Meeting the Challenge of Diabetes in China.
China's estimated 114 million people with diabetes pose a massive challenge for China's health policy-makers who have significantly extended health insurance coverage over the past decade. What China is doing now, what it has achieved, and what remains to be done should be of interest to health policy-makers, worldwide. We identify the challenges posed by China's two principal strategies to tackle diabetes: (1) A short-term pilot strategy of health promotion, detection and control of chronic diseases in 265 national demonstration areas (NDAs); and (2) A long-term strategy to extend health promotion and strengthen primary care capacity and health system integration throughout China. Finally, we consider how Chinese innovations in artificial intelligence (AI) and Big Data may contribute to improving diagnosis, controlling complications and increasing access to care. Health system integration in China will require overcoming the fragmentation of a system that still places excessive reliance on local government financing. Moreover, what remains to be done resembles deeper challenges faced by healthcare systems worldwide: the need to upgrade primary care and reduce inequalities in access to health services.


Urinary podocalyxin as a marker of preeclampsia in a Hispanic population.
Preeclampsia is associated with significant materno-fetal morbidity and mortality. Podocyturia due to podocyte damage seems to be associated with the disease. The objective of this study was to evaluate the usefulness of urinary podocalyxin as a marker of preeclampsia in a Hispanic population. 63 patients were studied. 25 patients had preeclampsia/eclampsia (PE-E). 38 patients had normal pregnancies and served as control group. 24 hour proteinuria, urine protein/creatinine (UPC), urinary podocalyxin and perinatal outcomes were measured. A Podocalyxin ELISA test was used to detect podocyturia. Mean age (years), mean±SD was 30.5±5.4 in normal patients vs 30.6±5.8 in PE-E, p=0.98. Median gestational age (weeks) was, 38 (range 21-42) for normal pregnancies and 36 (range 24-40) for patients with PE-E, <0.001. Urine podocalyxin/creatinine on admission (ng/mg), median [IQR] in normal patients was 55.9 [29.4, 74.9] vs 109.7 [63.8, 234.1] in PE-E, p=0.001. After adjusting for admission proteinuria, urinary podocalyxin remained independently associated with preeclampsia: OR=1.0040 (95% CI 1.0003-1.0078), p=0.03. There was low to moderate correlation between UPC and urinary podocalyxin, Spearman's =0.31, p=0.01. In PE-E, post-partum urine podocalyxin was lower, median [IQR]: 69.7 [32.7, 184.8] p=0.19 vs admission. There was a trend towards more podocyturia and proteinuria in patients with eclampsia, comparing to those with preeclampsia. There was no association observed between podocyturia and neonatal mortality, IUGR or Apgar scores. Significantly higher levels of urinary podocalyxin are seen in preeclampsia/eclampsia. They tend to normalize after delivery.


Primary cystic echinococcosis of the peritoneum: a case report.
Peritoneal cystic echinococcosis happens usually after traumatic rupture or after surgical treatment. Primary peritoneal cystic echinococcosis is a very rare case that constitutes a diagnostic and therapeutic challenge. A 30-year-old Tunisian man was admitted for hypogastric pain since 4 months. He has a 10 cm hypogastric mass. Biological-tests were normal. A computed tomography Scan showed a cystic mass on the pelvis measuring 13 × 17 cm without echinococcosis cyst in the liver. The patient was operated and we found a cystic mass of 17 cm located on the Douglas cul-de-sac that suggest a pelvic hydatid cyst. We have performed an aspiration of the cyst confirms the diagnosis followed by injection of hypertonic solution, extarction of the germinal layer and a maximal reduction of the pericyst. The postoperative course was uneventful. Trough our case, we try to focus on the diagnosis and therapeutic options of this rare entity that we should think of in front of a patient with isolated peritoneal cyst especially in endemic country.


Isoenzymes of alkaline phosphatases in seminomas. An immunohistochemical and biochemical study.
Placental alkaline phosphatase (the PLAP-like isoenzyme) and liver alkaline phosphatase (LAP) were demonstrated immunohistochemically by use of monoclonal antibodies in the tumor cells of twelve seminomas and one seminoma metastasis. Intestinal alkaline phosphatase (IAP) was not found. The PLAP-like and LAP enzymes showed high catalytic activities compared to normal testis. This is the first occasion that LAP has been demonstrated by immunochemistry in seminoma cells. The results suggest that demonstration of these tumor enzymes may be useful markers for seminomas in histopathological specimens.


Evaluation of Use of Adipose Cells in Various Procedures of Plastic Surgery and its Volumetric Quantification using High Resolution Ultrasound.
Autologous fat transfer is based on one of the principles of plastic surgery, replace like with like. It is used in wide variety of aesthetic procedures such as lip, facial augmentation and reconstructive procedures such as involutional disorders, post traumatic defects etc. This prospective study was on the use of adipose cells in various procedures of plastic surgery, the role of high resolution ultrasound in estimating the volume of the grafted fat, comparison of the results based on the different donor sites of the harvested fat and comparison of the effectiveness of grafted fat in extremities and craniofacial region. In this prospective study a total of 34 patients underwent fat grafting procedure at various sites of the body from May 2012 till November 2013. After noting the details of the patient, details of the defect, laboratory and radiological investigations, the consent for the fat grafting procedure was taken. Clinical photographs and High Resolution Ultrasound (HRUS) volume estimation was done on a regular basis as per the protocol. Out of 34 patients, 29 patients underwent free fat grafting and five patients underwent derma fat grafting. HRUS at six months revealed a mean 73.5% and 63.5% of the injected fat remained in contour deformity in extremities and craniofacial region respectively. HRUS at one year revealed a mean 57.4% and 41.4% of the injected fat remained in contour deformity in extremities and craniofacial region respectively. HRUS is an excellent handy modality for serial volume estimation, cost-effective, non-invasive, multi planar modality, does not require any preparation, and easily done outdoor procedure. Follow up is a practical proposition. Autologous fat grafting is a safe procedure with no significant complications other than fat reabsorption and it can be done under local anaesthesia in contour deformity of smaller areas. Disadvantage of autologous fat grafting is the fat reabsorption needing multiple sittings.


The BDNF Val66Met polymorphism modulates the generalization of cued fear responses to a novel context.
Brain-derived neurotrophic factor (BDNF) has a crucial role in activity-dependent synaptic plasticity and learning and memory. The human functional single-nucleotide BDNF rs6265 (Val66Met) polymorphism has been found to be associated with alteration in neural BDNF release and function correlating with altered emotional behavior. Here, we investigated for the first time the hypothesis that this polymorphism in humans modulates the context dependency of conditioned fear responses. Applying a new paradigm examining generalization of cued fear across contexts, 70 participants stratified for BDNF Val66Met polymorphism were guided through two virtual offices (context) in which briefly illuminated blue and yellow lights served as cues. In the fear context, one light (conditioned stimulus, CS+) but not the other light (CS-) was associated with an electric shock (unconditioned stimulus, US). In the safety context, both lights were presented too, but no US was delivered. During the test phase, lights were presented again both in learning contexts and in a novel generalization context without any US. All participants showed clear fear conditioning to the CS+ in the fear context as indicated by potentiation of startle responses and reports of fear. No fear reactions were found for the CS+ in the safety context. Importantly, generalization of fear responses indicated by the potentiation of startle response to the CS+ compared with the CS- in the novel context was evident only in the Met-carrying group. These are the first results to provide evidence in humans that BDNF modulates the generalization of fear responses. Such context-dependent generalization processes might predispose Met carriers for affective and anxiety disorders.


A comparative study to evaluate microstrain of low-profile attachment associated with and without bar connection in implant assisted mandibular overdenture (in vitro study).
The aim of this study was to compare the microstrain transmitted to peri-implant tissues of implant-assisted mandibular overdentures using two different low-profile attachment designs; OT- Equator attachment with and without bar attachment. A completely edentulous epoxy resin mandibular model was used, in which two parallel dental implants were inserted at the canine region bilaterally and one in the middle. Sixteen identical complete edentulous mandibular overdentures were fabricated following conventional, standardized techniques and were divided equally between two groups according to the design and placement of the OT-Equator. Group A implants were kept solitary with an OT-Equator attachment, while group B implants were kept splinted with a bar associated with two mini-OT-Equator attachments in between. Sixteen identical mandibular complete overdentures were constructed, to which attachments were picked up. The difference in stress distribution was measured using strain gauges and compared between the two studied groups. A vertical load of 100 N using the universal testing machine was applied unilaterally on the left mesial fossae of the mandibular first molar and bilaterally on the bar attached to the mandibular premolar molar region of the overdentures. Statistical analysis was conducted using IBM SPSS version 28. Normality was checked by using the Shapiro-Wilk test and normality plots. The Mann-Whitney U test was then used to analogize the groups. There was a statistically significant difference between groups A and B upon application of vertical unilateral and bilateral loadings of 100 N, with mean microstrain values of P 0.05. Group A (OT-Equator attachment) showed lower strain values than Group B (OT-Equator bar attachment) upon application of vertical, unilateral, and bilateral loadings of 100 N. Implant-assisted mandibular overdenture with a solitary attachment is associated with lower microstrain values around the implants after application of unilateral and bilateral vertical loadings of 100 N.


Patterns of extraocular innervation by the oculomotor complex in the chick.
The horseradish peroxidase retrograde tracer technique was used to map the projection pattern of the oculomotor nuclear complex to the extraocular muscles in the chick embryo. The following projection pattern was found: The dorsolateral oculomotor subnucleus innervates the ipsilateral inferior rectus muscle, the dorsomedial subnucleus innervates the ipsilateral medial rectus muscle, a lateral division of the ventromedial subnucleus innervates the ipsilateral inferior oblique muscle, and a medial division of the ventromedial subnucleus innervates the contralateral superior rectus muscle. The so-called central nucleus also innervates the contralateral superior rectus muscle. This pattern was extremely discrete, with virtually no overlapping representations. These results provide the first evidence for a functional medial-lateral subdivision of the ventromedial subnucleus. This pattern relates to the unusual development of this subnucleus and suggests that only part of the primordium for this cell group migrates across the midline during its ontogeny, rather than all of it, as was previously believed. The subnuclear organization of the avian oculomotor complex is also considered in comparison to such functional organization in other species.


