International Residency Program Directors on Implementing Educational Transformation: A Qualitative Study of Their Experiences and Strategies for Overcoming Challenges.
Residency program directors (PDs) need to navigate diverse roles and responsibilities as clinical teachers, administrators, and drivers of educational improvement. Little is known about the experience of PDs leading transformation of international residency programs. We explored the lived experiences of international residency PDs and developed an understanding of how PDs manage educational program transformation. Using a phenomenological approach, semi-structured interviews were conducted with current and former PDs involved in the transformation to competency-based medical education in the first international settings to be accredited by the Accreditation Council for Graduate Medical Education-International (ACGME-I). Thirty-three interviews with PDs from Qatar, Singapore, and the United Arab Emirates were conducted from September 2018 to July 2019, audio-recorded, and transcribed. Data were independently coded by 2 researchers. A thematic analysis was conducted and patterns that reflected coping and managing educational reform were identified. PDs described distinctive patterns of navigating the educational transformation. Five themes emerged: PDs (1) embraced continuous learning and self-development; (2) managed change in the context of their local settings; (3) anticipated problems and built support networks to effectively problem-solve; (4) maintained relationships with stakeholders for meaningful and constructive interactions; and (5) focused on intrinsic qualities that helped them navigate challenges. International PDs were presented with significant challenges in implementing educational transformation but coped successfully through distinctive patterns and methods.


Design of monolithically integrated GeSi electro-absorption modulators and photodetectors on a SOI platform.
We present a design of monolithically integrated GeSi electroabsorption modulators and photodetectors for electronic-photonic integrated circuits on a silicon-on-insulator (SOI) platform. The GeSi electroabsorption modulator is based on the Franz-Keldysh effect, and the GeSi composition is chosen for optimal performance around 1550 nm. The designed modulator device is butt-coupled to Si(core)/SiO(2)(cladding) high index contrast waveguides, and has a predicted 3 dB bandwidth of >50 GHz and an extinction ratio of 10 dB. The same device structure can also be used for a waveguide-coupled photodetector with a predicted responsivity of > 1 A/W and a 3 dB bandwidth of > 35 GHz. Use of the same GeSi composition and device structure allows efficient monolithic process integration of the modulators and the photodetectors on an SOI platform.


Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer.
Researchers conducted extensive investigations of hallucinogens in the 1950s and 1960s. By the early 1970s, however, political and cultural pressures forced the cessation of all projects. This investigation reexamines a potentially promising clinical application of hallucinogens in the treatment of anxiety reactive to advanced-stage cancer. To explore the safety and efficacy of psilocybin in patients with advanced-stage cancer and reactive anxiety. A double-blind, placebo-controlled study of patients with advanced-stage cancer and anxiety, with subjects acting as their own control, using a moderate dose (0.2 mg/kg) of psilocybin. A clinical research unit within a large public sector academic medical center. Twelve adults with advanced-stage cancer and anxiety. In addition to monitoring safety and subjective experience before and during experimental treatment sessions, follow-up data including results from the Beck Depression Inventory, Profile of Mood States, and State-Trait Anxiety Inventory were collected unblinded for 6 months after treatment. Safe physiological and psychological responses were documented during treatment sessions. There were no clinically significant adverse events with psilocybin. The State-Trait Anxiety Inventory trait anxiety subscale demonstrated a significant reduction in anxiety at 1 and 3 months after treatment. The Beck Depression Inventory revealed an improvement of mood that reached significance at 6 months; the Profile of Mood States identified mood improvement after treatment with psilocybin that approached but did not reach significance. This study established the feasibility and safety of administering moderate doses of psilocybin to patients with advanced-stage cancer and anxiety. Some of the data revealed a positive trend toward improved mood and anxiety. These results support the need for more research in this long-neglected field. clinicaltrials.gov Identifier: NCT00302744.


Reduced 1alpha-hydroxylase activity in human prostate cancer cells correlates with decreased susceptibility to 25-hydroxyvitamin D3-induced growth inhibition.
Evidence from epidemiological, molecular, and genetic studies suggests a role for vitamin D in the development and/or progression of prostate cancer. In experimental models and clinical trials, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] was shown to exert antiproliferative, prodifferentiating, and antimetastatic/invasive effects on prostatic epithelial cells. Because the direct clinical application of 1,25(OH)2D3 is limited by the major side effect of hypercalcemia, we investigated the potential therapeutic utility of its less calcemic precursor, 25-hydroxyvitamin D3 [25(OH)D3], which is converted locally within the prostate to 1,25(OH)2D3 by 1alpha-hydroxylase. Quantification of 1alpha-hydroxylase activity in human prostatic epithelial cells by enzyme-substrate reaction analyses revealed a significantly decreased activity in cells derived from adenocarcinomas compared with cells derived from normal tissues or benign prostatic hyperplasia (BPH). In growth assays, we found that 25(OH)D3 inhibited growth of normal or BPH cells similarly to 1,25(OH)2D3. In contrast, in primary cultures of cancer cells and established cell lines, the antiproliferative action of 25(OH)D3 was significantly less pronounced than that of 1,25(OH)2D3. Our results indicate that growth inhibition by 25(OH)D3 depends on endogenous 1alpha-hydroxylase activity, and that this activity is deficient in prostate cancer cells. This finding has ramifications for both the prevention and therapy of prostate cancer with vitamin D compounds.


Programmed cell death ligand-1 (PD-L1) as a biomarker for non-small cell lung cancer (NSCLC) treatment-are we barking up the wrong tree?
Immunotherapy with monoclonal antibodies targeting programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) has become a standard of care treatment for patients with advanced or metastatic non-small cell lung cancer (NSCLC) in first and later treatment lines with durable responses seen in approximately 10-20% of patients treated. However, the optimal selection of eligible patients who will benefit most, is far from being clear and the best biomarker has not yet been established. PD-L1 expression as a predictive biomarker for immunotherapy in NSCLC patients has shown some value for predicting response to immune checkpoint inhibitors in some studies, but not in others, and its use has been complicated by a number of factors which has prompted many researchers to establish better predictive biomarkers for immunotherapy of NSCLC. Most recently, two phase III first-line NSCLC studies have provided evidence that tumour mutational burden (TMB) correlates with the clinical response to the combination of nivolumab and ipilimumab (CheckMate-227; NCT02477826), whereas atezolizumab response was correlated with T effector gene signature expression (IMPower 150; NCT02366143). Both studies demonstrated a significant primary endpoint [progression-free survival (PFS)] benefit in the TMB group and in the group of patients expressing a T effector cell signature, respectively. However, PFS benefit in both studies was seen regardless of the PD-L1 status of all patients suggesting that TMB and T effector cell signatures may be more robust to predict clinical response following treatment with checkpoint inhibitors. The role of putative novel predictive biomarkers evaluated in the CheckMate-227 and the IMPower 150 trials may, if confirmed in future prospective studies, offer a new perspective for predicting immunotherapy treatment outcomes of NSCLC patients in the near future.


Li2O-Reinforced Cu Nanoclusters as Porous Structure for Dendrite-Free and Long-Lifespan Lithium Metal Anode.
A nanostructured protective structure, pillared by the copper nanoclusters and in situ filled with lithium oxide in the interspace, is constructed to efficiently improve the cyclic stability and lifetime of lithium metal electrodes. The porous structure of copper nanoclusters enables high specific surface area, locally reduced current density, and dendrite suppressing, while the filled lithium oxide leads to the structural stability and largely extends the electrode lifespan. As a result of the synergetic protection of the proposed structure, lithium metal could be fully discharged with efficiency ∼97% for more than 150 cycles in corrosive alkyl carbonate electrolytes, without dendrite formation. This approach opens a novel route to improve the cycling stability of lithium metal electrodes with the appropriate protective structure.


The simultaneous presentation of retinopathy of prematurity and central serous chorioretinopathy.
A case report of central serous chorioretinopathy (CSC) and retinopathy of prematurity (ROP) in the same patient is presented. CSC is a disease of the outer retinal layers, specifically the retinal pigment epithelium, which results in serous detachment of the neurosensory retina. ROP is a disease of the anterior retinal layers, affecting the retinal vasculature. Ocular manifestations may range from the peripheral neovascularization observed in the milder states to retinal detachment and secondary angle closure glaucoma that is often found in the later stages. Therefore it would appear that there is no direct relationship between the presence of ROP and the presence of CSC in a patient who presented with complaints of a unilateral relative central scotoma. To our knowledge this represents a heretofore unreported association.


Fas ligand- mediated killing by intestinal intraepithelial lymphocytes. Participation in intestinal graft-versus-host disease.
In vitro studies have demonstrated that intestinal intraepithelial lymphocytes (IEL) are constitutively cytotoxic; however, the mechanism and target of their cytotoxicity are unknown. Apoptosis of intestinal epithelial cells (IEC) and an increase in IEL numbers are classical signs of intestinal graft-versus-host disease (GVHD), although whether IEL can mediate IEC apoptosis directly in GVHD is unclear. Recent evidence suggests that target epithelial organ injury observed in GVHD is predominantly Fas-mediated; therefore, we investigated the possibility that IEL induce apoptosis of IEC through a Fas-mediated mechanism. Here, we demonstrate that the IEL isolated from normal mice readily display potent Fas ligand (FasL)-mediated killing activity after CD3 stimulation, and that IEC express Fas, suggesting that IEC are potential targets for FasL-mediated killing by IEL. In vitro, IEL isolated from GVHD mice have markedly increased FasL-mediated killing potential and are spontaneously cytolytic toward host-derived tumor cells predominantly through a Fas-mediated pathway. In vivo transfer of IEL isolated from GVHD mice induced significantly more IEC apoptosis in F1 wild-type mice than in Fas-defective F1lpr mice. Thus, these results demonstrate that FasL-mediated death of IEC by IEL is a major mechanism of IEC apoptosis seen in GVHD.


