A real-time integrated framework to support clinical decision making for covid-19 patients.
The COVID-19 pandemic affected healthcare systems worldwide. Predictive models developed by Artificial Intelligence (AI) and based on timely, centralized and standardized real world patient data could improve management of COVID-19 to achieve better clinical outcomes. The objectives of this manuscript are to describe the structure and technologies used to construct a COVID-19 Data Mart architecture and to present how a large hospital has tackled the challenge of supporting daily management of COVID-19 pandemic emergency, by creating a strong retrospective knowledge base, a real time environment and integrated information dashboard for daily practice and early identification of critical condition at patient level. This framework is also used as an informative, continuously enriched data lake, which is a base for several on-going predictive studies. The information technology framework for clinical practice and research was described. It was developed using SAS Institute software analytics tool and SAS® Vyia® environment and Open-Source environment R ® and Python ® for fast prototyping and modeling. The included variables and the source extraction procedures were presented. The Data Mart covers a retrospective cohort of 5528 patients with SARS-CoV-2 infection. People who died were older, had more comorbidities, reported more frequently dyspnea at onset, had higher d-dimer, C-reactive protein and urea nitrogen. The dashboard was developed to support the management of COVID-19 patients at three levels: hospital, single ward and individual care level. The COVID-19 Data Mart based on integration of a large collection of clinical data and an AI-based integrated framework has been developed, based on a set of automated procedures for data mining and retrieval, transformation and integration, and has been embedded in the clinical practice to help managing daily care. Benefits from the availability of a Data Mart include the opportunity to build predictive models with a machine learning approach to identify undescribed clinical phenotypes and to foster hospital networks. A real-time updated dashboard built from the Data Mart may represent a valid tool for a better knowledge of epidemiological and clinical features of COVID-19, especially when multiple waves are observed, as well as for epidemic and pandemic events of the same nature (e. g. with critical clinical conditions leading to severe pulmonary inflammation). Therefore, we believe the approach presented in this paper may find several applications in comparable situations even at region or state levels. Finally, models predicting the course of future waves or new pandemics could largely benefit from network of DataMarts.


Retrospective study of influencing factors on the outcomes of luteal phase stimulation in patients with dual stimulation.
Dual/double stimulation (DS) is an ovarian stimulation strategy that has emerged in recent years; it is characterized by two rounds of ovarian stimulation and oocyte retrieval in the same menstrual cycle. DS can greatly shorten the time required to obtain valid embryos in assisted reproduction. For fertility preservation, DS can speed up oocyte storage process. However, factors influencing luteal phase ovarian stimulation (LPS) outcomes in DS have not been elucidated. A total of 156 cycles from 78 cases were studied. Patients were grouped and analyzed according to their follicular phase ovarian stimulation (FPS) types. Female ages, ovarian stimulation protocols, number of oocytes retrieved, embryo quality were recorded. Comparisons of outcomes were conducted between different groups. Our study found that LPS obtained similar outcomes to follicular phase stimulation (FPS), and that the choice of FPS protocol affected the efficiency of LPS, the antagonist protocol and progestin-primed ovarian stimulation (PPOS) protocol resulted in better embryo outcomes in LPS. In LPS of DS, sufficient stimulation duration was the guarantee of embryo quality (number of available embryos: β = 0.145, 95% CI [0.078-0.211], P = 0.000; number of high-quality embryos: β = 0.114, 95% CI [0.057-0.171], P = 0.000). This study provided ideas for the precise use of DS. We suggest to further expand the sample size of DS in the future, conduct prospective controlled studies, unify the sample size of each subgroup, include the ovarian reserve of patients in the grouping basis, and exclude the influence of male factors. We hope that this study will help further refinement of DS so as to maximize patient benefits from it. When the DS strategy is considered in the follicular phase, the antagonist protocol and PPOS protocol are more recommended for better embryo outcomes in LPS. During LPS, adequate ovarian stimulation duration is the most important guarantee for LPS efficiency.