Comparison of pharmacokinetics of danofloxacin and enrofloxacin in calves challenged with Mannheimia haemolytica.
To compare concentrations of danofloxacin, enrofloxacin, and ciprofloxacin in plasma and respiratory tissues of calves treated after challenge with Mannheimia haemolytica. 75 calves. 24 hours after challenge with M. haemolytica, 72 calves with clinical signs of respiratory tract disease were randomly assigned to 1 of 12 equal treatment groups. Three nonchallenged, nontreated calves formed a control group. Challenged calves were treated with danofloxacin (6 and 8 mg/kg, SC) and enrofloxacin (8 mg/kg, SC) once. At 1, 2, 6, and 12 hours after treatment, 6 calves from each treatment group were euthanatized. Antimicrobial drug concentrations were assayed in various specimens. Peak plasma concentration (Cmax)-to-minimum inhibitory concentration (MIC; Cmax-to-MIC) ratios and the area under the concentration versus time curve over a 12-hour period-to-MIC ratios (AUC(12h)-to-MIC) were calculat-ed. Danofloxacin and enrofloxacin had MICs of 0.03 microg/mL for the M. haemolytica challenge isolate. Danofloxacin administered at doses of 6 and 8 mg/kg resulted in numerically higher geometric mean concentrations of danofloxacin in plasma and all respiratory tissues than geometric mean concentrations of enrofloxacin after treatment with enrofloxacin. Geometric mean concentrations of enrofloxacin were numerically higher than geometric mean concentrations of ciprofloxacin metabolite in plasma and almost all respiratory tissues. Danofloxacin and enrofloxacin achieved Cmax-to-MIC ratios >10 and AUC(12h)-to-MIC ratios >125 hours. When used to treat pneumonic pasteurellosis in calves, danofloxacin and enrofloxacin can be expected to deliver concentration-dependent bactericidal activity against M. haemolytica, the bacteria most commonly associated with bovine respiratory tract disease.


New perspectives on pancreatic islet glucokinase.
Control of blood sugar involves the complex interaction of the pancreatic glucose-sensing beta-cells with the liver, which serves as the primary site of glucose disposal after a meal. Glucokinase occupies an important role in controlling glucose phosphorylation and metabolism both in the liver and in pancreatic islets. In the beta-cells, glucokinase functions as pacemaker of glycolysis at physiological glucose levels. It determines the unique characteristics of islet hexose usage, that is, the rate, affinity, cooperativity, and anomeric discrimination of glucose metabolism. Because glycolysis controls hexose-induced insulin release, glucokinase is considered the best-qualified candidate for the elusive glucose sensor of beta-cells. A deficiency of glucokinase would disturb glucose homeostasis. Decreased islet glucokinase would diminish islet glycolysis and would result in a higher set point of beta-cells for glucose-induced insulin release. Decreased liver glucokinase would cause less efficient hepatic glucose disposal. Human maturity-onset diabetes (type II diabetes) has these characteristics. It is thus conceivable that certain forms of type II diabetes are due to a glucokinase deficiency.


Lens opacities in children using methylphenidate hydrochloride.
To assess clinical findings of eye examination in children having attention deficit hyperactivity disorder (ADHD) administered with methylphenidate hydrochloride. Fifty-seven consecutive patients diagnosed of ADHD and administered with oral methylphenidate hydrochloride treatment for at least one year were involved in this study (Group 1). Sixty healthy subjects (Group 2) having demographic features similar to group 1 were involved as a control group. All patients underwent detailed ophthalmological examination. One hundred and seventeen consecutive subjects with a mean age of 11.2 ± 2.4 years (7-18 years) were enrolled. Fifty-seven consecutive patient (32 males, 25 females) under oral methylphenidate hydrochloride treatment (Group 1) and 60 healthy control subjects (30 males, 30 females) (Group 2)) were recruited for this prospective study. The mean methylphenidate hydrochloride dosage was 0.9 ± 0.1 mg/kg/day and the mean duration of methylphenidate hydrochloride usage was for 2.73 ± 0.73 years (1-7 years). High intraocular pressure was not observed in any of the patients in our study. We detected lens opacities in five eyes of five patients in group 1 (p = 0.019). The patient with the highest degree of cataract formation had been using MPH for 84 months and this patient's cataract score was P4. Long-term use of methylphenidate may cause lens opacities. In particular, patients who have been using methylphenidate for more than two years should go for regular eye examination.


Sumoylated MEF2A coordinately eliminates orphan presynaptic sites and promotes maturation of presynaptic boutons.
Presynaptic differentiation of axons plays a fundamental role in the establishment of neuronal connectivity. However, the mechanisms that govern presynaptic differentiation in the brain remain largely to be elucidated. We report that knockdown of the transcription factor MEF2A in primary neurons and importantly in the rat cerebellar cortex in vivo robustly increases the density of orphan presynaptic sites. Remarkably, the sumoylated transcriptional repressor form of MEF2A drives the suppression of orphan presynaptic sites. We also identify the gene encoding synaptotagmin 1 (Syt1), which acts locally at presynaptic sites, as a direct repressed target gene of sumoylated MEF2A in neurons, and demonstrate that repression of Syt1 mediates MEF2A-dependent elimination of orphan presynaptic sites. Finally, we uncover a role for the MEF2A-induced elimination of orphan presynaptic sites in the accumulation of presynaptic material at large maturing presynaptic boutons. Collectively, these findings define sumoylated MEF2A and Syt1 as components of a novel cell-intrinsic mechanism that orchestrates presynaptic differentiation in the mammalian brain. Our study has important implications for understanding neuronal connectivity in brain development and disease.


Nimotuzumab promotes radiosensitivity of EGFR-overexpression esophageal squamous cell carcinoma cells by upregulating IGFBP-3.
Epidermal growth factor receptor (EGFR) is suggested to predict the radiosensitivity and/or prognosis of human esophageal squamous cell carcinoma (ESCC). The objective of this study was to investigate the efficacy of Nimotuzumab (an anti-EGFR monoclonal antibody) on ESCC radiotherapy (RT) and underlying mechanisms. Nimotuzumab was administrated to 2 ESCC cell lines KYSE30 and TE-1 treated with RT. Cell growth, colony formation and apoptosis were used to measure anti-proliferation effects. The method of RNA interference was used to investigate the role of insulin-like growth factor binding protein-3 (IGFBP-3) in ESCC cells radiosensitivity treated with Nimotuzumab. In vivo effect of Nimotuzumab on ESCC radiotherapy was done using a mouse xenograft model. Nimotuzumab enhanced radiation response of KYSE30 cells (with high EGFR expression) in vitro, as evidenced by increased radiation-inhibited cell growth and colony formation and radiation-mediated apoptosis. Mechanism study revealed that Nimotuzumab inhibited phosphorylated EGFR (p-EGFR) induced by EGF in KYSE30 cells. In addition, knockdown of IGFBP-3 by short hairpin RNA significantly reduced KYSE30 cells radiosensitivity (P<0.05), and even after the administration of Nimotuzumab, the RT response of IGFBP-3 silenced KYSE30 cells was not enhanced (P>0.05). In KYSE30 cell xenografts, Nimotuzumab combined with radiation led to significant tumor growth delay, compared with that of radiation alone (P=0.029), and also with IGFBP-3 up-regulation in tumor tissue. Nimotuzumab could enhance the RT effect of ESCC cells with a functional active EGFR pathway. In particular, the increased ESCC radiosensitivity by Nimotuzumab might be dependent on the up-regulation of IGFBP-3 through EGFR-dependent pathway.


Evaluation of adhesion to buccal epithelial cells in Candida species obtained from denture wearers after exposure to fluconazole.
The aim of this study was to assess the adhesion ability by Candida spp. obtained from denture wearer patients with and without denture stomatitis and the possible reduction in adhesion after exposure to fluconazole. Nine C. tropicalis, five C. glabrata and two C. parapsilosis obtained from the oral cavity of patients with denture stomatitis and 11 C. tropicalis, nine C. glabrata and six C. parapsilosis obtained from the oral cavity of denture wearers with normal palatal mucosa were compared for adhesion ability to buccal epithelial cells (BEC) and reduction in adhesion after exposure to fluconazole. Candida spp. obtained from denture stomatitis patients were more adherent to BEC, and there was a reduction in adhesion after exposure to fluconazole in all the species tested. Our results demonstrated that exposure to fluconazole reduces Candida spp. adherence to BEC. These results also suggest that adhesion, even in non-albicans species, could be factors that, along with predisposing conditions related to the host, determine if an individual will develop disease or remain as a healthy carrier and confirm that fluconazole has an impact in the adherence ability in Candida spp.


Neonatal iron distribution and infection susceptibility in full term, preterm and low birthweight babies in urban Gambia: study protocol for an observational study.
Background: Neonatal infection is the third largest cause of death in children under five worldwide. Nutritional immunity is the process by which the host innate immune system limits nutrient availability to invading organisms. Iron is an essential micronutrient for both microbial pathogens and their mammalian hosts. Changes in iron availability and distribution have significant effects on pathogen virulence and on the immune response to infection. Our previously published data shows that, during the first 24 hours of life, full-term neonates have reduced overall serum iron. Transferrin saturation decreases rapidly from 45% in cord blood to ~20% by six hours post-delivery. Methods: To study neonatal nutritional immunity and its role in neonatal susceptibility to infection, we will conduct an observational study on 300 full-term normal birth weight (FTB+NBW), 50 preterm normal birth weight (PTB+NBW), 50 preterm low birth weight (PTB+LBW) and 50 full-term low birth weight (FTB+LBW), vaginally-delivered neonates born at Kanifing General Hospital, The Gambia. We will characterize and quantify iron-related nutritional immunity during the early neonatal period and use ex vivo sentinel bacterial growth assays to assess how differences in serum iron affect bacterial growth. Blood samples will be collected from the umbilical cord (arterial and venous) and at serial time points from the neonates over the first week of life. Discussion: Currently, little is known about nutritional immunity in neonates. In this study, we will increase understanding of how nutritional immunity may protect neonates from infection during the first critical days of life by limiting the pathogenicity and virulence of neonatal sepsis causing organisms by reducing the availability of iron. Additionally, we will investigate the hypothesis that this protective mechanism may not be activated in preterm and low birth weight neonates, potentially putting these babies at an enhanced risk of neonatal infection. Trial registration: clinicaltrials.gov ( NCT03353051) 27/11/2017.