The diet factor in pediatric and adolescent migraine.
Diet can play an important role in the precipitation of headaches in children and adolescents with migraine. The diet factor in pediatric migraine is frequently neglected in favor of preventive drug therapy. The list of foods, beverages, and additives that trigger migraine includes cheese, chocolate, citrus fruits, hot dogs, monosodium glutamate, aspartame, fatty foods, ice cream, caffeine withdrawal, and alcoholic drinks, especially red wine and beer. Underage drinking is a significant potential cause of recurrent headache in today's adolescent patients. Tyramine, phenylethylamine, histamine, nitrites, and sulfites are involved in the mechanism of food intolerance headache. Immunoglobulin E-mediated food allergy is an infrequent cause. Dietary triggers affect phases of the migraine process by influencing release of serotonin and norepinephrine, causing vasoconstriction or vasodilatation, or by direct stimulation of trigeminal ganglia, brainstem, and cortical neuronal pathways. Treatment begins with a headache and diet diary and the selective avoidance of foods presumed to trigger attacks. A universal migraine diet with simultaneous elimination of all potential food triggers is generally not advised in practice. A well-balanced diet is encouraged, with avoidance of fasting or skipped meals. Long-term prophylactic drug therapy is appropriate only after exclusion of headache-precipitating trigger factors, including dietary factors.


Cardiomyocyte degeneration with calpain deficiency reveals a critical role in protein homeostasis.
Regulating the balance between synthesis and proteasomal degradation of cellular proteins is essential for tissue growth and maintenance, but the critical pathways regulating protein ubiquitination and degradation are incompletely defined. Although participation of calpain calcium-activated proteases in post-necrotic myocardial autolysis is well characterized, their importance in homeostatic turnover of normal cardiac tissue is controversial. Hence, we evaluated the consequences of physiologic calpain (calcium-activated protease) activity in cultured cardiomyocytes and unstressed mouse hearts. Comparison of in vitro proteolytic activities of cardiac-expressed calpains 1 and 2 revealed calpain 1, but not calpain 2, activity at physiological calcium concentrations. Physiological calpain 1 activation was evident in adenoviral transfected cultured cardiomyocytes as proteolysis of specific substrates, generally increased protein ubiquitination, and accelerated protein turnover, that were each inhibited by coexpression of the inhibitor protein calpastatin. Conditional forced expression of calpain 1, but not calpain 2, in mouse hearts demonstrated substrate-specific proteolytic activity under basal conditions, with hyperubiquitination of cardiac proteins and increased 26S proteasome activity. Loss of myocardial calpain activity by forced expression of calpastatin diminished ubiquitination of 1 or more specific myocardial proteins, without affecting overall ubiquitination or proteasome activity, and resulted in a progressive dilated cardiomyopathy characterized by accumulation of intracellular protein aggregates, formation of autophagosomes, and degeneration of sarcomeres. Thus, calpain 1 is upstream of, and necessary for, ubiquitination and proteasomal degradation of a subset of myocardial proteins whose abnormal accumulation produces autophagosomes and degeneration of cardiomyocytes with functional decompensation.


The evaluation of impact of BPH surgical treatment with the open prostatectomy and transurethral resection of the prostate methods on the quality of life.
Benign prostatic hyperplasia is one of the most common diseases in older men. The objective of this study was to evaluate the impact of the surgical treatment of the benign prostatic hyperplasia (BPH) with the methods of open prostatectomy (OP) and transurethral resection of the prostate (TURP) on the quality of life. The research material was based on 80 patients, out of whom 40 patients were treated with the method of open prostatectomy (Group A), and the other 40 patients with the method of transurethral resection of prostate gland (Group B) due to benign prostatic hyperplasia. All patients were under the age of 80 years old (approximate age in Group A 70.23 with variation interval of 21 years old, and in Group B 69.37 with variation interval of 22 years old), with the International Prostate Symptom Score (IPSS) value >19 points, postvoid residual urine higher than 150 ml, the weight of benign prostatic gland hyperplasia tissue over 30 grams for method of prostate transurethral resection, and over 80 grams for the method of open prostatectomy. The quantification of the quality of life, as a consequence of urinary symptoms, was done by the Quality of Life Index (QLI) which is question No 8 in IPSS. All patients were determined the value of this score before the operation, and then in postoperative period in time intervals of 4.8 and 12 weeks. The QLI arithmetic mean, before the operation, was 5.55 points in Group A, and 5.45 points in Group B. During postoperative checkups in time intervals of 4.8 and 12 weeks, the arithmetic means in Group A were 0.975, 0.450 and 0.100 points, and in Group B 1.850, 1.700 and 1.575 points. By analyzing the obtained results, there was a highly statistically significant difference between preoperative test results and the results during all the postoperative checkups in both groups, A and B. By testing the difference of the QLI arithmetic mean between the patients in both groups, preoperatively there was no statistically significant difference, but during all postoperative checkups, there was a highly statistically significant difference between the test values. The surgical treatment of BPH leads to significant improvement of the quality of life, as a consequence of urinary symptoms. The improvement of the quality of life was more evident in patients whose BPH was treated with the OP method.


Patients diagnosed with COVID-19 and treated with anakinra: a real-world study in the USA.
Anakinra, a recombinant, non-glycosylated human interleukin (IL)-1 receptor antagonist, has been used in real-world clinical practice to manage hyperinflammation in coronavirus disease 2019 (COVID-19). This retrospective, observational study analyses US hospital inpatient data of patients diagnosed with moderate/severe COVID-19 and treated with anakinra between 1 April and 31 August 2020. Of the 119 patients included in the analysis, 63.9% were male, 48.6% were of black ethnicity, and the mean (standard deviation [SD]) age was 64.7 (12.5) years. Mean (SD) time from hospital admission to anakinra initiation was 7.3 (6.1) days. Following anakinra initiation, 73.1% of patients received antibiotics, 55.5% received antithrombotics, and 91.0% received corticosteroids. Overall, 64.7% of patients required intensive care unit (ICU) admittance, and 28.6% received mechanical ventilation following admission. Patients who did not require ICU admittance or who were discharged alive experienced a significantly shorter time between hospital admission and receiving anakinra treatment compared with those admitted to the ICU (5 vs. 8 days; P = 0.002) or those who died in hospital (6 vs. 9 days; P = 0.01). Patients with myocardial infarction or renal conditions were six times (P < 0.01) and three times (P = 0.01), respectively, more likely to die in hospital than be discharged alive. A longer time from hospital admission until anakinra treatment was associated with significantly higher mortality (P = 0.01). Findings from this real-world study suggest that a shorter time from hospital admission to anakinra treatment is associated with significantly lower ICU admissions and mortality among patients with moderate/severe COVID-19.


Callosal connections of dorso-lateral premotor cortex.
This study investigated the organization of the callosal connections of the two subdivisions of the monkey dorsal premotor cortex (PMd), dorso-rostral (F7) and dorso-caudal (F2). In one animal, Fast blue and Diamidino yellow were injected in F7 and F2, respectively; in a second animal, the pattern of injections was reversed. F7 and F2 receive a major callosal input from their homotopic counterpart. The heterotopic connections of F7 originate mainly from F2, with smaller contingent from pre-supplementary motor area (pre-SMA, F6), area 8 (frontal eye fields), and prefrontal cortex (area 46), while those of F2 originate from F7, with smaller contributions from ventral premotor areas (F5, F4), SMA-proper (F3), and primary motor cortex (M1). Callosal cells projecting homotopically are mostly located in layers II-III, those projecting heterotopically occupy layers II-III and V-VI. A spectral analysis was used to characterize the spatial fluctuations of the distribution of callosal neurons, in both F7 and F2, as well as in adjacent cortical areas. The results revealed two main periodic components. The first, in the domain of the low spatial frequencies, corresponds to periodicities of cell density with peak-to-peak distances of approximately 10 mm, and suggests an arrangement of callosal cells in the form of 5-mm wide bands. The second corresponds to periodicities of approximately 2 mm, and probably reflects a 1-mm columnar-like arrangement. Coherency and phase analyses showed that, although similar in their spatial arrangements, callosal cells projecting to dorsal premotor areas are segregated in the tangential cortical domain.


Altered bladder function in transgenic mice expressing rat elastin.
The elasticity of tissues subjected to repeated deformation is provided by the presence of elastic fibers in the extracellular matrix (ECM). The most abundant component of elastic fibers is elastin, whose soluble precursor is tropoelastin. To establish the role elastin plays in the bladder, this study describes the biosynthetic, histologic, and physiologic consequences of expression of an isoform of rat tropoelastin in transgenic mouse bladder. The polymerase chain reaction (PCR) was used to determine expression of a rat tropoelastin minigene in transgenic mice. Histochemical methods were used to demonstrate changes in elastic fibers in frozen sections of bladder. Cystometric analysis was carried out in transgenic and non-transgenic mice, prior to and after 3 weeks of partial outlet obstruction. The PCR assay demonstrated that bladder tissue of transgenic mice expressed rat tropoelastin mRNA, whereas non-transgenes did not. Increased deposition of elastic fibers was demonstrated with the Verhoeff-van Gieson stain. Bladders of transgenic animals were more compliant than bladders of their non-transgenic littermates. Partial outlet obstruction resulted in increased bladder volume and more compliant bladders in non-transgenic mice. In contrast, the bladder volume and compliance in transgenes was almost unchanged by obstruction. This study demonstrates that normal elastic fiber assembly is prerequisite for the compliant properties of the bladder wall. Moreover, the response of the bladder to obstruction is critically influenced by elastin synthesis.


Measurement of the W boson mass using electrons at large rapidities
We report a measurement of the W boson mass based on an integrated luminosity of 82 pb(-1) from p&pmacr; collisions at sqrt[s] = 1.8 TeV recorded in 1994-1995 by the D0 detector at the Fermilab Tevatron. We identify W bosons by their decays to enu, where the electron is detected in the forward calorimeters. We extract the mass by fitting the transverse mass and the electron and neutrino transverse momentum spectra of 11 089 W boson candidates. We measure M(W) = 80.691+/-0.227 GeV. By combining this measurement with our previously published central calorimeter results from data taken in 1992-1993 and 1994-1995, we obtain M(W) = 80.482+/-0.091 GeV.


Palliative care in South Australian nursing homes.
A survey of directors of nursing and registered nurses working in 151 South Australian nursing homes was conducted to identify the proportion of residents who received palliative care and the nursing implications of providing this care. The 71 (47%) responding directors of nursing reported that their homes had provided and/or were providing palliative care and that, at the time of the survey, approximately 10% of the residents were receiving palliative care. The registered nurses documented a range of specialized and time-consuming nursing procedures and care that were required by 89 recipients of palliative care. These residents were each receiving approximately 42 hours of nursing and personal care per week, but none were assessed as meeting the criteria for their nursing home to receive the maximum Resident Classification Instrument funding for 27 hours of nursing and personal care per week.