Impact of medically recalcitrant chronic rhinosinusitis on incidence of asthma.
The long-term impact of chronic rhinosinusitis (CRS) with or without allergic rhinitis (AR) on asthma is poorly documented. This study analyzed potential associations of ongoing CRS and AR on asthma. Using the MarketScan™ claims database, patients with CRS and endoscopic sinus surgery (ESS) in 2010 were identified. The date of first sinusitis was determined for all. Patients with asthma at time of first sinusitis diagnosis were excluded. The remaining patients were grouped based on duration of sinusitis, from first diagnosis to surgery-group 1: 1 to <2 years (n = 181); group 2: 2 to <3 years (n = 195); group 3: 3 to <4 years (n = 292); and group 4: 4 to <5 years (n = 536). Yearly incidence and prevalence of newly diagnosed asthmatics was analyzed for all groups. A secondary analysis evaluated the association between AR and asthma. Preoperatively, yearly incidence of patients with new asthma diagnoses averaged 4.48% (95% confidence interval [CI], 3.93% to 5.11%) and was significantly greater for patients with AR (5.93%; 95% CI, 4.56% to 7.66%) vs non-AR (4.15%; 95% CI, 3.56% to 4.82%); p = 0.03. Postoperatively, yearly incidence of asthma was 0.42% (95% CI, 0.18% to 0.88%). No patient had asthma at time of first diagnosis; however, by time of surgery, 9.4%, 12.8%, 18.2%, and 22.40% of patients had been diagnosed with asthma, in groups 1 through 4, respectively. AR was a significant risk factor for asthma in patients with CRS. Medically recalcitrant CRS was associated with high incidence rates of asthma, which declined post-operatively. Patients operated earlier in the disease continuum were therefore at decreased risk of developing asthma.


Leishmanicidal activity of some aliphatic diamines and amino-alcohols.
A number of aliphatic diamines and amino-alcohols and several of their alkyl, acyl and carbamoyl derivatives, have been synthesised and evaluated in vitro on cultures of Leishmania spp. In general, diamine derivatives resulted to be more potent than their amino-alcohol or amino-ether analogues. Two diamine derivatives (8b and 9d) and one amino-alcohol (6a) showed a fair inhibition of parasite growth, at concentrations below 10 microg/mL, with potencies close to that of the reference drug, amphotericin B. Some SAR considerations have been deduced.


Pride in social anxiety disorder.
The present study examined differences in the experience of pride between individuals with and without social anxiety disorder (SAD), and is the first to examine both the effects of context on pride and the temporal relationship between pride and anxiety in participants' daily lives. Eighty-eight participants took part in the study, half (n = 44) met diagnostic criteria for SAD and half (n = 44) did not. Both groups completed an experience sampling measurement (ESM) to assess the levels of pride and anxiety and the nature of interpersonal contexts in which these emotions were experienced every day for 21 consecutive days. Using multilevel linear modeling, our findings suggest that pride is diminished among individuals with SAD, that situations percieved as highly neagative and positive, or as highly meaningful and positive are associated with the highest levels of pride, and that the experience of pride is associated with subsequent reductions in anxiety among individuals with SAD. These findings point to the role of pride in the disorder and can be used to inform and enhance therapeutic interventions for SAD.


Depolarization and stimulation of neurons in nucleus tractus solitarii by carbon dioxide does not require chemical synaptic input.
The effects of elevated CO2 (i.e. hypercapnia) on neurons in the nucleus tractus solitarii were studied using extracellular (n = 82) and intracellular (n = 33) recording techniques in transverse brain slices prepared from rat. Synaptic connections from putative chemosensitive neurons in the ventrolateral medulla were removed by bisecting each transverse slice and discarding the ventral half. In addition, the response to hypercapnia in 20 neurons was studied during high magnesium-low calcium synaptic blockade. Sixty-five per cent of the neurons (n = 75) tested were either insensitive or inhibited by hypercapnia. However, 35% (n = 40) were depolarized and/or increased their firing rate during hypercapnia. Nine out of 10 CO2-excited neurons retained their chemosensitivity to CO2 in the presence of high magnesium-low calcium synaptic blockade medium. Our findings demonstrate that many neurons in the nucleus tractus solitarii were depolarized and/or increased their firing rate during hypercapnia. These neurons were not driven synaptically by putative chemosensitive neurons of the ventrolateral medulla since this region was removed from the slice. Furthermore, because chemosensitivity persisted in most neurons tested during synaptic blockade, we conclude that some neurons in the nucleus tractus solitarii are inherently CO2-chemosensitive. Although the function of dorsal medullary chemosensitive neurons cannot be determined in vitro, their location and their inherent chemosensitivity suggest a role in cardiorespiratory central chemoreception.