Comparison of pregnancy outcomes following intrauterine insemination in young women with decreased versus normal ovarian reserve.
To evaluate pregnancy outcomes following intrauterine insemination (IUI) in young women with low ovarian reserve compared to age-matched controls. Retrospective cohort SETTING: Single infertility center (July 2001-August 2018) PATIENT(S): Patients <35 years of age undergoing at least one IUI cycle with a documented serum anti-Müllerian hormone (AMH) level, patent fallopian tubes, and total motile sperm count of ≥10 million at the time of IUI. None MAIN OUTCOME MEASURE(S): The primary outcome was the presence of a positive serum hCG pregnancy test (>2 mIU/mL) obtained 2 weeks after the IUI procedure. Secondary outcomes included the incidence of live birth, biochemical loss, clinical miscarriage, and ectopic pregnancy. Additionally, cumulative reproductive outcomes including up to seven IUI cycles were calculated and compared between groups. A post-hoc power calculation demonstrated that the study sample size yielded >80% power to detect a 7% difference between groups in the primary outcome. There were 3019 patients included: 370 with AMH <1.0 ng/mL and 2649 with AMH ≥1.0 ng/mL. When adjusting for IUI treatment strategy, number of dominant follicles at time of IUI and body mass index, no difference in per-cycle or cumulative reproductive outcomes was identified between patients with low AMH (<1.0 ng/mL) and normal AMH (≥1.0 ng/mL). Analyses by treatment strategy also showed no difference in reproductive outcomes. Young patients (<35 years of age) with diminished ovarian reserve conceived as often and had per-cycle and cumulative pregnancy outcomes similar to those of age-matched controls after IUI, regardless of treatment strategy.


Crime seriousness and participation in restorative justice: The role of time elapsed since the offense.
Restorative justice policies and programs aimed at facilitating victim-offender mediation (VOM) are part of many criminal justice systems around the world. Given its voluntary nature and potential for positive outcomes, the appropriateness and feasibility of VOM after serious offenses is subject to debate in the literature. In light of this discussion, this study first aimed to unravel the prevalence of serious offenses in cases registered for VOM and examined whether crime seriousness predicts whether mediated contact is reached between victims and offenders. Second, it tested the hypothesis that victims of increasingly serious, harmful crimes are more willing to participate when more time has elapsed since the offense-in contrast to victims of less serious, harmful crimes. We analyzed 199 cases registered for VOM in the Netherlands and coded the perceived wrongfulness, harmfulness, and average duration of incarceration of an offense as 3 distinct indicators of crime seriousness in these cases. The findings revealed that cases registered for VOM (a) are, in terms of the incarceration duration, on average more serious than all offenses in the population, and (b) resulted in mediated contact (or not) independently of the 3 seriousness indicators. In addition, empirical support was found for the hypothesis that victims' willingness to participate in VOM increased over time after more harmful offenses, whereas it decreased when offenses inflicted less harm. These findings suggest that when VOM programs operate irrespectively of the time elapsed after crime, mediated contact between parties may be as likely after minor and serious offenses. (PsycINFO Database Record


Rem2 is an activity-dependent negative regulator of dendritic complexity in vivo.
A key feature of the CNS is structural plasticity, the ability of neurons to alter their morphology and connectivity in response to sensory experience and other changes in the environment. How this structural plasticity is achieved at the molecular level is not well understood. We provide evidence that changes in sensory experience simultaneously trigger multiple signaling pathways that either promote or restrict growth of the dendritic arbor; structural plasticity is achieved through a balance of these opposing signals. Specifically, we have uncovered a novel, activity-dependent signaling pathway that restricts dendritic arborization. We demonstrate that the GTPase Rem2 is regulated at the transcriptional level by calcium influx through L-VGCCs and inhibits dendritic arborization in cultured rat cortical neurons and in the Xenopus laevis tadpole visual system. Thus, our results demonstrate that changes in neuronal activity initiate competing signaling pathways that positively and negatively regulate the growth of the dendritic arbor. It is the balance of these opposing signals that leads to proper dendritic morphology.


Screening for Alzheimer's Disease: Cognitive Impairment in Self-Referred and Memory Clinic-Referred Patients.
Cognitive assessment is essential in tracking disease progression in AD. Presently, cohorts including preclinical at-risk participants are recruited by different means, which may bias cognitive and clinical features. We compared recruitment strategies to levels of cognitive functioning. We investigate recruitment source biases in self-referred and memory clinic-referred patient cohorts to reveal potential differences in cognitive performance and demographics among at-risk participants. We included 431 participants 40-80 years old. Participants were classified as controls (n = 132) or symptom group (n = 299). The symptom group comprised of subjective cognitive decline (SCD, n = 163) and mild cognitive impairment (MCI, n = 136). We compared cognitive performance and demographics in memory clinic-referrals (n = 86) to self-referred participants responding to advertisements and news bulletins (n = 179). Participants recruited by other means were excluded from analysis (n = 34). At symptom group level, we found significant reductions in cognitive performance in memory clinic-referrals compared to self-referrals. However, here reductions were only found within the MCI group. We found no differences in cognitive performance due to recruitment within the SCD group. The MCI group was significantly impaired compared to controls on all measures. Significant reductions in learning, and executive functions were also found for the SCD group. Regardless of recruitment method, both the SCD and MCI groups showed reductions in cognitive performance compared to controls. We found differences in cognitive impairment for memory clinic-referrals compared to self-referrals only within the MCI group, SCD-cases being equally affected irrespective of referral type.


[First results of emergency treatment in massive fulminant lung embolism by means of a rapidly injected streptokinase in a high initial dose (author's transl)].
Five cases of patients with massive fulminant lung embolism are reported who were successfully reanimated in spite of one or several cardiac arrests by bolus injection of 750,000 to 1,000,000 I.U. streptokinase applicated intraveneously within a few seconds up to about 3 min. The effect of this rapidly injected high initial dose of streptokinase on the embolus in the A. pulmonalis and on the disturbed microcirculation in prefinale states of shock is discussed. In consequence of the aggressive therapy with streptokinase severe haemorrhagic complications occurred in all cases reported. As the patients would not have survived the massive fulminant lung embolism without this therapy it is concluded that in certain cases of fulminant lung embolism the bolus injection of streptokinase should be tried besides other measures of reanimation as a ultima ratio in spite of a contraindicated lysis. We think that this aggresive therapy is indicated for patients with massive fulminant lung embolism who were treated in a conventional way without success, who could not be operated or who had already suffered from a cardiac arrest. It is suggested to treat a massive fulminant lung embolism not only with conventional measures of reanimation but also with rapid i.v.-injection of 750,000 to 1,000,000 I.U. of streptokinase.


Setting up a nurse-run young person's drop-in clinic.
This article explains the background and work of a young person's drop-in clinic which was set up by the author in lpswich. Over a 16-week period the clinic saw 17 clients, most of them (n = 11) female. Issues raised included child protection, depression, bullying and sexuality. Seven clients were referred to other health professionals and social care.


AIRE is a critical spindle-associated protein in embryonic stem cells.
Embryonic stem (ES) cells go though embryo-like cell cycles regulated by specialized molecular mechanisms. However, it is not known whether there are ES cell-specific mechanisms regulating mitotic fidelity. Here we showed that Autoimmune Regulator (Aire), a transcription coordinator involved in immune tolerance processes, is a critical spindle-associated protein in mouse ES(mES) cells. BioID analysis showed that AIRE associates with spindle-associated proteins in mES cells. Loss of function analysis revealed that Aire was important for centrosome number regulation and spindle pole integrity specifically in mES cells. We also identified the c-terminal LESLL motif as a critical motif for AIRE's mitotic function. Combined maternal and zygotic knockout further revealed Aire's critical functions for spindle assembly in preimplantation embryos. These results uncovered a previously unappreciated function for Aire and provide new insights into the biology of stem cell proliferation and potential new angles to understand fertility defects in humans carrying Aire mutations.


The protease-activated receptor-2 upregulates keratinocyte phagocytosis.
The protease-activated receptor-2 (PAR-2) belongs to the family of seven transmembrane domain receptors, which are activated by the specific enzymatic cleavage of their extracellular amino termini. Synthetic peptides corresponding to the tethered ligand domain (SLIGRL in mouse, SLIGKV in human) can activate PAR-2 without the need for receptor cleavage. PAR-2 activation is involved in cell growth, differentiation and inflammatory processes, and was shown to affect melanin and melanosome ingestion by human keratinocytes. Data presented here suggest that PAR-2 activation may regulate human keratinocyte phagocytosis. PAR-2 activation by trypsin, SLIGRL or SLIGKV increased the ability of keratinocytes to ingest fluorescently labeled microspheres or E. coli K-12 bioparticles. This PAR-2 mediated increase in keratinocyte phagocytic capability correlated with an increase in actin polymerization and *-actinin reorganization, cell surface morphological changes and increased soluble protease activity. Moreover, addition of serine protease inhibitors downmodulated both the constitutive and the PAR-2 mediated increases in phagocytosis, suggesting that serine proteases mediate this functional activity in keratinocytes. PAR-2 involvement in keratinocyte phagocytosis is a novel function for this receptor.


CPAF selectively degrades chlamydial T cell antigens for inhibiting antigen presentation.
Chlamydia trachomatis is the leading cause of sexually transmitted bacterial disease, which may cause significant threats, such as pelvic inflammatory disease and tubal factor infertility, to women if untreated. The pathological mechanisms of chlamydia-induced disease remain largely unknown, but it has been proposed that CPAF, a chlamydia-secreted serine protease, may play major roles in aiding chlamydial infection and contribute to chlamydia pathogenesis during in vivo infection. According to previous results, CPAF targets host immunity by degrading antimicrobial peptides and neutralizing complement activity; however, whether CPAF is involved in chlamydial antigen presentation has never been reported. Antigen presentation assay was used to monitor the effects of CPAF on OT1-, OT2-, and chlamydia T cell antigen-mediated antigen presentation. In vitro cell-free degradation assay was used to detect CPAF processing of chlamydia T cell antigens. We found that CPAF preferably inhibits OT2- but not OT1-mediated antigen presentation. CPAF inhibits OT2 antigen presentation by direct proteolytic cleavage in the wild type CPAF, but not enzymatic mutants. Importantly, several previously identified chlamydial T cell antigens were selectively degraded by CPAF when co-incubated in vitro. In addition, specific inhibition T cell antigen presentation by CPAF was correlated with T cell antigen cleavage by CPAF in vitro assay. Our experiments demonstrated that CPAF selectively and specifically degrades chlamydial T cell antigens, which chlamydia may utilize as a novel mechanism for evading host immune responses to promote chlamydia survival.