Immunological role of nasal staphylococcus aureus carriage in patients with persistent allergic rhinitis.
Nasal carriage of staphylococcus aureus (S.aureus) exerts immunomodulatory effect in patients with atopic dermatitis and it may contribute to airway inflammation and allergic response in patients with allergic rhinitis. We Aim to investigate the frequency of nasal S.aureus carriage in patients with persistent allergic rhinitis and its possible influence on their symptoms and immune markers. We chosed 20 non smoker patients with house dust mite (HDM) allergy causing allergic rhinitis and 20 non smoker healthy subjects matched for age and sex. For all subjects rhinoscopy was done, skin prick test, nasal culture for S.aureus, nasal interleukin 4,nasal total IgE, serum total IgE and serum specific IgE(SSIgE) for HDM. Nasal S.aureus was detected in 16/20 patients (80%) and 5/20 (25%) in healthy subjects with highly significant statistical difference p<0.01. Correlation of nasal staph.aureus count and different systemic and local immune markers revealed highly significant positive correlation between nasal S.aureus count and serum total IgE (r = 0.78, p<0.01) and significant positive correlation with SSIgE (HDM) (r = 0.53, p<0.05), nasal total IgE (r = 0.39, p<0.05) and nasal IL-4 (r = 0.55, p<0.05). Nasal staph.aureus actively modulated the immune reaction in persistent allergic rhinitis patients by promoting local IgE production, so we recommend early detection and treatment of S.aureus carriage in patients.


Estrogen modulates hepatic gene expression and survival of rainbow trout infected with pathogenic bacteria Yersinia ruckeri.
In the aquatic environment, fish are exposed to various stimuli at once and have developed different response mechanisms to deal with these multiple stimuli. The current study assessed the combined impacts of estrogens and bacterial infection on the physiological status of fish. Juvenile rainbow trout were exposed to two different concentrations of 17β-estradiol (E2) (2 or 20 mg/kg feed) and then infected with three concentrations of Yersinia ruckeri, a bacterial pathogen causing massive losses in wild and farmed salmonid populations. Organism-level endpoints to assess the impact of the single and combined treatments included hepatic vitellogenin transcript expression to evaluate the E2 exposure efficiency and survival rate of pathogen-challenged fish. The two E2 doses increased vitellogenin levels within the physiological range. Infection with Y. ruckeri caused mortality of trout, and this effect was significantly enhanced by a simultaneous exposure to high E2 dose. The hormone reduced survival at intermediate and high (10(4) and 10(6) colony forming units, cfu) bacterial concentrations, but not for a low one (10(2) cfu). Analysis of hepatic gene expression profiles by a salmonid 2 k cDNA microarray chip revealed complex regulations of pathways involved in immune responses, stress responses, and detoxicification pathways. E2 markedly reduced the expression of several genes implicated in xenobiotic metabolism. The results suggest that the interaction between pathogen and E2 interfered with the fish's capability of clearing toxic compounds. The findings of the current study add to our understanding of multiple exposure responses in fish.


Three dimensional microstructural network of elastin, collagen, and cells in Achilles tendons.
Similar to most biological tissues, the biomechanical, and functional characteristics of the Achilles tendon are closely related to its composition and microstructure. It is commonly reported that type I collagen is the predominant component of tendons and is mainly responsible for the tissue's function. Although elastin has been found in varying proportions in other connective tissues, previous studies report that tendons contain very small quantities of elastin. However, the morphology and the microstructural relationship among the elastic fibres, collagen, and cells in tendon tissue have not been well examined. We hypothesize the elastic fibres, as another fibrillar component in the extracellular matrix, have a unique role in mechanical function and microstructural arrangement in Achilles tendons. It has been shown that elastic fibres present a close connection with the tenocytes. The close relationship of the three components has been revealed as a distinct, integrated and complex microstructural network. Notably, a "spiral" structure within fibril bundles in Achilles tendons was observed in some samples in specialized regions. This study substantiates the hierarchical system of the spatial microstructure of tendon, including the mapping of collagen, elastin and tenocytes, with 3-dimensional confocal images. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1203-1214, 2017.


Body Mass Index Change Between Referral to and Enrollment in Pediatric Weight Management.
This study describes changes in body mass index z score (BMIz) and percent of 95th percentile (P95) between referral to pediatric weight management (PWM) and initial PWM visit. We conducted a prospective cohort analysis among subjects (n = 77) aged 5 to 11 years referred to PWM and compared height and weight at time of referral versus initial PWM visit. Mean BMIz decreased by 0.05, and P95 decreased by 1.48 across all age groups (both P < .01) from time of referral to initial visit. Children 5 to 8 years old experienced a greater BMIz change than older children (-0.07 vs -0.02; P < .05). Interval BMIz change was greater for non-Hispanic White and Hispanic children compared with non-Hispanic Blacks (-0.10 vs -0.01; P < .001). There were no subgroup differences in P95. Interval BMI changes between referral and treatment approach half the effect reported by some PWM programs. Referral to PWM may motivate pretreatment lifestyle changes in some patients.


Site-specific presentation of single recombinant proteins in defined nanoarrays.
The authors describe the deposition of single biomolecules on substrates at defined spacing by pure self-assembly. The substrate is equipped with an array of 8 nm large gold particles which form the template for biomolecule binding. The authors verified the successful binding of single biomolecules via specific antibody labeling and imaging by fluorescence microscopy. Scanning force microscopy provided evidence that every gold nanoparticle of the pattern is occupied by at least one biomolecule. Furthermore, gold conjugated secondary antibodies in combination with scanning electron microscopy proved that at least 75% of the nanoparticles carried only one active biomolecule. The precision given by such surface densities is molecularly defined and such considerably higher than in any other case reported so far.


Cholesterol inhibitory effects on human sperm-induced acrosome reaction.
Progesterone (P4) is known to induce an acrosome reaction in mammalian sperm in vitro, whereas cholesterol is a major inhibitor of acrosome reaction. This study had three objectives: to study the in vitro effects of exogenous cholesterol on acrosome reactions in human sperm, to study the mechanism by which cholesterol affects P4-induced acrosome reaction and those induced by dibutyryl cyclic adenosine monophosphate (db-cAMP), and to study the status of the P4 surface receptor during capacitation and acrosome reaction and its relationship with cholesterol and different acrosome reaction inducers. Acrosome reaction was induced with exposure to 10 microg/mL of P4 for 30 minutes and 1 mM of db-cAMP for 30 minutes in motile sperm either in the presence or absence of 0.1-1 microg/mL of cholesterol for 30 minutes. The effects of a 30-minute exposure to 1 microg/mL of beta-sitosterol, a cholesterol plant analogue, as well as the effects of cholesterol on P4-induced acrosome reactions were compared. Fluorescein isothiocyanate-labeled albumin-progesterone conjugate (P4-FITC-BSA) was used as the probe in order to quantify the percentage of sperm in which the P, surface receptor was exposed. The results of this study indicate that cholesterol inhibited P4-induced acrosome reactions when added to the sperm during capacitation (long incubation) and when it was added with P4 during the induction of acrosome reactions (short incubation). Similarly, acrosome reaction that was induced by db-cAMP was also inhibited by cholesterol. Fifty percent of P4-induced acrosome reaction was inhibited by a cholesterol concentration of 0.2 microg/mL. Cholesterol's inhibition of induced acrosome reaction was independent of P4 concentration. Beta-sitosterol inhibited P4-induced acrosome reaction in a dose-dependent manner that was identical to that of cholesterol. We observed that increases in the P4 surface receptor exposure were time-dependent and receptors migrated toward the equatorial segment during the first 2 hours of capacitation. We also found that db-cAMP induced the appearance of the P4 surface receptor in the sperm plasma membrane and that cholesterol inhibited it. The results of this study suggest that cholesterol inhibits acrosome reaction in a noncompetitive manner by modifying the structure of the sperm plasma membrane, which prevents exposure of the P4 surface receptor for P4 binding.


Alternative Splicing Regulator RBM20 and Cardiomyopathy.
RBM20 is a vertebrate-specific RNA-binding protein with two zinc finger (ZnF) domains, one RNA-recognition motif (RRM)-type RNA-binding domain and an arginine/serine (RS)-rich region. RBM20 has initially been identified as one of dilated cardiomyopathy (DCM)-linked genes. RBM20 is a regulator of heart-specific alternative splicing and Rbm20 ΔRRM mice lacking the RRM domain are defective in the splicing regulation. The Rbm20 ΔRRM mice, however, do not exhibit a characteristic DCM-like phenotype such as dilatation of left ventricles or systolic dysfunction. Considering that most of the RBM20 mutations identified in familial DCM cases were heterozygous missense mutations in an arginine-serine-arginine-serine-proline (RSRSP) stretch whose phosphorylation is crucial for nuclear localization of RBM20, characterization of a knock-in animal model is awaited. One of the major targets for RBM20 is the TTN gene, which is comprised of the largest number of exons in mammals. Alternative splicing of the TTN gene is exceptionally complicated and RBM20 represses >160 of its consecutive exons, yet detailed mechanisms for such extraordinary regulation are to be elucidated. The TTN gene encodes the largest known protein titin, a multi-functional sarcomeric structural protein specific to striated muscles. As titin is the most important factor for passive tension of cardiomyocytes, extensive heart-specific and developmentally regulated alternative splicing of the TTN pre-mRNA by RBM20 plays a critical role in passive stiffness and diastolic function of the heart. In disease models with diastolic dysfunctions, the phenotypes were rescued by increasing titin compliance through manipulation of the Ttn pre-mRNA splicing, raising RBM20 as a potential therapeutic target.


