient Sample who underwent RC for BCa between 2006 and 2012 were identified. First, prevalence of SBO and ileus was analyzed. Second, predictors of these bowel-related complications were identified using multivariable regression analyses. Third, the association between SBO, ileus, and length of stay was evaluated using logistic regression models adjusted for clustering. Prolonged length of stay was defined as hospital stay above mean stay of the population (>10 days). Fourth, the effect of SBO and ileus on mean inpatient cost of healthcare was examined. Of overall 41,498 patients, 1071 (2.6%) experienced SBO, and 11,155 (26.9%) experienced ileus. Predictors of ileus included age, male gender, black race, hospital characteristics, anemia, chronic pulmonary disease, drug abuse, hypothyroidism, fluid and electrolyte disorders, and neurological disorders (all p < 0.05) Predictors of SBO included male gender, Asian/Pacific islander race, hospital characteristics, congestive heart failure, fluid and electrolyte disorders, and psychosis (all p < 0.05). . Postoperative SBO (odds ratio (OR) 19.587; 95% confidence interval (CI):15.869-24.167) and ileus (OR 5.646; 95% CI:5.336-5.974) were associated with prolonged length of stay (all p < 0.001).Median cost of hospital stay was $56.315 for patients who developed SBO, $32,472 for patients who developed ileus, and $24,600 for patients after cystectomy without ileus or SBO. Significant prevalence of bowel-related complications in patients after RC was observed. These complications are strongly associated with prolonged length of stay and higher healthcare cost. Increasing awareness of SBO and ileus, identification of patients at risk prior to surgery, and implementation of protective strategies are strongly indicated in cystectomy patients. .


A sporadic case of paraganglioma undetected by urine metabolite screening.
Phaeochromocytoma is a rare cause of hypertension in children, but important to be recognised, as hypertension can be severe and surgery is often curative. Here, we report on a 7-year-old boy with a phaeochromocytoma, who had normal levels of commonly assayed catecholamine metabolites in the urine. Postoperatively, the patient developed renal vein thrombosis. Appropriate screening tests for phaeochromocytomas, peri-operative management, and the high incidence of an underlying genetic basis, even in sporadic cases, are discussed.


A portable system for in-situ re-calibration of force platforms: theoretical validation.
The periodic calibration of measurement devices, such as force platforms (FPs), guarantees and optimizes the quality of the acquired data. In this study, the theoretical validation of a portable system for the in-situ calibration of six-component FPs is presented. A least-squares algorithm, that estimates the FP re-calibration matrix, was designed and tested using a simulation approach. The algorithm is the core of a portable system, described in a separate paper, and represents a refinement of an algorithm previously presented by Cappello et al. [Cappello A, Lenzi D, Chiari L. Periodical in-situ re-calibration of force platforms: a new method for the robust estimation of the calibration matrix. Med Biol Eng Comput 2004;42:350-5]. The new algorithm assumes that the calibration inputs are known, 3-D, time-varying loads, applied to the FP at known coordinates, and not constrained in their direction of application. Simulation results confirmed the a priori identifiability of the re-calibration matrix and some of the algorithm features were optimized in the perspective of an actual building of the system. With the aid of simple sinusoidal loads, applied in at least five different points, we proved that the algorithm can ensure errors less than 0.2N and 0.4 Nm when calculating force and moment components of an applied load.