Controlling dipole transparency with magnetic fields.
We describe how magnetic fields can be exploited to control dipole-induced transparency in quantum dot cavity systems. Coupling a linearly-polarized microcavity mode to two spin charged exciton states of a single quantum dot, we demonstrate how cavity-mediated interference and magnetic-field resonance shifts can be utilized to control the transmission of light and on-chip photons, in both magnitude and phase. In particular, we show a triple resonance feature, which also survives with weakly coupled cavities, as long as one operates in the good cooperativity regime. The central peak, which is mediated by the applied magnetic field, is shown to exhibit spectral squeezing. We also demonstrate how the magnetic field allows five regions in which the phase changes by 2π over a small frequency window, where a possible phase gate could be implemented.


[Study of the photodynamic effect of new photosensitizers on the single neuron].
We studied reactions of isolated crayfish mechanoreceptor neurons to photodynamic effects of various photosensitizers: methylene blue, chlorins e6 and p6, sulfated allumophthalocyanin Photosens, Janus green B, protoporphyrin IX, and two derivatives of hematoporphyrin IX, Photoheme and Photosan-3. The neurons were irradiated by a helium-neon laser (632.8 nm, 0.3 Wt/cm3) after 30-min photosensitization. They proved to be very sensitive to the photodynamic effect: When the cells stained by photosensitizers at nanomolar concentrations were irradiated, their firing activity underwent irreversible changes and they died. The dynamics of the firing activity of the neurons depended on the photosensitizer type and concentration. Photosens, Photoheme and chlorin p6 proved to be the most efficient.


p73 Induces apoptosis via PUMA transactivation and Bax mitochondrial translocation.
p73, an important developmental gene, shares a high sequence homology with p53 and induces both G(1) cell cycle arrest and apoptosis. However, the molecular mechanisms through which p73 induces apoptosis are unclear. We found that p73-induced apoptosis is mediated by PUMA (p53 up-regulated modulator of apoptosis) induction, which, in turn, causes Bax mitochondrial translocation and cytochrome c release. Overexpression of p73 isoforms promotes cell death and bax promoter transactivation in a time-dependent manner. However, the kinetics of apoptosis do not correlate with the increase of Bax protein levels. Instead, p73-induced mitochondrial translocation of Bax is kinetically compatible with the induction of cell death. p73 is localized in the nucleus and remains nuclear during the induction of cell death, indicating that the effect of p73 on Bax translocation is indirect. The ability of p73 to directly transactivate PUMA and the direct effect of PUMA on Bax conformation and mitochondrial relocalization suggest a molecular link between p73 and the mitochondrial apoptotic pathway. Our data therefore indicate that PUMA-mediated Bax mitochondrial translocation, rather than its direct transactivation, correlates with cell death. Finally, human DeltaNp73, an isoform lacking the amino-terminal transactivation domain, inhibits TAp73-induced as well as p53-induced apoptosis. The DeltaNp73 isoforms seem therefore to act as dominant negatives, repressing the PUMA/Bax system and, thus, finely tuning p73-induced apoptosis. Our findings demonstrate that p73 elicits apoptosis via the mitochondrial pathway using PUMA and Bax as mediators.


Insulin-like growth factor binding proteins in follicular fluid from normal dominant and cohort follicles, polycystic and multicystic ovaries.
There is now considerable evidence that the insulin-like growth factors (IGFs) play an important role in the human ovary. It has also recently become apparent that the physiological activity of the IGFs is modulated by a number of specific binding proteins (IGFBPs). In order to understand the role of the IGFs in ovarian physiology, the presence and functions of these IGFBPs will need to be characterized. As an initial step towards this we have investigated the presence of the various binding proteins by Western ligand blotting and have measured the levels of one of them, IGFBP-1, in follicular fluid (FF) obtained from unstimulated dominant and cohort follicles in 19 normal women and in eight patients with polycystic and one with multicystic ovaries. In normal women, IGFBP-1 levels in dominant follicles were similar to matched serum levels but were significantly lower in cohort follicles. IGFBP-1 levels correlated with FF-volume (r = 0.58, P less than 0.001) and with paired serum levels (r = 0.63, P less than 0.001). In post-LH surge dominant follicles this relationship with serum levels no longer held and in three out of nine subjects FF levels were higher than in serum. Thus IGFBP-1 in normal human FF appears to be partly derived from the circulation but with additional local production in the larger developing dominant follicles. Western ligand blotting revealed five IGF-binding proteins in FF running parallel with those identified in serum, suggesting that the IGFBP species previously identified in serum may also be present in FF. The two bands in positions corresponding to the components of the large (150kDa) binding complex were, as in serum, the predominant forms and in most FF samples these were even more prominent than in the accompanying serum sample. This contrasts with previous studies in lymph which suggested that the 150kDa complex was largely retained in the circulation. All three small IGFBPs varied considerably between FF samples even within an individual; each IGFBP varied independently of the other IGFBPs. Our results demonstrate that at least four discrete IGFBPs are present in FF and suggest that each may be produced independently within the ovary.


Acute myocardial infarction with concomitant pulmonary embolism as a result of patent foramen ovale.
Acute myocardial infarction (MI) and pulmonary embolism canal one lead to life-threatening conditions such as sudden cardiac death and congestive heart failure. We discuss a case of a 74-year-old man presented to the emergency department with acute dyspnea and chest pain. Acute anterior MI and pulmonary embolism concomitantly were diagnosed. Primary percutaneous coronary intervention performed because of preliminary acute anterior MI diagnosis. Transthoracic echocardiography was performed to determine further complications caused by acute MI because patient had a continuous tachycardia and dyspnea although hemodynamically stable. Transthoracic echocardiography revealed a thrombus that was stuck into the patent foramen ovale with parts in right and left atria. Anticoagulation therapy was started; neither fibrinolytic therapy nor operation was performed because of low survey expectations of the patient's recently diagnosed primary disease stage IV lung cancer. Patient was discharged on his 20th day with oral anticoagulation and antiagregant therapy.


Global effects of the cell-to-cell signaling molecules autoinducer-2, autoinducer-3, and epinephrine in a luxS mutant of enterohemorrhagic Escherichia coli.
Intrakingdom cell-to-cell communication and interkingdom cell-to-cell communication play essential roles in the virulence of enterohemorrhagic Escherichia coli (EHEC). Four signals, autoinducer 2 (AI-2), AI-3, and the human hormones epinephrine and norepinephrine, are important in this communication. The effect of these signaling compounds on the transcriptome of EHEC was examined in this study. We demonstrated that the luxS mutation affects primarily central metabolic genes in both pathogenic and nonpathogenic strains of E. coli and that addition of exogenous AI-2 does not fully restore the expression profile in a luxS-deficient strain lacking the ability to synthesize AI-2. Addition of AI-3 or epinephrine increased expression of the locus of enterocyte effacement regulon, which is known to play a pivotal role in EHEC virulence. Moreover, when epinephrine was added to the culture medium, the greatest number of gene alterations was observed. These alterations included a greater proportion of alterations in EHEC genes than in MG1655 genes, suggesting that epinephrine may be a global virulence signal. Detailed examination with real-time reverse transcriptase PCR (RT-PCR) confirmed the increases in virulence gene expression with addition of AI-3 and epinephrine. Additional studies with real-time RT-PCR examining the EHEC secreted effectors and putative fimbrial gene expression showed a variable expression profile, indicating that there is differential regulation of the secreted molecules. This study began to examine the global signaling networks in EHEC and revealed expression profiles that are signal and pathogen specific.


Telehealth Monitoring of Patients with Schizophrenia and Suicidal Ideation.
A telehealth system was developed to monitor risk following hospitalization for suicidal ideation. We hypothesized that 3 months of telehealth monitoring will result in a greater reduction in suicidal ideation. Veterans with schizophrenia admitted with recent suicidal ideation and/or a suicidal attempt were recruited into a discharge program of VA Usual Care with daily Health Buddy© monitoring (HB) or Usual Care (UC) alone. Fifteen of 25 were randomized to HB and 10 received UC. Daily adherence in the use of the HB system during months 1-3 was, respectively, 86.9%, 86.3%, and 84.1%. There were significant improvements in Beck Scale for Suicide Ideation scores in HB participants. There were no changes in depressive symptoms. Telehealth monitoring for this population of patients appears to be feasible.


In vitro fertilization of in vitro-matured equine oocytes: effect of maturation medium, duration of maturation, and sperm calcium ionophore treatment, and comparison with rates of fertilization in vivo after oviductal transfer.
Three experiments were conducted to evaluate the effect of oocyte and sperm treatments on rates of in vitro fertilization (IVF) in the horse and to determine the capacity of in vitro-matured horse oocytes to be fertilized in vivo. There was no effect of duration of oocyte maturation (24 vs. 42 h) or calcium ionophore concentration during sperm capacitation (3 microM vs. 7.14 microM) on in vitro fertilization rates. Oocytes matured in 100% follicular fluid had significantly higher fertilization (13% to 24%) than did oocytes matured in maturation medium or in 20% follicular fluid (0% to 12%; P < 0.05). There was no significant difference in fertilization rate among 3 sperm treatments utilizing 7.14 microM calcium ionophore (12% to 21%). Of in vitro-matured oocytes recovered 40-44 h after transfer to the oviducts of inseminated mares, 77% showed normal fertilization (2 pronuclei to normal cleavage). Cleavage to 2 or more cells was seen in 22% of oocytes matured in follicular fluid and 63% of oocytes matured in maturation medium; this difference was significant (P < 0.05). We conclude that in vitro-matured horse oocytes are capable of being fertilized at high rates in the appropriate environment and that in vitro maturation of oocytes in follicular fluid increases fertilization rate in vitro but reduces embryo development after fertilization in vivo. Further work is needed to determine the optimum environment for sperm capacitation and IVF in the horse.


[Evaluation of Conversion Factors for Genetically Modified Maize Quantification].
To quantify the amount of authorized GM maize or soybean, conversion factor (Cf) values are required for converting the copy number ratio of GM sequence to an endogenous sequence into weight-based GMO amounts. Cf values are available for the several latest real-time PCR instruments such as QuantStudio5, QuantStudio12K Flex, LightCycler 96, and LightCycler 480 for GM soybeans but not for GM maize. For the quantification of GM maize, we experimentally determined the Cf values targeting Cauliflower mosaic virus 35S promoter (P35S), GA21 construct specific, MIR604 event specific and MIR162 event specific sequences using the four real-time PCR instruments.