Continuous pump-tube enteric hyperalimentation.
The enteric route remains an overlooked site of alimentation. An intact functioning gastrointestinal tract can and should be used, even if the patient will not or cannot eat. The use of continuous pump-tube feeding of liquid diets through a small caliber feeding tube into the distal part of the duodenum or proximal portion of the jejunum is superior to previous methods of bolus tube feeding through large bore tubes placed in the stomach. A small tube has been developed which is inserted easily and positioned in the distal portion of the duodenum or proximal part of the jejunum. This tube has excellent patient tolerance. A suitable pump is essential to success. Elemental diets are not needed for routine enteric alimentation. They are expensive and, because of their hyperosmolarity, require a period of patient adaptation. Isocal, a complete liquid diet, essentially isotonic and lactose-free, provides 1 calorie per milliliter and has been used successfully as a pump-tube feeding diet. It rapidly converts the nitrogen balance of patients from negative to positive when given in quantities exceeding 30 calories per kilogram of body weight.


Night-time ground hyperspectral imaging for urban-scale remote sensing of ambient PM--modal concentrations retrieval.
Retrieval of aerosol loading in vertical atmospheric columns is a common product of satellite and ground instruments that measure spectral extinction of solar radiation throughout the entire atmosphere. Here we study ground hyperspectral imaging of artificial light sources as a complementary method for retrieving fine aerosol concentrations along quazi-horizontal ambient open paths. Previously, we reported hyperspectral measurements of the aerosol optical thickness in the 500-900 nm range over urban-scale distances (180 m to 4 km), measuring the extinction of radiation emitted from a halogen source. Here we confirm in a laboratory-setup the basic premise that different accumulation-size aerosols generate distinct hyperspectral signatures in this spectral range. Measured hyperspectral attenuation signatures of fine aerosols were comparable to calculated Mie scattering signatures, suggesting that modal aerosol concentrations can be retrieved. A genetic algorithm was adapted to estimate the aerosol modal concentrations from its hyperspectral extinction signature. Retrievals of aerosol concentrations from measured and synthetic hyperspectral signatures indicated a robust algorithm, with an expected retrieval error of 0.2-22% for typical ambient concentrations along an urban-scale open path. The retrieval accuracy was found to depend on the relative aerosol modal concentrations, especially when there is a substantial overlap between the modal spectral signatures.


Barriers to HIV treatment adherence among adults living with HIV in the eastern Dominican Republic.
Despite access to nationally supplied antiretroviral treatment, viral load suppression rates remain suboptimal in the Dominican Republic. Counseling and support services are available but mainly targeted to those identified as having the most need. At Clínica de Familia La Romana (CFLR) in La Romana, all patients undergo a structured baseline interview including exploration of expected barriers to care. We conducted a retrospective cohort study of a random sample of patients at CFLR with treatment initiation between 1 January 2015 and 1 December 2017 to determine if self-identified barriers to HIV care predict viral load suppression. Viral load suppression occurred in 63% of the 203 patients evaluated. Lack of food (n = 19) was significantly associated with lack of viral suppression (OR 3.0, 95% CI 1.14-7.87). Nondisclosure of HIV status (n = 24) showed evidence for a protective effect (OR 0.33; 95% CI 0.11-1.0). Further steps should be taken to address food insecurity as well as to understand associated barriers to care among individuals with food insecurity.


New Synthetic Nitro-Pyrrolomycins as Promising Antibacterial and Anticancer Agents.
: Pyrrolomycins (PMs) are polyhalogenated antibiotics known as powerful biologically active compounds, yet featuring high cytotoxicity. The present study reports the antibacterial and antitumoral properties of new chemically synthesized PMs, where the three positions of the pyrrolic nucleus were replaced by nitro groups, aiming to reduce their cytotoxicity while maintaining or even enhancing the biological activity. Indeed, the presence of the nitro substituent in diverse positions of the pyrrole determined an improvement of the minimal bactericidal concentration (MBC) against Gram-positive (i.e., Staphylococcus aureus) or -negative (i.e., Pseudomonas aeruginosa) pathogen strains as compared to the natural PM-C. Moreover, some new nitro-PMs were as active as or more than PM-C in inhibiting the proliferation of colon (HCT116) and breast (MCF 7) cancer cell lines and were less toxic towards normal epithelial (hTERT RPE-1) cells. Altogether, our findings contribute to increase the knowledge of the mode of action of these promising molecules and provide a basis for their rationale chemical or biological manipulation.


Production of tocotrienols in seeds of cotton (Gossypium hirsutum L.) enhances oxidative stability and offers nutraceutical potential.
Upland cotton (Gossypium hirsutum L.) is an economically important multi-purpose crop cultivated globally for fibre, seed oil and protein. Cottonseed oil also is naturally rich in vitamin E components (collectively known as tocochromanols), with α- and γ-tocopherols comprising nearly all of the vitamin E components. By contrast, cottonseeds have little or no tocotrienols, tocochromanols with a wide range of health benefits. Here, we generated transgenic cotton lines expressing the barley (Hordeum vulgare) homogentisate geranylgeranyl transferase coding sequence under the control of the Brassica napus seed-specific promoter, napin. Transgenic cottonseeds had ~twofold to threefold increases in the accumulation of total vitamin E (tocopherols + tocotrienols), with more than 60% γ-tocotrienol. Matrix assisted laser desorption ionization-mass spectrometry imaging showed that γ-tocotrienol was localized throughout the transgenic embryos. In contrast, the native tocopherols were distributed unequally in both transgenic and non-transgenic embryos. α- Tocopherol was restricted mostly to cotyledon tissues and γ-tocopherol was more enriched in the embryonic axis tissues. Production of tocotrienols in cotton embryos had no negative impact on plant performance or yield of other important seed constituents including fibre, oil and protein. Advanced generations of two transgenic events were field grown, and extracts of transgenic seeds showed increased antioxidant activity relative to extracts from non-transgenic seeds. Furthermore, refined cottonseed oil from the two transgenic events showed 30% improvement in oxidative stability relative to the non-transgenic cottonseed oil. Taken together, these materials may provide new opportunities for cottonseed co-products with enhanced vitamin E profile for improved shelf life and nutrition.


Contributions to early HIV diagnosis among patients linked to care vary by testing venue.
Early HIV diagnosis reduces transmission and improves health outcomes; screening in non-traditional settings is increasingly advocated. We compared test venues by the number of new diagnoses successfully linked to the regional HIV treatment center and disease stage at diagnosis. We conducted a retrospective cohort study using structured chart review of newly diagnosed HIV patients successfully referred to the region's only HIV treatment center from 1998 to 2003. Demographics, testing indication, risk profile, and initial CD4 count were recorded. There were 277 newly diagnosed patients meeting study criteria. Mean age was 33 years, 77% were male, and 46% were African-American. Median CD4 at diagnosis was 324. Diagnoses were earlier via partner testing at the HIV treatment center (N = 8, median CD4 648, p = 0.008) and with universal screening by the blood bank, military, and insurance companies (N = 13, median CD4 483, p = 0.05) than at other venues. Targeted testing by health care and public health entities based on patient request, risk profile, or patient condition lead to later diagnosis. Test venues varied by the number of new diagnoses made and the stage of illness at diagnosis. To improve the rate of early diagnosis, scarce resources should be allocated to maximize the number of new diagnoses at screening venues where diagnoses are more likely to be early or alter testing strategies at test venues where diagnoses are traditionally made late. Efforts to improve early diagnosis should be coordinated longitudinally on a regional basis according to this conceptual paradigm.


Sludge yield and degradation of suspended solids by a large pilot-scale anaerobic membrane bioreactor for the treatment of real municipal wastewater at 25 °C.
Sludge yield and suspended solid are important factors concerned in the anaerobic treatment of municipal wastewater. In this study, a large pilot-scale anaerobic membrane bioreactor (AnMBR) was constructed for effectively treating real municipal wastewater at an ambient temperature of 25 °C. The sludge yield and the degradation of influent suspended solids were evaluated during the long-term operation of the AnMBR. This reactor with 5.0 m3 effective volume is the largest one-stage submerged AnMBR that has ever been used to treat municipal wastewater. During the long-term operation of 217 days, this AnMBR obtained excellent COD and BOD5 removal efficiency over 90%. Stable biogas production was also successfully obtained from treating municipal wastewater. The sludge yield of the AnMBR was approximately 0.19-0.26 g MLSS g-1 COD removed for the treatment of real municipal wastewater. The shortest SRT of the AnMBR was calculated as 29 days for an HRT of 6 h at an empirical MLSS of 10 g L-1. While the influent suspended solid (SS) contained in the municipal wastewater was completely removed by the AnMBR, only 57%-66% of the influent SS was degraded. The rest of influent SS was directly converted to MLSS instead of being degraded. The AnMBR maintained a stable membrane filtration using a hollow-fiber membrane with a total area of 72 m2, realizing a flux of 2.75-17.83 LMH, and the mean transmembrane pressure (TMP) was 0.9-23.5 kPa. An online chemical backwash cleaning system helped to lower the TMP timely using sodium hypochlorite and citric acid when the TMP increased rapidly and reached the rated limit of membrane. This is the first report on demonstrating the successful operation and detailed performance of a large pilot-scale AnMBR applied to the treatment of real municipal wastewater.


Time spent for activation of non-profit studies in oncology in Italy.
The aim of this paper is to describe the time spent to activate oncological non-profit clinical trials promoted in Italy by the National Cancer Institute of Naples, following the implementation of recent European laws. Data about the process of activation of 5 non-profit multicentre clinical trials were prospectively collected through a web-based system. The impact of European guidelines was assessed by comparing the efficiency of the process between applications started before and after the decree introducing in Italy the Clinical Trial Application form (MD-CTA). Outcomes of the descriptive analyses were the time to EC opinion, the time to administrative agreement signature after a positive EC opinion, and the cumulative percentage of submissions that came to closure (either positive or negative) within four subsequent time cohorts. From March 2007 to October 2009, 202 applications were submitted to 107 centres. Forty-four (59%) applications of those submitted before were successful, compared to 71 (55%) of those submitted after MD-CTA. Most of the failures were due to missing EC response (27% and 22%) or administrative reasons (10% and 16%, before and after, respectively); very few (4% and 7%) were due to EC refusal. The impact of the MD-CTA on time to EC opinion looked positive (median 4.1 vs 2.4 months, before and after, respectively) but a subgroup analysis revealed that the impact was limited to a comparison biased by the selection of EC. After a positive EC opinion, there was no difference before and after MD-CTA in the time to administrative agreement signature (median 3.6 and 3.8 months, respectively). A trend to shortening time to closure of the whole submission process over the time was evident, with 58% of the applications coming to closure within 6 months from submission in the most recent cohort. In our experience there is reassuring evidence of a trend toward shortening the time spent to activate non-profit clinical trials in Italy, but the whole process still remains inefficient. Efforts should be made to improve the process, also focusing on administrative procedures.