Adenosine-induced renal vasoconstriction in diabetes mellitus rats: role of nitric oxide.
In rats with streptozotocin (STZ)-induced diabetes, the renal vasoconstrictor effect of adenosine is enhanced. We investigated the role of nitric oxide (NO) in the renal vascular response to exogenous and endogenous adenosine in control and STZ diabetic rats. Exogenous adenosine (0.01-100 nmol) injected into the abdominal aorta decreased renal blood flow (RBF) in a dose-dependent manner to a much greater extent in STZ rats than in control rats (P < 0.001). Inhibition of NO synthesis with Nomega-nitro-L-arginine (L-NNA, 30 micromol/kg iv) and with renal perfusion pressure controlled potentiated the adenosine-induced renal vasoconstriction to a significantly greater extent in control rats than in STZ rats. In control rats, L-NNA shifted the dose-response curve of exogenous adenosine-induced RBF reductions to the left by a factor of 32 [half-maximal effective dose (ED50), from 5.5 to 0.17 nmol adenosine, n = 6] and in STZ rats only by a factor of 4.6 (ED50, from 0.32 to 0.07 nmol adenosine, n = 6). The renal response to endogenous adenosine was assessed by the magnitude of the postocclusive reduction of RBF (POR) after a 30-s renal artery occlusion. POR was markedly enhanced in STZ rats (-67.8 +/- 3.8%, P < 0.001) compared with control rats (-38.8 +/- 4.3%). L-NNA markedly enhanced POR in control rats but did not increase POR in STZ rats. These findings demonstrate a greater potentiation of the adenosine-induced renal vasoconstriction in the presence of L-NNA infusion in control rats compared with STZ rats. We conclude that the increased vasoconstrictor sensitivity of the diabetic renal vasculature to adenosine is caused by a defective NO-dependent renal vasodilation of the afferent arteriole in diabetic rats.


Permeability of the blood-retinal and blood-aqueous barriers in galactose-fed rats.
Blood-retinal barrier (BRB) and blood-aqueous barrier (BAB) permeability were assessed by various methods to clarify conflicting reports on whether blood-retinal barrier permeability changes occur in diabetic and galactose-fed rats and to assess the potential role of aldose reductase in this process. Different molecular weight probes were utilized in rats fed for 7-11 months either a normal diet or a diet containing 50% galactose with/without the aldose reductase inhibitor AI1576 or Ponalrestat. BRB and BAB were assessed through radiolabelled sucrose permeability studies in eyes where the anterior segment was frozen during dissection compared to eyes where the anterior segments were not frozen and by quantitative autoradiography. In addition, histological studies using Evans Blue dye, microperoxidase and horseradish peroxidase were conducted. In untreated galactose-fed rats a 4-fold increase in the mean permeability surface area product (PA) to sucrose at the BRB was observed when the aqueous humor was not frozen during retinal dissection. However, no increase in the mean PA to sucrose was observed when the aqueous humor of similar eyes was frozen during dissection. Similarly, no retinal vessel permeability increase was observed by either quantitative autoradiography of [3H]-sucrose after 15 minutes of circulation or histological studies with microperoxidase, horseradish peroxidase or Evans Blue dye. Examination of the BAB revealed an increase in the permeability of iris vessels but not the ciliary body in galactose-fed rats which was reduced by treatment with the aldose reductase inhibitor AI1576. These data indicate that while BRB permeability is not increased in galactose-fed rats, BRB permeability measurements with isotopes are subject to possible contamination from the aqueous humor in untreated galactose-fed rats, which can result in false observations of increased BRB permeability.


How (much) do food prices contribute to obesity in Russia?
High BMI and obesity contribute to the Russian health crisis. Previous studies have shown that weight status varies along socioeconomic lines but remains largely unaffected by economic shocks over time. This study is the first that explicitly analyses the impact of food prices on adult BMI and obesity in the Russian Federation. Using panel data from the Russia Longitudinal Monitoring Survey from 1994 to 2005, that included 10,551 urban respondents over 18 years, a reduced form weight demand function is estimated. Controlling for individual heterogeneity by a fixed-effects model, price-weight elasticities are derived. The main result is that food prices are not the essential determinants of BMI and obesity in Russia. Elasticities of BMI with respect to single food prices are low and show absolute values smaller than 0.01. However, some products like chicken meat, milk, onions and butter show significant price effects on body mass. A 20% increase in the price of chicken meat would cause a reduction in body weight of 112 g on average. In contrast to the United States, it is mainly high-income households that show significant weight reactions to food prices in Russia. Separate regressions by gender showed significant effects of milk and butter prices on male BMI and of onion prices on female BMI. The risk of being obese is even less affected by price.


Serum concentrations of 20K human growth hormone in normal adults and patients with various endocrine disorders. Study Group of 20K hGH.
The 20K hGH isoform is produced by alternative splicing of GH mRNA, and comprises approximately 10% of all GH in the pituitary. The physiological role of 20K hGH remains to be determined partly because of the lack of a simple and specific assay. We have established sensitive enzyme-linked immunoadsorbent assays (ELISAs) specific to 20K and 22K hGH. The serum levels of 20K hGH after overnight fasting was 118 +/- 178 pg/mL (N=282) in normal women, significantly higher than in normal men (64 +/- 170 pg/mL, N=226). However, there was no difference in the proportion of 20K hGH to 20K plus 22K hGH between men (6.3 +/- 2.6%, N=176) and women (6.3 +/- 2.1%, N = 263). No correlation was detected between the ratio of 20K hGH and age, body height, body weight or body fat mass in normal subjects. The proportion of 20K hGH was significantly (P < 0.001) higher in patients with active acromegaly (9.2 +/- 2.2%, N=33) and in patients with anorexia nervosa (9.0 +/- 1.9, N=8), both of which are characterized by chronic elevation of circulating GH levels. The proportion of the 20K hGH in successfully treated acromegalic patients did not differ from that in normal subjects, suggesting that GH-producing pituitary tumors secrete a higher proportion of 20K hGH, or chronic excess of 22K hGH altering the metabolic clearance rate of 20K hGH. The values in patients with adult growth hormone deficiency (GHD), hyperthyroidism, primary hypothyroidism, or GH-independent short stature did not differ from those in normal subjects. The 20K ratio did not change after acute GH provocative tests such as insulin tolerance test and GRH test. These results suggest that secretion of 20K hGH from the pituitary is under the same control as that of 22K hGH.


Induction of drug-metabolizing enzymes in liver microsomes of mice and rats by softwood bedding.
Induction of three drug-metabolizing enzymes occurred in liver microsomes of mice and rats kept on softwood bedding of either red cedar, white pine, or ponderosa pine. This induction was reversed when animals were placed on hardwood bedding composed of a mixture of beech, birch, and maple. Differences in the capacity of various beddings to induce may partially explain divergent results of studies on drug-metabolizing enzymes. The presence of such inducing substances in the environment may influence the pharmacologic responsiveness of animals to a wide variety of drugs.


Phenotypic novelty in experimental hybrids is predicted by the genetic distance between species of cichlid fish.
Transgressive segregation describes the occurrence of novel phenotypes in hybrids with extreme trait values not observed in either parental species. A previously experimentally untested prediction is that the amount of transgression increases with the genetic distance between hybridizing species. This follows from QTL studies suggesting that transgression is most commonly due to complementary gene action or epistasis, which become more frequent at larger genetic distances. This is because the number of QTLs fixed for alleles with opposing signs in different species should increase with time since speciation provided that speciation is not driven by disruptive selection. We measured the amount of transgression occurring in hybrids of cichlid fish bred from species pairs with gradually increasing genetic distances and varying phenotypic similarity. Transgression in multi-trait shape phenotypes was quantified using landmark-based geometric morphometric methods. We found that genetic distance explained 52% and 78% of the variation in transgression frequency in F1 and F2 hybrids, respectively. Confirming theoretical predictions, transgression when measured in F2 hybrids, increased linearly with genetic distance between hybridizing species. Phenotypic similarity of species on the other hand was not related to the amount of transgression. The commonness and ease with which novel phenotypes are produced in cichlid hybrids between unrelated species has important implications for the interaction of hybridization with adaptation and speciation. Hybridization may generate new genotypes with adaptive potential that did not reside as standing genetic variation in either parental population, potentially enhancing a population's responsiveness to selection. Our results make it conceivable that hybridization contributed to the rapid rates of phenotypic evolution in the large and rapid adaptive radiations of haplochromine cichlids.


Perinatal mortality: a sporadic event or a recurrent catastrophe?
The purpose of this study was to determine whether women who experienced perinatal mortality in their first delivery had, in their subsequent birth, a higher risk for adverse perinatal outcome. A population-based study was undertaken to compare all second deliveries of women with previous perinatal mortality in their first delivery to those with no such history. Deliveries occurred from 1988 to 2004 in a tertiary medical center. Patients lacking prenatal care, multiple gestations, and congenital malformations were excluded from the analysis. A multivariable logistic regression model and the Mantel-Haenszel procedure were carried out to control for confounders. During the study period, out of 25,876 singleton second deliveries, 230 (0.9%) cases were of patients with previous perinatal mortality. Multivariable analysis with backward elimination showed a significant association between previous perinatal mortality and the following conditions: hypertensive disorders (OR=2.6, 95% CI 1.7-3.9, P<0.001), diabetes mellitus (OR=2.4, 95% CI 1.5-3.7, P<0.001), fertility treatment (OR=2.7, 95% CI 1.6-4.7, P=0.001), and younger maternal age (OR=0.9, 95% CI 0.92-0.98, P<0.001). Controlling for preterm delivery, using the Mantel-Haenszel procedure, the association between previous and subsequent perinatal mortality remained significant (weighted OR=2.2, 95% CI 1.2-3.9, P=0.010). Previous perinatal loss poses an independent risk for subsequent perinatal mortality. Prospective studies are warranted in order to establish the appropriate means of surveillance and/or interventions needed to decrease future adverse perinatal outcomes.


Enhanced surveillance for the Third United Nations Conference on Small Island Developing States, Apia, Samoa, September 2014.
The Ministry of Health in Samoa, in partnership with the Pacific Community, successfully implemented enhanced surveillance for the high-profile Third United Nations Conference on Small Island Developing States held concurrently with the popular local Teuila festival during a widespread chikungunya outbreak in September 2014. Samoa's weekly syndromic surveillance system was expanded to 12 syndromes and 10 sentinel sites from four syndromes and seven sentinel sites; sites included the national hospital, four private health clinics and three national health service clinics. Daily situation reports were produced and were disseminated through PacNet (the e-mail alert and communication tool of the Pacific Public Health Surveillance Network) together with daily prioritized line lists of syndrome activity to facilitate rapid response and investigation by the Samoan EpiNet team. Standard operating procedures for surveillance and response were introduced, together with a sustainability plan, including a monitoring and evaluation framework, to facilitate the transition of the mass gathering surveillance improvements to routine surveillance. The enhanced surveillance performed well, providing vital disease early warning and health security assurance. A total of 2386 encounters and 708 syndrome cases were reported. Influenza-like illness was the most frequently seen syndrome (17%). No new infectious disease outbreaks were recorded. The experience emphasized: (1) the need for a long lead time to pilot the surveillance enhancements and to maximize their sustainability; (2) the importance of good communication between key stakeholders; and (3) having sufficient staff dedicated to both surveillance and response.


Protein kinase C-dependent activation of P44/42 mitogen-activated protein kinase and heat shock protein 70 in signal transduction during hepatocyte ischemic preconditioning.
To investigate the significance of protein kinase C(PKC), P44/42 mitogen-activated protein kinase (MAPKs) and heat shock protein (HSP)70 signal transduction during hepatocyte ischemic preconditioning. In this study we used an in vitro ischemic preconditioning (IP) model for hepatocytes and an in vivo model for rat liver to investigate the significance of protein kinase C (PKC), P44/42 mitogen-activated protein kinase (P44/42 MAPKs) and heat shock protein 70 (HSP70) signal transduction in IP. Through a normal liver cell hypoxic preconditioning (HP) model in which cultured normal liver cells were subjected to 3 cycles of 5 min of incubation under hypoxic conditions followed by 5 min of reoxygenation and subsequently exposed to hypoxia and reoxygenation for 6 h and 9 h respectively. PKC inhibitor, activator and MEK inhibitor were utilized to analyze the phosphorylation of PKC, the expression of P44/42 MAPKs and HSP70. Viability and cellular ultrastructure were also observed. By using rat liver as an in vivo model of liver preconditioning (3 cycles of 10-min occlusion and 10-min reperfusion), in vivo phosphorylation of PKC and P44/42MAPKs, HSP70 expression were further analyzed. AST/ALT concentration, cellular structure and ultrastructure were also observed. All the data were statistically analyzed. Similar results were obtained in both in vivo and in vitro IP models. Compared with the control without IP (or HP), the phosphorylation of PKC and P44/42 MAPKs and the expression of HSP70 were obviously increased in IP (or HP) treated model in which cytoprotection could be found. The effects of preconditioning were mimicked by stimulating PKC with 4beta phorobol-12-myristate13-acetate (PMA). Conversely, inhibiting PKC with chelerythrine abolished the protection given by preconditioning. PD98059, inhibitor of MEK (the upstream kinase of P44/42MAPKs), also reverted the cytoprotection exerted by preconditioning. The results demonstrate that preconditioning induces a rapid activation of P44/42MAPKs and PKC activation plays a pivotal role in the activation of P44/42 MAPKs pathway that participates in the preservation of liver cells. HSP expression is regulated by signals in PKC dependent P44/42 MAPKs pathway.


Current challenges of modeling diiron enzyme active sites for dioxygen activation by biomimetic synthetic complexes.
This tutorial review describes recent progress in modeling the active sites of carboxylate-rich non-heme diiron enzymes that activate dioxygen to carry out several key reactions in Nature. The chemistry of soluble methane monooxygenase, which catalyzes the selective oxidation of methane to methanol, is of particular interest for (bio)technological applications. Novel synthetic diiron complexes that mimic structural, and, to a lesser extent, functional features of these diiron enzymes are discussed. The chemistry of the enzymes is also briefly summarized. A particular focus of this review is on models that mimic characteristics of the diiron systems that were previously not emphasized, including systems that contain (i) aqua ligands, (ii) different substrates tethered to the ligand framework, (iii) dendrimers attached to carboxylates to mimic the protein environment, (iv) two N-donors in a syn-orientation with respect to the iron-iron vector, and (v) a N-rich ligand environment capable of accessing oxygenated high-valent diiron intermediates.


Improvement of early functional atherosclerotic changes in males with hypercholesterolemia after vitamin E supplementation.
Vitamin E as an antioxidant vitamin reduces the susceptibility of low-density lipoprotein (LDL) cholesterol to oxidation and may have antiatherosclerotic effects. We tested the hypothesis that six months of 400 mg vitamin E supplementation favourably affects early functional changes in atherosclerotic process in subjects with hypercholesterolemia. The diameter of the brachial artery at rest, after reactive hyperemia (representing endothelium-dependent vasodilatation) and after sublingual glyceryl-trinitrate (representing endothelium-independent vasodilatation), were determined by ultrasonographic method (B mode) before and after the intervention period. After the intervention period the brachial endothelium-dependent vasodilatation increased significantly in the vitamin E group while it did not change in the placebo group. In conclusion, six months of oral vitamin E supplementation results in improvement of the endothelium-dependent vasodilatation in men with hypercholesterolemia.


A prospective study assessing agreement and reliability of a geriatric evaluation.
The present study takes place within a geriatric program, aiming at improving the diagnosis and management of geriatric syndromes in primary care. Within this program it was of prime importance to be able to rely on a robust and reproducible geriatric consultation to use as a gold standard for evaluating a primary care brief assessment tool. The specific objective of the present study was thus assessing the agreement and reliability of a comprehensive geriatric consultation. The study was conducted at the outpatient clinic of the Service of Geriatric Medicine, University of Lausanne, Switzerland. All community-dwelling older persons aged 70 years and above were eligible. Patients were excluded if they hadn't a primary care physician, they were unable to speak French, or they were already assessed by a geriatrician within the last 12 months. A set of 9 geriatricians evaluated 20 patients. Each patient was assessed twice within a 2-month delay. Geriatric consultations were based on a structured evaluation process, leading to rating the following geriatric conditions: functional, cognitive, visual, and hearing impairment, mood disorders, risk of fall, osteoporosis, malnutrition, and urinary incontinence. Reliability and agreement estimates on each of these items were obtained using a three-way Intraclass Correlation and a three-way Observed Disagreement index. The latter allowed a decomposition of overall disagreement into disagreements due to each source of error variability (visit, rater and random). Agreement ranged between 0.62 and 0.85. For most domains, geriatrician-related error variability explained an important proportion of disagreement. Reliability ranged between 0 and 0.8. It was poor/moderate for visual impairment, malnutrition and risk of fall, and good/excellent for functional/cognitive/hearing impairment, osteoporosis, incontinence and mood disorders. Six out of nine items of the geriatric consultation described in this study (functional/cognitive/hearing impairment, osteoporosis, incontinence and mood disorders) present a good to excellent reliability and can safely be used as a reference (gold standard) to evaluate the diagnostic performance of a primary care brief assessment tool. More objective/significant measures are needed to improve reliability of malnutrition, visual impairment, and risk of fall assessment before they can serve as a safe gold standard of a primary care tool.


Differential effects of GABA and bicuculline on rapidly- and slowly-adapting neurons in primary somatosensory cortex of primates.
In cortical area 3b of monkeys, responses of 71 single neurons to controlled indentations of glabrous skin were recorded before and during iontophoretic application of GABA and bicuculline methiodide (BMI), a GABA receptor antagonist. Constant amplitude indentations were applied to selected sites within the receptive fields of neurons representing the glabrous skin on the digits and palm. Profiles of response magnitudes across stimulation sites were used to quantify receptive field dimensions before and during antagonism of GABAergic inhibition. During administration of BMI, the receptive fields of 26 rapidly-adapting neurons were increased by 3-4 times their original size. Response latencies were substantially longer in the region of expansion than in the original receptive field, suggesting that expansion might be mediated by intracortical connections. The expansion of RFs onto adjacent digits after blockade of GABAergic inhibition suggests that somatotopic reorganization following digit amputations may be subserved by existing excitatory connections. The responses of slowly-adapting neurons were separated into two components, a "dynamic" response corresponding to activity elicited by the initial indenting ramp and a "static" response produced by the sustained indentation. Among 8 slowly-adapting neurons tested with BMI, the receptive fields of the dynamic response component increased to an extent that was similar to the change produced in rapidly-adapting neurons. By contrast, the static response component was rarely altered by BMI. Comparison of the responses to administration of GABA revealed that only 12 of 27 slowly-adapting neurons were inhibited in a dose-dependent manner, whereas 37 of 44 rapidly-adapting neurons exhibited significant reduction of responses in the presence of GABA. Hypotheses are proposed to explain the differential effect of BMI and GABA on slowly- and rapidly-adapting cortical neurons.


Prognostic implications of tumor extent in early-stage diffuse large B-cell lymphoma.
Therapeutic strategies for early-stage diffuse large B-cell lymphoma (DLBCL) are often influenced by tumor extent, but the prognostic value of this parameter is rarely defined. Here, a retrospective analysis was performed to define the impact of tumor extent on survival of patients with early-stage DLBCL. Eighty-six patients with stage II DLBCL, diagnosed from 2000-2007, were categorized into localized (n = 55, 64 %) and disseminated groups (n = 31, 36 %) based on tumor extent at time of diagnosis. Treatment modalities, chemotherapy regimen and number of chemotherapy cycles were the same between groups. With a median follow-up of 7.6 years (range 2.1-12.1 years), overall 5-year event-free survival (EFS) and overall survival (OS) were 70.6 and 76.5 %, respectively. EFS (P = 1.00) and OS (P = 0.20) did not differ between the two groups. Older age (>60 years) was significantly associated with poor EFS (P = 0.01) and OS (P = 0.04). High-risk patients as rated by stage-modified international prognostic index (IPI) had inferior EFS (P = 0.04) and OS (P = 0.06) compared with the intermediate-risk group. These results indicate that tumor extent has no prognostic value in patients with early-stage DLBCL. Consistent with previous studies, age and stage-modified IPI were useful prognostic indices for these patients.