[Methods of reducing the number of complications and relapses after microvascular decompression in patients with trigeminal neuralgia].
Techniques and methods of preventing the disease relapses and possible postoperative complications, e.g. vestibuloatactic syndrome, impairment or loss of hearing, paresis of the mimic muscles, syndrome of intracranial hypotension etc., are suggested on the basis of an analysis of results of 94 microvascular decompression operations of the trigeminal nerve root implemented in patients with trigeminal neuralgia. A contact with venous vessel is not a reason, according to the authors, of trigeminal neuralgia. The authors point out the need in a thorough revision of all surfaces of the trigeminal nerve root (but not only of its portal zone) for the purpose of detecting and removing all possible conflict points, which significantly reduces the number of possible disease relapses. The preservation of the petrosal vein and of its tributaries and, primarily, of the lateral inversion vein of ventricle IV is an important factor in preventing the postoperative vestibular-and-cerebellar disorders. The controllable exfusion of liquor, before opening up the dura matter of the brain, facilitates the approach to the neurovascular-conflict location by avoiding tension of the roots of cranial-and-cerebral nerves. The autoliquortransfusion, made at final operation stage, ensures the recovery of the intracranial pressure to normal values, thus, preventing a possible hypotensive syndrome and hydrops labyrinthine, which can lead to an impaired hearing and vestibuloatactic syndrome.


Genetic parameters for claw health and feet and leg conformation traits in Finnish Ayrshire cows.
Genetic parameters for different claw disorders, overall claw health and feet and leg conformation traits were estimated for Finnish Ayrshire cows. The merged data set with records of claw health and feet and leg conformation traits consisted of 105,000 observations from 52,598 Finnish Ayrshire cows between 2000 and 2010. The binary claw health data and the linearly scored conformation data were analysed using an animal model and restricted maximum likelihood method by applying the statistical package ASReml. Binomial logistic models with mixed effects were used to estimate genetic parameters for sole haemorrhages, chronic laminitis, white-line separation, sole ulcer, interdigital dermatitis, heel horn erosion, digital dermatitis, corkscrew claw and overall claw health. Estimated heritabilities for different claw disorders using a binomial logistic model ranged from 0.01 to 0.20. Estimated heritability for overall claw health using a binomial logistic model was 0.08. Estimated heritabilities for feet and leg conformation traits ranged from 0.07 to 0.39. The genetic correlations between claw health and feet and leg conformation traits ranged from -0.40 to 0.42. All phenotypic correlations were close to zero. The moderate genetic correlation, together with higher heritability of feet and leg conformation traits, showed that RLSV (rear leg side view) is a useful indicator trait to be used together with claw trimming information to increase the accuracy of breeding values for claw health in genetic evaluation.


[Morphogenesis of the cranium of Cavia porcellus L. II: Comparative part and literature].
The development of the chondrocranium of Cavia porcellus is compared to those of other rodents. The tectum posterius of the investigated rodents is orientated vertically. This position is functionally caused by the attachment of the muscles of the neck and shoulder girdle. The paracondylar process is a typical feature of rodents although absent in Mesocricetus. Only in Cavia and Tatera, the connection between the lamina supraoccipitalis and the auditory capsule-the supraoccipitocapsular commissure-is missing. Youssef's (1966) generalization that the course of the notochord in rodents is of transbasal type cannot be confirmed. In Cavia, the auditory capsule is connected with the occipital region only by the exoccipitocapsular commissure. The connection between auditory capsule and basal plate is established by the alicochlear and the anterior basicapsular commissures. In comparison to other rodents, the number of commissures in Cavia is reduced. In rodents, there is always a subarcuate fossa which in later stages of development is filled out by the flocculus cerebelli. In contrary to Rajtova's (1972a) statement, Cavia shows a suprafacial commissure as all mammals do (Reinbach 1952). As the tegmen tympani is absent in Otomys and Erethizon, it is not a typical rodent feature. The carotid foramen is well developed in Cavia but the internal carotid artery obliterates until the 25 mm CRL-stage. In embryonic rodents, the ala temporalis may have a foramen ovale but not a foramen rotundum. During ontogeny rodents show the ala hypochiasmatica for the attachment of the straight muscles of the eyeball. In Cavia the ala hypochiasmatica develops independently and fuses with the postoptic root of the ala orbitalis in later stages. In myomorphs and sciumorphs, the orbitoparietal and orbitonasal commissures are present. Only in caviomorphs this part of the primary sidewall of the skull is uncomplete. Erethizon, however, shows an orbitonasal commissure whereas in Cavia both commissures are missing. In this respect the guinea-pig resembles the condition of primates. There is no interorbital septum in rodents. The nasal capsule of rodents contains 1 atrioturbinal, 1 maxilloturbinal, 1 nasoturbinal, and at least 3 ethmoturbinals. Due to the strong development of the alveoli of the incisors, the maxilloturbinale is flected in the caviomorphs. The epiphanial foramina are present. The lamina transversalis anterior is continuous with the nasal septum so that there is a complete zona anularis in rodents. The paraseptal cartilages are continuous with the lamina transversalis anterior but not with the lamina transversalis posterior.(ABSTRACT TRUNCATED AT 400 WORDS)


Wildlife identified as major source of Escherichia coli in agriculturally dominated watersheds by BOX A1R-derived genetic fingerprints.
The presence of Escherichia coli in recreational and potable waters is a major concern to the general public as elevated levels of E. coli suggest the presence of pathogenic bacteria and viruses. Unfortunately, traditional microbial techniques do not allow specific identification of the source of E. coli. This reduces the ability to target management practices that reduce bacterial contamination. In the Finger Lakes region of western New York, USA, wildlife resides in relatively high densities on watersheds dominated by people and dairy farms, and as a result, the sources of fecal degradation of potable and recreational waters are often unknown. In the Conesus Lake watershed, the sources of microbial contamination were assessed using Rep-PCR molecular tools, a method of amplifying repetitive DNA sequences found throughout the E. coli genome to produce distinct fingerprints for a given ecotype. Molecular fingerprints of E. coli isolated from regional populations of cattle, humans, geese and deer were compared to E. coli isolated from stream water samples. Canonical discriminant function analysis indicated that the DNA fingerprints of the original source group isolates were correctly predicted 90.2% of the time. Since land use in the sub-watersheds was dominated by dairy and cash crop farms, it was expected that the majority of E. coli isolated would be identified as cows; however, an unexpectedly high percentage of isolates were identified as wildlife (geese and deer). Geese were the dominant source of E. coli (44.7-73.7% of the total sources) in four sub-watersheds followed by cows (10.5-21.1%), deer (10.5-18.4%), humans (5.3-12.9%) and unidentifiable sources (0.0-11.8%). Management practices intended to decrease the number of cattle or the amount of manure spread in a sub-watershed were reflected in a decrease of E. coli ecotypes associated with dairy cows.


Polymorphism of the human complement C4 and steroid 21-hydroxylase genes. Restriction fragment length polymorphisms revealing structural deletions, homoduplications, and size variants.
Several autoimmune disorders as well as congenital adrenal hyperplasia (CAH) are either associated or closely linked with genetic variants of the fourth component of complement (C4A and C4B) and the enzyme steroid 21-hydroxylase (21-OH). These proteins are encoded by genes that are located downstream from the genes for complement proteins, C2 and factor B (BF) between HLA-B and -DR in the major histocompatibility complex (MHC). Previous studies of variants and null alleles were based on electrophoretic mobility of C4 protein and linkage with disease phenotypes. These data did not permit analysis of the basis for the observed null alleles and duplicated variants. We studied this region of the MHC in 126 haplotypes for a structural analysis of the four adjacent loci, C4A, 21-OHA, C4B, and 21-OHB. About half of the C4 genes typed as C4 null are deleted and several unrecognized homoduplicated C4 alleles were detected. Hence the frequencies of different C4 structural variants must be recalculated based on a direct analysis of the genes. Analysis of the C4/21-OH genes of patients with the classical (salt-wasting) form of CAH showed that some involve a deletion of the C4B and 21-OHB genes; whereas for two only the 21-OHB gene is deleted, i.e., the C4B gene is present. Together, these data provide a better understanding of the mechanisms generating and importance of deleted C4 and 21-OH null alleles in human disease.


The suppression of Antarctic bottom water formation by melting ice shelves in Prydz Bay.
A fourth production region for the globally important Antarctic bottom water has been attributed to dense shelf water formation in the Cape Darnley Polynya, adjoining Prydz Bay in East Antarctica. Here we show new observations from CTD-instrumented elephant seals in 2011-2013 that provide the first complete assessment of dense shelf water formation in Prydz Bay. After a complex evolution involving opposing contributions from three polynyas (positive) and two ice shelves (negative), dense shelf water (salinity 34.65-34.7) is exported through Prydz Channel. This provides a distinct, relatively fresh contribution to Cape Darnley bottom water. Elsewhere, dense water formation is hindered by the freshwater input from the Amery and West Ice Shelves into the Prydz Bay Gyre. This study highlights the susceptibility of Antarctic bottom water to increased freshwater input from the enhanced melting of ice shelves, and ultimately the potential collapse of Antarctic bottom water formation in a warming climate.


Results from a new global oral health course: a case study at one dental school.
To channel students' interest in global oral health and prepare them to respond adequately to the health effects of globalization as future practitioners, new courses in dental curricula may be needed. This article documents the results of Harvard School of Dental Medicine (HSDM)'s new course, Global Oral Health: Interdisciplinary Approaches. To the authors' knowledge, this is the first course of its kind in dental education. HSDM developed learning objectives for the course based on the literature, the training and experience of HSDM global health faculty, and the mission of the HSDM Global Health Initiative. Dental residents and public health students enrolled, and some dental students audited. The discussion-based critical thinking course examined the extensive relationship between oral health and global health, and concept development was determined by in-class participation. After taking the course, students' assessments of their global oral health knowledge increased on average 100 percent. Nearly all students reported that they were very likely to use the concepts of global oral health in their careers and that they would definitely recommend the course to others. This course model seems to have met the expectations of students and faculty, and its fundamentals appear to be readily transferrable to other dental schools.