Gadobenate dimeglumine-enhanced MR imaging breast vascular maps: association between invasive cancer and ipsilateral increased vascularity.
To retrospectively compare three different doses of gadobenate dimeglumine with a standard dose of gadopentetate dimeglumine for magnetic resonance (MR) imaging evaluation of breast vessels and to evaluate the accuracy of one-sided increased vascularity seen on gadobenate dimeglumine-enhanced MR images as an indicator of ipsilateral breast cancer. The original study had local ethics committee approval; informed consent was obtained from all enrolled patients. Ninety-five patients known to have or suspected of having breast cancer were randomly assigned to four groups to receive gadobenate dimeglumine at a dose of 0.05, 0.10, or 0.20 mmol per kilogram of body weight or gadopentetate dimeglumine at a dose of 0.10 mmol/kg. T1-weighted gradient-echo MR images were acquired before and 2 minutes after intravenous contrast material injection. Subtracted images were used to obtain maximum intensity projections (MIPs). Two readers blinded to the type and dose of contrast agent administered scored the MIPs obtained in the dose groups for vessel number, length, and conspicuity from 0, which indicated absent or low breast vascularity, to 3, which indicated high breast vascularity. The sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) of one-sided increased vascularity in association with ipsilateral malignancy for 69 histopathologically confirmed lesions (reference standard) were determined after gadobenate dimeglumine-enhanced MR imaging. The mean MIP scores assigned to the gadobenate dimeglumine groups were significantly higher than those assigned to the gadopentetate dimeglumine group (P < or = .044). Histopathologic analysis revealed malignant lesions in 52 of 69 patients examined with gadobenate dimeglumine MR imaging: invasive ductal carcinoma in 45, invasive lobular carcinoma in four, and invasive mixed ductal-lobular carcinoma in three patients. Seventeen patients had benign lesions. Two cases of bilateral invasive cancer with symmetric breast vascular maps were excluded. Thus, the overall sensitivity, specificity, accuracy, PPV, and NPV of one-sided increased vascularity as a finding associated with ipsilateral malignancy were 88% (44 of 50 patients), 82% (14 of 17 patients), 87% (58 of 67 patients), 94% (44 of 47 patients), and 70% (14 of 20 patients), respectively. Gadobenate dimeglumine is effective for MR imaging evaluation of breast vessels at doses as low as 0.05 mmol/kg. One-sided increased vascularity is an MR imaging finding frequently associated with ipsilateral invasive breast cancer.


p53 protein overexpression in infiltrating ductal carcinoma of female breast and its association with lymph node metastasis.
Traditionally, prognosis in carcinoma of the breast is evaluated based on size and differentiation of the tumor and status of lymph node metastasis. In addition to these established markers, in this molecular age other parameters such as overexpression of p53, c-erbB-2 and c-myc proteins are increasingly used to assess the prognosis. At present, the prognostic value of the molecular markers, at best, is controversial and conflicting. In this study, we examined 67 infiltrating ductal. carcinomas of female breast with and without lymph node metastasis for p53 protein overexpression by immunohistochemistry on formalin-fixed, paraffin-embedded tissue sections to ascertain if p53 positive tumors have greater metastatic potential than p53 negative tumors. In addition, p53 overexpression was also correlated with tumor size, grade, expression of estrogen and progesterone receptors, and age of the patient to clarify the issue of relevance of p53 overexpression in prognostication, p53 overexpression was observed in 39% of tumors and showed strong correlation only with the histological grade of the tumor. The incidence of p53 overexpression in grade 1, grade 2 and grade 3 tumors was 0%, 33% and 58% respectively. Lymph node metastasis was less frequent in tumors that overexpressed p53 protein. Twenty-seven percent of primary tumors with lymph node metastasis showed p53 protein overexpression, in contrast to 44% of tumors without metastasis. No correlation was observed between p53 overexpression and all the other parameters evaluated except progesterone receptor negative status. These results suggest that p53 overexpression is not an independent prognostic indicator and should not be used to predict lymph node metastasis or aggressive behavior of the tumor.


[A comparison of two antigens for Montenegro skin test].
Intradermal reactions were performed in 399 individuals by using, simultaneously, the antigen produced by both the Universidade Federal de Minas Gerais and Fundação Instituto Oswaldo Cruz. Each of these antigens was manufactured with promastigotes of Leishmania (L) amazonensis (IFLA/BR/67/PH8). The Fundação Oswaldo Cruz antigen caused a larger number of positive reactions. Discordant reactions occurred in 22% of the individuals.


Modulation of membrane currents by cyclic AMP in cleavage-arrested Drosophila neurons.
A number of Drosophila learning mutants have defective intracellular second-messenger systems. In an effort to develop techniques that will allow direct measurement of the effects of these mutations on whole-cell neuronal membrane currents, the perforated-patch whole-cell (PPWC) technique has been applied to cleavage-arrested cultured embryonic Drosophila neurons. This technique permits the measurement of membrane currents without disturbing the intracellular environment. As a result of the maintenance of the intracellular environment, Drosophila neuron currents are found to be much more stable than when measured using the conventional whole-cell (CWC) patch-clamp technique. Ca2+ channel currents, which typically 'wash out' within a few minutes of the beginning of CWC recording, are stable for the duration of the seal (tens of minutes) when measured using the PPWC technique. Since the learning mutations dunce and rutabaga disrupt cyclic AMP signalling, the action of externally applied dibutyryl cyclic AMP (db-cAMP) and theophylline on Ca2+ and K+ channel currents were studied. db-cAMP and theophylline enhanced the Ba2+ current, carried by Ca2+ channels, but had no effect on the K+ current in the cleavage-arrested neurons. However, the large variability and reduction in density of Ba2+ and K+ currents raise questions about the suitability of using these cleavage-arrested cells as models for Drosophila neurons.


A Fluorescence Based Measurement Technique to Quantify Water Contaminants at Pipe Surfaces During Flow.
This paper provides a detailed account of the development of a fluorescence based measurement technique for measuring the mass of contaminant on solid surfaces in the presence of water flow. A test apparatus was designed and developed for the purpose of studying adsorption and desorption of diesel to and from a copper test surface in the presence of contaminated and fresh water flow, respectively. A calibration technique was developed to correlate the measured fluorescence intensity to the mass of diesel adsorbed per unit surface area (the excess surface density) and the bulk concentration of the diesel in the flow. Both bulk composition and the excess surface density measurements were achieved via a traverse of the fluorescent measurement probe perpendicular to the test surface. The measured diesel excess surface density varied between zero and 0.02 kg/m2 for the variation in the bulk mass fraction and Reynolds number of the flow.


Cefotaxime and desacetylcefotaxime pharmacokinetics in infants and children with meningitis.
The pharmacokinetics and cerebrospinal fluid (CSF) penetration of cefotaxime (Ctx) and desacetylcefotaxime (dCtx) were evaluated in 13 infants and children with meningitis after dose 6 of Ctx in a multiple-dose intermittent intravenous infusion regimen (50 mg/kg every 6 h). Model-dependent and noncompartmental pharmacokinetic parameters were determined and were found to be congruous. The disposition of both Ctx and dCtx was described adequately by a one-compartment, open model. Noncompartmental pharmacokinetic parameters are reported. The mean Ctx serum concentration at 0.25 h postinfusion was 121.2 micrograms/ml, and the mean CSF concentration at 1 h postinfusion was 6.2 micrograms/ml. The CSF/serum ratio was variable (0 to 20%), with a mean penetration of 10.1%. The mean Ctx elimination half-life, apparent steady-state volume of distribution, and total body clearance were 0.8 h, 0.361 liter/kg, and 0.289 liter/h per kg, respectively. For Ctx, 61% of the dose was excreted unchanged in the urine during the 6-h postinfusion period, and the estimated renal clearance was 0.174 liter/h per kg. No significant correlations were observed between Ctx pharmacokinetic parameters and demographic parameters. The mean peak concentration of dCtx in serum (21.6 micrograms/ml) occurred at approximately 1.5 h postinfusion, and the mean concentration in CSF at 1 h postinfusion was 5.6 micrograms/ml. The CSF/serum ratio was extremely variable (0 to 103%), and the mean penetration was 28.8%. The mean apparent elimination half-life for dCtx was 2.1 h. In infants and children with normal renal function, a 50-mg/kg dose of Ctx administered every 6 h should provide adequate concentrations in serum and CSF in the majority of patients with meningitis.


Characterizing health services interventions for evidence syntheses by using the theme, intensity, provider/platform (TIP) framework.
Health services interventions comprise a range of elements and procedures that contribute to their effects. However, there is currently limited guidance to systematically classify different features of health services interventions. We propose an approach to aid in classifying health services interventions using three potential elements: theme, intensity, and provider/platform (TIP). We designed the TIP framework to be analogous to three elements of a medication intervention that contribute to its pharmaceutical effects: 1) active ingredient, 2) dose, and 3) dosage form or route of administration. Health services interventions encompass similar elements: 1) "theme", which corresponds to the active ingredient and specifies the main element of the intervention; 2) "intensity", which corresponds to the dose regimen; and 3) "provider" or "platform", which corresponds to the dosage form or route of administration and indicates how the main element is delivered. Each health services intervention can be classified into a set of unique TIP features, which can then be compared with others using either a qualitative or qualitative approach. The TIP framework is not suitable for multicomponent health services interventions, in which a singular main theme or active component cannot be identified. The TIP framework enables researchers to systematically characterize health services interventions according to their unique features that contribute to its effects. It also helps to generate evidence to determine not only what service is more effective, but also how to best deliver such service.


Experimental gonococcal genital tract infection and opacity protein expression in estradiol-treated mice.
The development of effective prophylactic agents against gonorrhea and the study of adaptation by Neisseria gonorrhoeae to the urogenital mucosa are hindered by the lack of a well-established animal model of gonococcal genital tract infection. Here, a murine model of long-term gonococcal genital tract infection is described. Female BALB/c mice were treated with 17-beta-estradiol and inoculated intravaginally with wild-type gonococcal strain FA1090 or MS11. N. gonorrhoeae was recovered from vaginal swabs for an average of 12 to 13 days following inoculation with 10(6) CFU of either strain. Inflammation occurred in over 80% of infected mice, and diplococci were associated with epithelial cells and neutrophils in stained vaginal smears. Ascended infection occurred in 17 to 20% of mice inoculated with strain FA1090. An outbred mouse strain (SLC:ddY) previously reported to be naturally susceptible to N. gonorrhoeae was also tested; however, as with BALB/c mice, estradiol was required for prolonged infection. Although piliation was not maintained during experimental murine infection, 46 to 100% of vaginal isolates from four of eight BALB/c mice and three of four SLC:ddY mice expressed one or more opacity (Opa) proteins within 4 days after inoculation with an Opa-negative variant of strain FA1090. The observed selection for and/or induction of gonococcal Opa protein expression during murine infection appears to parallel events that occur during experimental urethritis in volunteers.


Design of protonated polyazamacrocycles based on phenanthroline motifs for selective uptake of aromatic carboxylate anions and herbicides.
Three novel large polyazamacrocycles containing two 1,10-phenanthroline units connected by different polyamine spacers have been synthesised and their protonated forms used as receptors for several aromatic carboxylate anions. The receptors bind to the anions in a 1:1 stoichiometry and exhibit remarkable binding selectivity (see figure). Analysis shows that molecular recognition is governed by pi-pi stacking interactions and multiple N--HO==C hydrogen bonds.Three novel large polyazamacrocycles containing two 1,10-phenanthroline (phen) units connected by two polyamine spacers of different length, [32]phen(2)N(4), [30]phen(2)N(6) and Me(2)[34]phen(2)N(6), have been synthesised and their protonated forms used as receptors for binding studies with several aromatic carboxylate anions (benzoate (bzc(-)), 1-naphthalate (naphc(-)), 9-anthracenate (anthc(-)), pyrene-1-carboxylate (pyrc(-)), phthalate, (ph(2-)), isophthalate (iph(2-)), terephthalate (tph(2-)), 2,5-dihydroxy-1,4-benzenediacetate (dihyac(2-)) and, 1,3,5-benzenetricarboxylate (btc(3-))) and three herbicides (4-amino-3,5,6-trichloropyridine-2-carboxylate (ATCP(-)), dichlorophenoxyacetate (2,4-D(-)) and glyphosate (PMG(2-))) in water solution. The [30]phen(2)N(6) receptor was found to be the most suitable for binding the anions considered in a 1:1 stoichiometry. The three receptors exhibit a remarkable binding selectivity towards the extended aromatic anion pyrc(-) at low pH values. Their binding affinities for the monocarboxylate anions decrease with the extension of the aromatic system in the order pyrc(-)>anthc(-)>naphc(-)>bzc(-), which indicates the presence of pi-pi stacking interactions in the molecular recognition of these anions. Molecular dynamics simulations carried out for the binding of {H(4)[30]phen(2)N(6)}(4+) and {H(6)Me(2)[34]phen(2)N(6)}(6+) with pyrc(-), anthc(-), naphc(-), iph(2-) and btc(3-) in water showed that these receptors adopt a folded conformation with the anion inserted between the two phen heads and that the molecular recognition is governed by pi-pi stacking interactions and multiple N--HO==C hydrogen bonds. The binding free energies estimated theoretically are very similar to those found by potentiometric methods, which supports the proposed binding arrangement.


Constitutive expression of IL-22 in the human intervertebral disc and its reduction by exposure to pro-inflammatory cytokines in vitro.
The importance of cytokines in disc degeneration is well recognized. Little is known about IL-22 expression in the human intervertebral disc. We investigated IL-22 immuno-localization in disc tissue, and molecular expression and production of IL-22 by annulus cells cultured in three-dimensional (3D) culture. We examined human disc tissue using immunohistochemistry and we cultured isolated annulus cells in 3D to analyze IL-22 expression and production, and its receptor, IL-22R, in conditioned media. Ingenuity pathway analysis (IPA) also was used to identify significant gene expression networks within the molecular data. IL-22 and IL-22R were immunolocalized in many cells in the human outer and inner annulus; fewer cells exhibited localization in the nucleus. Three-dimensional culture of annulus cells demonstrated production of IL-22 in conditioned media; exposure to IL-1ß or TNF-α significantly reduced IL-22 levels. Significant decreases also were identified in conditioned media assayed for IL-22R in TNF-α treated cells. IPA analysis showed that IL-22 ranked among the top canonical pathways. We found constitutive expression and production of IL-22 and IL-22R in the disc, which expands our understanding of the effect of pro-inflammatory cytokines on IL-22 expression and production. Three-dimensional cultured annulus cells exposed to IL-1ß or TNF produced significantly lower levels of IL-22 into their conditioned media compared to levels produced by control cells. Our findings have clinical relevance because of the elevated pro-inflammatory milieu within the degenerating human disc.


Feasibility of Biochar Derived from Sewage Sludge to Promote Sustainable Agriculture and Mitigate GHG Emissions-A Review.
Sewage sludge (SS) has been connected to a variety of global environmental problems. Assessing the risk of various disposal techniques can be quite useful in recommending appropriate management. The preparation of sewage sludge biochar (SSB) and its impacts on soil characteristics, plant health, nutrient leaching, and greenhouse gas emissions (GHGs) are critically reviewed in this study. Comparing the features of SSB obtained at various pyrolysis temperatures revealed changes in its elemental content. Lower hydrogen/carbon ratios in SSB generated at higher pyrolysis temperatures point to the existence of more aromatic carbon molecules. Additionally, the preparation of SSB has an increased ash content, a lower yield, and a higher surface area as a result of the rise in pyrolysis temperature. The worldwide potential of SS output and CO2-equivalent emissions in 2050 were predicted as factors of global population and common disposal management in order to create a futuristic strategy and cope with the quantity of abundant global SS. According to estimations, the worldwide SS output and associated CO2-eq emissions were around 115 million tons dry solid (Mt DS) and 14,139 teragrams (Tg), respectively, in 2020. This quantity will rise to about 138 Mt DS sewage sludge and 16985 Tg CO2-eq emissions in 2050, a 20% increase. In this regard, developing and populous countries may support economic growth by utilizing low-cost methods for producing biochar and employing it in local agriculture. To completely comprehend the benefits and drawbacks of SSB as a soil supplement, further study on long-term field applications of SSB is required.


Emerging Opportunities and Challenges in Cancer Immunotherapy.
Immunotherapy strategies against cancer are emerging as powerful weapons for treatment of this disease. The success of checkpoint inhibitors against metastatic melanoma and adoptive T-cell therapy with chimeric antigen receptor T cells against B-cell-derived leukemias and lymphomas are only two examples of developments that are changing the paradigms of clinical cancer management. These changes are a result of many years of intense research into complex and interrelated cellular and molecular mechanisms controling immune responses. Promising advances come from the discovery of cancer mutation-encoded neoantigens, improvements in vaccine development, progress in delivery of cellular therapies, and impressive achievements in biotechnology. As a result, radical transformation of cancer treatment is taking place in which conventional cancer treatments are being integrated with immunotherapeutic agents. Many clinical trials are in progress testing potential synergistic effects of treatments combining immunotherapy with other therapies. Much remains to be learned about the selection, delivery, and off-target effects of immunotherapy used alone or in combination. The existence of numerous escape mechanisms from the host immune system that human tumors have evolved still is a barrier to success. Efforts to understand the rules of immune cell dysfunction and of cancer-associated local and systemic immune suppression are providing new insights and fuel the enthusiasm for new therapeutic strategies. In the future, it might be possible to tailor immune therapy for each cancer patient. The use of new immune biomarkers and the ability to assess responses to therapy by noninvasive monitoring promise to improve early cancer diagnosis and prognosis. Personalized immunotherapy based on individual genetic, molecular, and immune profiling is a potentially achievable future goal. The current excitement for immunotherapy is justified in view of many existing opportunities for harnessing the immune system to treat cancer.


Teaching pediatric laboratory medicine to pathology residents.
Laboratory data are essential to the medical care of fetuses, infants, children, and adolescents. However, the performance and interpretation of laboratory tests on specimens from these patients, which may constitute a significant component of the workload in general hospitals and integrated health care systems as well as specialized perinatal or pediatric centers, present unique challenges to the clinical pathologist and the laboratory. Therefore, pathology residents should receive training in pediatric laboratory medicine. Children's Health Improvement through Laboratory Diagnostics, a group of pathologists and laboratory scientists with interest and expertise in pediatric laboratory medicine, convened a task force to develop a list of curriculum topics, key resources, and training experiences in pediatric laboratory medicine for trainees in anatomic and clinical pathology or straight clinical pathology residency programs and in pediatric pathology fellowship programs. Based on the experiences of 11 training programs, we have compiled a comprehensive list of pediatric topics in the areas of clinical chemistry, endocrinology, hematology, urinalysis, coagulation medicine, transfusion medicine, immunology, microbiology and virology, biochemical genetics, cytogenetics and molecular diagnostics, point of care testing, and laboratory management. This report also includes recommendations for training experiences and a list of key texts and other resources in pediatric laboratory medicine. Clinical pathologists should be trained to meet the laboratory medicine needs of pediatric patients and to assist the clinicians caring for these patients with the selection and interpretation of laboratory studies. This review helps program directors tailor their curricula to more effectively provide this training.


Oxygen isotopic compositions of asteroidal materials returned from Itokawa by the Hayabusa mission.
Meteorite studies suggest that each solar system object has a unique oxygen isotopic composition. Chondrites, the most primitive of meteorites, have been believed to be derived from asteroids, but oxygen isotopic compositions of asteroids themselves have not been established. We measured, using secondary ion mass spectrometry, oxygen isotopic compositions of rock particles from asteroid 25143 Itokawa returned by the Hayabusa spacecraft. Compositions of the particles are depleted in (16)O relative to terrestrial materials and indicate that Itokawa, an S-type asteroid, is one of the sources of the LL or L group of equilibrated ordinary chondrites. This is a direct oxygen-isotope link between chondrites and their parent asteroid.


[Balneotherapy and modification of risk factors in cardiovascular disease prevention programs].
Cardiovascular disease (CVD) is the leading cause of death in the Russian Federation, as in many other countries. Taking into consideration the observed increase in the spread of risk factors, modern demographic trends (an increase in the proportion of elderly people), and a high economic burden of circulatory system diseases, the search for new forms and effective strategies of prevention is becoming relevant. OBJECTIVE: To provide the data available in the scientific literature on the effectiveness of the measures to modify risk factors and lifestyle, which are implemented during balneotherapy under both resort and in non-resort conditions, and to define areas for further investigators in this field. Investigations evaluating the effectiveness of these measures were sought in the Embase, PubMed, PEDro, Web of Science, eLIBRARY databases in January 2012 to August 2018. The analysis included seven trials that showed an improvement of estimated endpoints (blood pressure, body mass index, lipid profile, physical activity, and morbidity and mortality rates). The generalization of results of the analyzed trials was limited by the high heterogeneity of their protocols and methodological quality, which does not allow for a final conclusion on the effectiveness of preventive measures implemented during balneotherapy. Future research should provide more evidence of the benefits of this approach. The analysis will be able to take into account the existing experience and to develop a strategy to enhance the effectiveness of cardiovascular disease prevention programs based on high-quality randomized clinical trials.