[The chronobiological peculiarities of the hepatobiliary system function in chronic cholecystitis with dysfunction of the gallbladder].
Study of biological cycles in chronic cholecystitis with dysfunction of gallbladder has a great practical importance. The results of chronoanalysis testify a dominance of 24-hours cycle in structure of cycles of functional activity of organs of hepatobiliary system. The comparative analysis of trust intervals reveals the intensification of internal connections, expressed intensification of synchronization of cycles of functional activity of system and a breach of synchronism of central regulation and self-regulation, testifying overstrain of proper adaptive possibilities and unconcordance in system of regulation. This manifestations of desynchronization provokes development and progress of dysfunction of gallbladder and dysbalance of vegetative nervous system, that make worse the present disturbances.


Osteosarcoma in a patient with neurofibromatosis type 1: a case report and review of the literature.
Neurofibromatosis type 1 (NF1) or von Recklinghausen's disease is a genetic disease generally characterized by café-au-lait spots and neurofibromas. Malignant tumors of the nervous system, such as malignant schwannomas, gliomas, or astrocytomas, have been well known to coexist with neurofibromatosis. However, occurrence of malignant tumors unrelated to the nervous system is rare. We report an unusual case of a 29-year-old NF1 female suffering from malignant peripheral nerve sheath tumor (MPNST) that eventually developed osteosarcoma in the proximal femur. Osteosarcoma is the most common high-grade malignant bone tumor in which the neoplastic cells produce osteoid. At 23 and 24 years old, she underwent excision of MPNST in the left posterior thigh. No osteosarcomatous portion was identified in these specimens. The patient underwent postoperative chemotherapy. At 29, left proximal thigh pain and swelling appeared. Computed tomography demonstrated cortical bone destruction in the left proximal femur where MPNST occurred. Magnetic resonance imaging revealed extraskeletal growth of the tumor. Bone scintigraphy demonstrated increased uptake in the left proximal femur. Hip disarticulation was performed. The removed tumor was composed of highly anaplastic cells. Lace-like irregular osteoid formation was observed among the tumor cells. MPNST component was totally absent. The tumor was diagnosed as osteoblastic type osteosarcoma. Two months after disarticulation the patient died of bilateral pulmonary metastasis. The correlation between the histogenesis of osteosarcoma and the genetic abnormality in NF1 patients has not been elucidated, but the finding of osteosarcomatous transformation in this case suggests the divergent cellular differentiation to mesenchymal malignant tumors of neuroectodermal tissue in NF1 patients.


Snare-assisted Trans-brachial Stenting for the Cervical Internal Carotid Artery Stenosis of Patient with Aorto-Iliac Occlusion. Technical Case Report.
We describe a case of endo-luminal stent placement with Snare-assist for a cervical internal carotid artery stenosis in which percutaneous access was obtained via the brachial artery. A 68-year-old man with known disease of the carotid, peripheral, and coronary arteries, with Human T-cell Lymphotrophic Virus type-1 (HTLV-1) Associated Myelopathy (HAM) presented for endoluminal revascularization of a severe, progressive right internal carotid artery stenosis, but with aorto-iliac occlusion. Transfemoral access was complicated by an aorto-iliac occlusion. A trans-brachial approach was successfully attempted, and a SMARTer stent (Cordis Endovascular, Miami Lakes, FL) was successfully placed through a 7-French Shuttle-SL guide sheath (Cook, Bloomington) under Snare-assist. The trans-brachial approach is becoming an increasingly viable alternative route for stent placement in patients with contra-indicated or complicated femoral access routes. As devices become increasingly more pliable and smaller, the trans-brachial route will be used with increasing frequency in the select patient population for stenting of both the cervical and intracranial circulation.


A fast protein-protein docking algorithm using series expansion in terms of spherical basis functions.
We describe a fast protein-protein docking algorithm using a series expansion in terms of newly designed bases to efficiently search the entire six-dimensional conformational space of rigid body molecules. This algorithm is an ab initio docking algorithm designed to list candidates of putative conformations from a global conformational space for unbound docking. In our algorithm, a scoring function is constructed from terms that are the inner products of two scalar fields expressing individual molecules. The mapping from a molecule to a scalar field can be arbitrarily defined to express an energy term. Since this scoring scheme has the same expressiveness as that of a method using a fast Fourier transform (FFT), it has the flexibility to introduce various physicochemical energies. Currently, we are using scalar fields that approximate desolvation free energy and steric hindrance energy. Fast calculation of the scoring function for each conformation of the six-dimensional search space is realized by expansion of the fields in terms of basis functions which are combinations of spherical harmonics and modified Legendre polynomials, and the use of only low-order terms, which carry most of the information on the scalar field. We have implemented this algorithm and evaluated the computation time and precision by using actual protein structure data of complexes and their monomers. This paper presents the results for six unbound cases and in all the cases we obtained at least one conformation close to the native structures (interface RMSD < 3.0 A) within the top 1000 candidates with about 40 seconds of computation time using a single Pentium4 2.4 GHz CPU.


Citrate concentrations increase with hypoperfusion in pediatric diffuse intrinsic pontine glioma.
Citrate, a tricarboxylic acid cycle intermediate, is present in high concentrations in pediatric diffuse intrinsic pontine gliomas (DIPG). Since citrate increases during hypoxia in animal studies, we hypothesized that it accumulates in DIPG when hypoperfused. Relative tumor blood volumes (rTBV) were determined, using dynamic susceptibility contrast-enhanced magnetic resonance imaging, in twelve children [median age 8.2 (range 3.2-14.5) years] with DIPG and compared to citrate concentrations measured with in vivo proton magnetic resonance spectroscopy ((1)H MRS). Tissue perfusion and metabolite concentration were assessed at initial presentation and over the clinical course, yielding 36 and 46 perfusion and MR spectroscopy datasets, respectively. At presentation, DIPG blood volume was 60 ± 27 % of that measured for normal cerebellum. Citrate, which is not detectable in normal brain tissue, was present in DIPG at concentrations of 3.81 ± 1.44 mmol/kg tissue. Over the course of the disease and treatment, rTBV increased and citrate decreased (both p < 0.05) with an inverse correlation (p = 0.028). Citrate accumulation is associated with tissue hypoperfusion in DIPG.


The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (Mpro).
The COVID-19 pandemic, instigated by the SARS-CoV-2 coronavirus, continues to plague the globe. The SARS-CoV-2 main protease, or Mpro, is a promising target for development of novel antiviral therapeutics. Previous X-ray crystal structures of Mpro were obtained at cryogenic temperature or room temperature only. Here we report a series of high-resolution crystal structures of unliganded Mpro across multiple temperatures from cryogenic to physiological, and another at high humidity. We interrogate these datasets with parsimonious multiconformer models, multi-copy ensemble models, and isomorphous difference density maps. Our analysis reveals a temperature-dependent conformational landscape for Mpro, including mobile solvent interleaved between the catalytic dyad, mercurial conformational heterogeneity in a key substrate-binding loop, and a far-reaching intramolecular network bridging the active site and dimer interface. Our results may inspire new strategies for antiviral drug development to counter-punch COVID-19 and combat future coronavirus pandemics.


Facial paralysis in Lyme disease.
Lyme disease is a multisystemic illness caused by a tick-borne spirochete. Once considered unique to the Connecticut coastline, thousands of cases are now documented throughout the United States, northern Europe, and Australia. Unilateral and bilateral facial paralysis may occur in up to 11% of patients with Lyme disease. This paper reviews the clinical course, distinguishing features, and outcome of 124 such palsies in 101 patients seen between 1975 and 1984. The 99.2% spontaneous recovery rate demonstrates the unequivocally excellent prognosis of this palsy and confirms that operative intervention is not indicated. The otolaryngologist should consider this etiology in all otherwise idiopathic facial paralyses, especially when presenting in summer months in endemic areas, or when bilateral. Positive Lyme disease spirochete titers are helpful in the diagnosis. We believe antibiotics should be given to patients with this facial palsy in order to treat any other concurrent manifestations of the illness and to prevent subsequent complications.


[Formation and properties of S-protein complexes with S-peptide-containing hybrid polypeptides].
The fused polypeptides of human epidermal growth factor and one or two S-peptide of RNase A was shown to form stoichiometric (1:1) strong noncovalent and enzymatically active complexes with S-protein of RNase A. The dissociation constants for these complexes were found to be 5.0 x 10(-7) M and 1.1 x 10(-7) M. The complexes of polypeptides with S-protein were capable to hydrolyze ribopolynucleotides, and pyrimidine-2',3'-cyclophosphates specifically, like RNase S'. A possibility was shown of effective purification of the S-peptide-containing polypeptides by affinity chromatography in which S-protein is immobilized on solid supports.


Disturbance of kidney aldosterone sensitivity and the mechanism of its development during neurodystrophy.
It has been established that neurodystrophy resulting from the sectioning of an animal's left sciatic nerve and treatment of its central stump with formalin leads to a prolonged disturbance of the water- and salt-excreting function of the kidneys. As a rule, this is expressed as oligouria and decreased excretion of sodium in the urine. The indicated changes are due to disturbance of both intra- and extrarenal mechanisms. Intrarenal mechanisms of oligouria basically involve an acute depression in filtration of primary urine, and the hyponatriuresis is due to a decrease in the sodium load of the nephron and to an increase in the tubular reabsorption of sodium. Extrarenal mechanisms implicated in the indicated changes in sodium reabsorption involve an increased concentration of mineralocorticoid hormones of the body. Further studies have shown that the hyponatriuresis which arises during neurodystrophy is related not only to the increased concentration of the above-mentioned hormones in the fluid media of the body, but also is related to a change in the kidneys' sensitivity to them.


Slitrk6 expression profile in the mouse embryo and its relationship to that of Nlrr3.
Slitrk6 is a member of the Slitrk family of proteins, which are integral membrane proteins possessing two leucine-rich repeat (LRR) domains and a carboxy-terminal domain partially similar to that in the trk neurotrophin receptor proteins. Here, I show that Slitrk6 is uniquely expressed in various organs, different from other Slitrk genes which are predominantly expressed in neural tissues. In the developing mouse embryo, Slitrk6 expression was detected in the otic cyst, lateral trunk epidermis and its underlying mesenchymal tissue, limb bud, maxillary process, pharyngeal arches, cochlea, retina, tongue, tooth primordium, central nervous system (CNS), and the visceral organ primordia including of the lung, gastrointestinal tract (particularly in the enteric neurons) and pancreas. The expression in these organs occurred in a spatially restricted manner. In the CNS, the expression was highly compartmentalized in the dorsal thalamus, cerebellum and medulla. The expression compartment in the thalamus in which Slitrk6 was expressed was closely related to the Gbx2-expressing prosomere 2. Interestingly, the Slitrk6 expression in the CNS, cochlea, tongue, tooth primordial, and other organs was partially complementary to the expression of Nlrr3, which belongs to another family of neuronal LRR-containing transmembrane proteins. The complementary expression of the two proteins in the dorsal thalamus persisted from E13.5 to the adult stage.


Technical and economic analysis of real anaerobic digester centrate by means of partial nitrification and sustainable heterotrophic denitrification.
The reliability of partial nitrification coupled with heterotrophic denitrification for the treatment of real anaerobic digester centrate produced in a wastewater treatment plant was technically and economically assessed in two sequencing batch reactors. Removal efficiencies above 90% were consistently achieved at N-ammonium loads above 1.2 g N L⁻¹ d⁻¹. Ethanol, affluent from a waste water treatment plant (biological treatment inlet) and a zero-cost liquid residue from a chemical industry containing polyethylene glycol and sorbitol were employed as carbon source for denitrification. In this last case, a total organic carbon (TOC) requirement of 4.5 g TOC g⁻¹ NO₂⁻-N was calculated. The denitrification rate was 0.26 g NO₂⁻-N g VSS⁻¹ d⁻¹ (VSS: volatile suspended solids). These results show that a carbon-rich waste can serve as a no-cost feed for denitrifying bioreactors. An in-depth economic analysis considering the main investment and operating costs of the process was developed, showing that it can suppose yearly savings above 50% with respect to the most widely used alternative of returning anaerobic digester centrate untreated to the head of the facility.


[Locoregional recurrent rectal cancer: the place of radiotherapy].
Currently, locoregional recurrence of rectal cancer is rare due to the therapeutic progress of total mesorectal excision and pre-operative radiotherapy. Nevertheless, a curative treatment could be proposed provided that surgical removal is possible and complete. Here, we will discuss the position of both external and intra-operative radiotherapy, and concomitant chemotherapy. Actually, multimodal therapy provides the best results for local control and overall survival. Exclusive external radiotherapy is indicated for palliative treatment of unresectable cases of recurrence.


A proposed sustainable BNR plant with the emphasis on recovery of COD and phosphate.
Water problems have to be solved in an integrated way, and sustainability has become a major issue. For this reason, developing more sustainable wastewater treatment processes is needed. New discoveries and good understanding on microbial conversions of nitrogen and phosphorus make more sustainable processes possible. New options for decentralized sustainable sanitation are generally compared to conventional sewage systems, we think that for a proper comparison also innovative centralized treatment schemes should be evaluated. In this article, a more sustainable WWTP is proposed for municipal wastewater treatment, mainly based on the principles of denitrifying dephosphatation and anaerobic ammonium oxidation (ANAMMOX). The proposed system consists of a first stage of the A/B process in which maximal sludge production is achieved. In this way, COD is regained as sludge for methanation. The following BCFS and CANON processes can remove N and P with minimal or no COD need. As a potential fertiliser, struvite can easily be removed from the sludge water by adding magnesium compounds. A case study is done on the basis of the mass balance over the proposed plant. The effluent from the system has a good quality to be recycled. This could also make a contribution to meeting the world's water needs and lessening the impact on the world's water environment. Since all the separate units are already applied or tested on pilot-scale, no problems for technical implementation are foreseen.


Therapeutic Antitumor Efficacy of Cancer Stem Cell-Derived DRibble Vaccine on Colorectal Carcinoma.
Dendritic cell (DC)-based immunotherapy has been a promising strategy for colon cancer therapy, but the efficacy of dendritic cell vaccines is in part limited by immunogenicity of loaded antigens. In this study, we aimed to identify a putative tumor antigen that can generate or enhance anti-tumor immune responses against colon cancer. CD44+ colon cancer stem cells (CCSCs) were isolated from mouse colorectal carcinoma CT-26 cell cultures and induced to form defective ribosomal products-containing autophagosome-rich blebs (DRibbles) by treatment with rapamycin, bortezomib, and ammonium chloride. DRibbles were characterized by western blot and transmission electron microscopy. DCs generated from the mice bone marrow monocytes were cocultured with DRibbles, then surface markers of DCs were analyzed by flow cytometry. Meanwhile, the efficacy of DRibble-DCs was examined in vivo. Our results showed that CCSC-derived DRibbles upregulated CD80, CD86, major histocompatibility complex (MHC)-I, and MHC-II on DCs and induced proliferation of mouse splenic lymphocytes and CD8+ T cells. In a model of colorectal carcinoma using BALB/c mice with robust tumor growth and mortality, DC vaccine pulsed with CCSC-derived DRibbles suppressed tumor growth and extended survival. A lactate dehydrogenase test indicated a strong cytolytic activity of cytotoxic T-cells derived from mice vaccinated with CCSC-derived DRibbles against CT-26 cells. Furthermore, flow cytometry analyses showed that the percentages of IFN-γ-producing CD8+ T-cells were increased in SD-DC group compare with the other groups. These findings provide a rationale for novel immunotherapeutic anti-tumor approaches based on DRibbles derived from colon cancer stem cells.


A missense mutation of the muscle glycogen synthase gene (M416V) is associated with insulin resistance in the Japanese population.
Muscle glycogen synthase (GYS1) is a key enzyme of non-oxidative pathway of glucose metabolism that has been reported to be related to insulin resistance in non-insulin-dependent diabetic (NIDDM) patients. We scanned the GYS1 gene for mutation by single strand conformational polymorphism in 244 non-obese Japanese NIDDM patients and 181 non-diabetic control subjects, and found two missense mutations; Met to Val at position 416 in the exon 10 (M416V) and Pro to Ala at position 442 in the exon 11 (P442A). The P442A mutation was found in only one NIDDM patient treated with sulfonylureas. On the other hand, the M416V mutation was widely found in the Japanese population. The mutant allele frequency in the NIDDM patients (13.7%) was slightly higher but not statistically significant compared with that in non-diabetic subjects (9.7%). However, the insulin sensitivity index [SI: x 10(-4) x min(-1) x (microU/ml)(-1)] estimated by Minimal Model analysis in the NIDDM patients carrying the M416V mutation was significantly lower than that in those without the mutation (1.18 +/- 0.27, n = 21 vs 2.20 +/- 0.20, n = 60, mean +/- SEM, p < 0.01). Glucose effectiveness, age, body mass index, and levels of glycated haemoglobin and serum lipids were not significantly different between the two groups. The same trend could be seen in non-diabetic subjects (SI: 3.70 +/- 0.46, 9 subjects with the mutation vs 5.94 +/- 0.66, 19 subjects without the mutation, p < 0.05). These findings indicate that the M416V mutation of the GYS1 gene is one of the factors contributing to the insulin resistance in the Japanese population and may play some role in the pathogenesis of NIDDM.


[Principles of diabetes mellitus type 2 therapy regarding some aspects of insulin deficiency development].
Clinical examination of 224 patients with type 2 diabetes mellitus has been carried out. The role of hyperglycemia in the development of cardiovascular complications resulting from the disease was shown in the article. With pathomorphological study of pancreas carried out, vascular factor of insulin deficiency was determined. The article presents current methods of type 2 diabetes mellitus therapy.


[Criminal prosecution for medical errors].
A policy document providing instructions on the decision to prosecute in medical errors came into effect on November 1st 2010. In this document the Dutch Public Prosecution Service has attempted to make clear which criteria should be adopted when deciding to prosecute in the case of a medical error. There have also been other recent developments in this context: the public prosecutor can now demand access to medical files in certain, highly exceptional circumstances, such as when patients are themselves suspected of committing a criminal offence; and the Dutch Health Care Inspectorate may only pass on a patient's medical file to the public prosecutor if the prosecutor is already in possession of a copy of it. The new policy document leaves several questions unanswered. It does not consider the criminal liability of health care institutions, for example, and there is too much focus on the responsibilities of individual health care workers.


Effect of perceived social support on psychosocial adjustment of Turkish patients with breast cancer.
To identify the psychosocial adjustment of Turkish patients with breast cancer and the effects of perceived social support on their adjustment. The sample comprised 100 volunteering patients diagnosed with breast cancer in the last six months reporting to the Outpatient Chemotherapy Unit at the Medical Faculty Hospital in northern Turkey. The data for the study were collected through the Descriptive Information Form, the Psychosocial Adjustment to Illness Scale-Self-reflection (PAIS-SR) and the Cancer-Specific Social Support Scale and analyzed via SPSS 16.0 for Windows. Descriptive statistics, Chi square test, ANOVA and correlation were used to evaluate data. There was a negative significant correlation between mean scores in the sub-scales of the social support scale and the ones in the sub-scales of the psychosocial adjustment to illness scale (p<0.05). Similarly, there was a negative significant correlation between confidence support and health care orientation as well as adjustment to social environment. Likewise, emotional support was in a negative significant correlation with health care orientation, adjustment to domestic environment, extended family relationships and adjustment to social environment. It was concluded that social support for patients with breast cancer had an influence on their psychosocial adjustment to illness. Holistic care should be given to breast cancer patients by oncology nurses especially in the first six months of treatment. It could be concluded that patients should be accompanied by their family/relatives in treatment and care following their diagnosis with breast cancer, that their family should be made more aware of the fact that the patient should be physically and psychologically supported, that patients with breast cancer should be provided with domiciliary care, and that they should be encouraged to participate in social support groups.


Rapid detection and identification of JC virus and BK virus in human urine by using immunofluorescence microscopy.
An indirect immunofluorescence method was developed and used to detect urinary excretion of abnormal transitional cells infected with JC virus (JCV) or BK virus (BKV). This method was compared with urinary cytology, electron microscopy, viral culture, and viral serology in groups of immunosuppressed renal transplant recipients and normal controls. The indirect immunofluorescence method detected and identified JCV excretion in four persons, BKV excretion in one person, and both JCV and BKV excretion in eight others. Viral antigen was identified only in the nuclei of cytologically abnormal cells. Of these 13 persons, 8 also had polyoma virions detected in the urine by electron microscopy. With repeated study of sequential urine samples, 30% of transplant recipients and 6% of normal controls were positive by one or more microscopy methods. Serological results confirmed a high incidence of both JCV and BKV multiplication in the immunosuppressed patients. However, serology did not correlate directly with urinary virological findings. Urinary cytology and the indirect immunofluorescence method were rapid and sensitive methods for detecting and identifying urinary excretion of JCV and BKV.


Inhibition of the spontaneous apoptosis of neutrophil granulocytes by the intracellular parasite Leishmania major.
Macrophages are the major target cell population of the obligate intracellular parasites Leishmania. Although polymorphonuclear neutrophil granulocytes (PMN) are able to internalize Leishmania promastigotes, these cells have not been considered to date as host cells for the parasites, primarily due to their short life span. In vitro coincubation experiments were conducted to investigate whether Leishmania can modify the spontaneous apoptosis of human PMN. Coincubation of PMN with Leishmania major promastigotes resulted in a significant decrease in the ratio of apoptotic neutrophils as detected by morphological analysis of cell nuclei, TUNEL assay, gel electrophoresis of low m.w. DNA fragments, and annexin V staining. The observed antiapoptotic effect was found to be associated with a significant reduction of caspase-3 activity in PMN. The inhibition of PMN apoptosis depended on viable parasites because killed Leishmania or a lysate of the parasites did not have antiapoptotic effect. L. major did not block, but rather delayed the programmed cell death of neutrophils by approximately 24 h. The antiapoptotic effect of the parasites could not be transferred by the supernatants, despite secretion of IL-8 by PMN upon coculture with L. major. In vivo, intact parasites were found intracellularly in PMN collected from the skin of mice 3 days after s.c. infection. This finding strongly suggests that infection with Leishmania prolongs the survival time of neutrophils also in vivo. These data indicate that Leishmania induce an increased survival of neutrophil granulocytes both in vitro and in vivo.


Development of hepatocellular carcinoma in patients with chronic hepatitis C who had a sustained virological response to interferon therapy: a multicenter, retrospective cohort study of 1124 patients.
Interferon (IFN) improves hepatic inflammation/fibrosis and reduces the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CH-C). However, HCC develops in some patients who have a sustained virological response (SVR) to IFN therapy. We designed this study to establish a follow-up protocol for patients with CH-C who have SVR to IFN therapy. We retrospectively studied 1124 patients with CH-C who received IFN. HCC developed in 3.5% of patients with SVR to IFN. As compared with SVR patients without HCC, SVR patients with HCC were predominantly male (P=0.003), older at the initiation of IFN therapy (P=0.002), and at a more advanced histologic stage of disease (P<0.001). However, three of the 13 SVR HCC patients had mild fibrosis. The mean interval from IFN therapy to the detection of HCC in SVR HCC patients was 5.8 years and did not differ significantly from that in non-SVR HCC patients (P=0.304). Although most patients with HCC received curative therapy, the prognosis of some SVR HCC patients was poor, probably because of insufficient follow-up, resulting in delayed detection of HCC. SVR patients with CH-C who are elderly, male, or have an advanced histologic stage are at a high risk for the development of HCC after IFN therapy. We recommend that SVR patients should be observed carefully for more than 10 years after the completion of IFN therapy, even if they only have early fibrosis.


[Effect of normo- and hypobaric hypoxia on ultrastructure of the lung and myocardial tissue].
Priority of effect of oxygen concentration and/or atmospheric pressure changes on morphofunctional state of lung tissue and myocardium under exasperate influence on the organism, which lead to the development of different hypoxic states, was investigated. It was shown, that the intermittent hypoxia without barometric pressure lowering influence on ultrastructure of tissues less traumatically, then hypobaric hypoxia. Additional acute hypoxic influence and acute hemorrhage accompanied with less significant structural violations in lung tissue and myocardium of animals, which were adapted to hypobaric hypoxia. Stress exchanges were less considerable after normobaric hypoxic trainings.


Health risks of micropollutants - the need for a new approach.
Micropollutants in water provide a challenge to both science and society. The final consideration is to understand whether they are harmful to human health or to aquatic life and to determine what actions should be taken. The numbers of substances that are being identified requires a new approach to risk assessment and to solving the problem based on proper prioritisation of the needs for more targeted and multidisciplinary research delivering high quality data. The concept of threshold of toxicological concern has been applied to food and could usefully be applied to water. However, this approach also needs to be combined with practical and pragmatic assessments of the behaviour of substances in water and their removal by drinking water treatment. Such an approach provides a bridge from problem identification to problem solving.


Low-Cost Feedback Program for Reducing the Door-to-Computed Tomography Time.
Early restoration of blood flow in stroke patients can be achieved by reducing the door-to-computed tomography (DTC) time. Previous research has proposed several methods to reduce the DTC time, but the implementation costs limit its transferability. This study aimed to propose a novel, simple, and low-cost method for reducing the DTC time by providing feedback on each patient's DTC time to a small group of medical workers and physicians. A field experiment was conducted for 233 days, and the DTC time of 249 patients with stroke symptoms who were transported via ambulance to a medium-sized university hospital in Japan within 24 h after stroke onset was obtained. The first and second feedback reports on the 59th day and 154th day, respectively, were provided at the beginning of the field experiment. Using the data collected during the first 58 days as baseline data, the baseline data were compared with the post-intervention data. As part of the intervention, feedback on the DTC time for each patient was provided to six medical workers and physicians during regular meetings. The primary outcome was a continuous measure of DTC time (in min). The feedback effect hypothesis was formulated prior to data collection. In a sample of 68 patients at baseline, the mean DTC time was 18.16 min with a standard deviation of 7.38 min. As a result of the two feedback reports, in the sample with outliers, the mean and standard deviation decreased to 15.64 min and 5.97 min, respectively. The difference in means was 2.51 min (p = 0.021 in t tests). Results of the test of the equality of the standard deviations suggested that the two standard deviations were not equal (p = 0.065). The low-cost interventions successfully reduced both the mean DTC time and variation, suggesting an improvement in the quality and consistency of medical services. The result of our fine-grained analysis with a field-experiment design supports the role of feedback in achieving early treatment as suggested in the Target: Stroke initiative.


Predicting plant invasions under climate change: are species distribution models validated by field trials?
Climate change may facilitate alien species invasion into new areas, particularly for species from warm native ranges introduced into areas currently marginal for temperature. Although conclusions from modelling approaches and experimental studies are generally similar, combining the two approaches has rarely occurred. The aim of this study was to validate species distribution models by conducting field trials in sites of differing suitability as predicted by the models, thus increasing confidence in their ability to assess invasion risk. Three recently naturalized alien plants in New Zealand were used as study species (Archontophoenix cunninghamiana, Psidium guajava and Schefflera actinophylla): they originate from warm native ranges, are woody bird-dispersed species and of concern as potential weeds. Seedlings were grown in six sites across the country, differing both in climate and suitability (as predicted by the species distribution models). Seedling growth and survival were recorded over two summers and one or two winter seasons, and temperature and precipitation were monitored hourly at each site. Additionally, alien seedling performances were compared to those of closely related native species (Rhopalostylis sapida, Lophomyrtus bullata and Schefflera digitata). Furthermore, half of the seedlings were sprayed with pesticide, to investigate whether enemy release may influence performance. The results showed large differences in growth and survival of the alien species among the six sites. In the more suitable sites, performance was frequently higher compared to the native species. Leaf damage from invertebrate herbivory was low for both alien and native seedlings, with little evidence that the alien species should have an advantage over the native species because of enemy release. Correlations between performance in the field and predicted suitability of species distribution models were generally high. The projected increase in minimum temperature and reduced frosts with climate change may provide more suitable habitats and enable the spread of these species.


Idiopathic acquired diffuse osteosclerosis in a young woman.
We describe a young woman who acquired a painful, diffuse osteosclerosis of the cervical, thoracic, and lumbar spine, pelvis, and long bones of the legs as an adult. Bone densitometry showed a large increase in apparent bone density. Skeletal radiographs demonstrated progressive endosteal and periosteal thickening of the cortices. A bone scan showed increased uptake of radiolabel. The serum total alkaline phosphatase and 1,25-(OH)2D3 levels were substantially elevated and the immunoreactive PTH was mildly elevated. Bone biopsy showed increased bone turnover, especially on endocortical and intracortical surfaces, but the structural indices were normal. By 4 years after presentation the bone pain had remitted and the serum alkaline phosphatase, 1,25-(OH)2D3, and PTH were normal. No cause for the occurrence of osteosclerosis in this patient could be found.


Development of automated imaging and analysis for zebrafish chemical screens.
We demonstrate the application of image-based high-content screening (HCS) methodology to identify small molecules that can modulate the FGF/RAS/MAPK pathway in zebrafish embryos. The zebrafish embryo is an ideal system for in vivo high-content chemical screens. The 1-day old embryo is approximately 1mm in diameter and can be easily arrayed into 96-well plates, a standard format for high throughput screening. During the first day of development, embryos are transparent with most of the major organs present, thus enabling visualization of tissue formation during embryogenesis. The complete automation of zebrafish chemical screens is still a challenge, however, particularly in the development of automated image acquisition and analysis. We previously generated a transgenic reporter line that expresses green fluorescent protein (GFP) under the control of FGF activity and demonstrated their utility in chemical screens. To establish methodology for high throughput whole organism screens, we developed a system for automated imaging and analysis of zebrafish embryos at 24-48 hours post fertilization (hpf) in 96-well plates. In this video we highlight the procedures for arraying transgenic embryos into multiwell plates at 24 hpf and the addition of a small molecule (BCI) that hyperactivates FGF signaling. The plates are incubated for 6 hours followed by the addition of tricaine to anesthetize larvae prior to automated imaging on a Molecular Devices ImageXpress Ultra laser scanning confocal HCS reader. Images are processed by Definiens Developer software using a Cognition Network Technology algorithm that we developed to detect and quantify expression of GFP in the heads of transgenic embryos. In this example we highlight the ability of the algorithm to measure dose-dependent effects of BCI on GFP reporter gene expression in treated embryos.