Local anaesthetic wound infiltration for postcaesarean section analgesia: A systematic review and meta-analysis.
Wound infiltration with local anaesthetics has been investigated as a potentially useful method for providing analgesia after caesarean delivery, but the literature is inconclusive. The objective is to assess the efficacy of local anaesthetic wound infiltration in reducing pain scores and opioid consumption in women undergoing caesarean delivery. Systematic review of randomised controlled trials with meta-analyses. MEDLINE, EMBASE, CINAHL, and Cochrane Central Register of Controlled trials (CENTRAL) until December 2015. Randomised controlled trials that assessed the efficacy of local anaesthetic wound infiltration using an infusion or single injection technique for postcaesarean section analgesia. A total of 21 studies were included in the final analysis (11 studies using an infusion technique and 10 studies using single infiltration). Local anaesthetic wound infiltration significantly decreased opioid consumption at 24 h [mean difference -9.69 mg morphine equivalents, 95% confidence interval (CI), -14.85 to -4.52] and pain scores after 24 h at rest (mean difference -0.36, 95% CI, -0.58 to -0.14) and on movement (mean difference -0.61, 95% CI, -1.19 to -0.03). Subgroup analysis did not suggest a difference in primary outcomes between infusions and single infiltration. Opioid consumption was reduced in patients who did not receive intrathecal morphine but not in those who received intrathecal morphine, although there were very little data in patients receiving intrathecal morphine. Pain scores at rest and on movement at 24 h were reduced with catheter placement below the fascia but not above the fascia. There were no statistically significant reductions in nausea, vomiting or pruritus with local anaesthetic infiltration. Local anaesthetic wound infiltration reduces postoperative opioid consumption but had minimal effect on pain scores and did not reduce opioid-related side-effects in women who had undergone delivery by caesarean section. The review is limited by a paucity of studies using intrathecal morphine and by the indirect comparisons performed for subgroup analyses.


Extended pelvic resections for the treatment of locally advanced and recurrent anal canal and colorectal cancer: technical aspects and morbimortality predictors aftet 24 consecutive cases.
to evaluate the profile of morbidity and mortality and its predictors related to extensive pelvic resections, including pelvic exenteration, to optimize the selection of patients and achieve better surgical results. we performed 24 major resections for anorectal pelvic malignancy from 2008 to 2015 in the Instituto do Câncer do Ceará. The factors analyzed included age, weight loss, resected organs, total versus posterior exenteration, angiolymphatic and perineural invasion, lymph node metastasis and overall and disease-free survival. the median age was 57 years and the mean follow-up was ten months. Overall morbidity was 45.8%, with five (20.8%) serious complications. There were no deaths in the first 30 postoperative days. The median overall survival was 39.5 months, and disease-free survival, 30.7 months. Concomitant resection of the bladder was an isolated prognostic factor for higher risk of complications (87.5% vs. 26.7%, p = 0.009). Angiolymphatic invasion and lymph node metastasis did not reach significance with respect to disease-free survival. treatment of advanced anorectal tumors is challenging, often requiring combined resections, such as cystectomy and sacrectomy, and complex reconstructions. The magnitude of the operation still carries a high morbidity rate, but is a procedure considered safe and feasible, with a low mortality and adequate locoregional tumor control when performed in referral centers. avaliar o perfil de morbimortalidade e seus fatores preditivos relacionados às ressecções pélvicas extensas, incluindo a exenteração pélvica, com o intuito de otimizar a seleção dos pacientes e obtenção de melhores resultados cirúrgicos. foram realizadas 24 grandes ressecções pélvicas por neoplasia maligna anorretal de 2008 a 2015 no Instituto do Câncer do Ceará. Os fatores analisados incluíram idade, perda de peso, órgão ressecados, exenteração total versus posterior, invasão angiolinfática e perineural, metástase linfonodal e sobrevida global e livre de doença. a mediana de idade foi 57 anos e o tempo médio de seguimento foi dez meses. A morbidade global foi 45,8%, com cinco (20,8%) complicações graves. Não houve óbito nos primeiros 30 dias de pós-operatório. A sobrevida global média foi 39,5 meses e a sobrevida livre de doença foi 30,7 meses. A ressecção concomitante da bexiga foi fator prognóstico isolado com maior risco para complicações (87,5% vs. 26,7%, p=0.009). Invasão angiolinfática e metástase linfonodal não alcançaram significância com relação à sobrevida livre de doença. o tratamento dos tumores anorretais avançados é desafiador, necessitando frequentemente de ressecções combinadas, como a cistectomia e sacrectomia, além de reconstruções complexas. A magnitude da cirurgia ainda carrega uma elevada taxa de morbidade, porém é um procedimento considerado seguro e factível, com uma baixa mortalidade e adequado controle locorregional tumoral quando realizado em centros de referência.


A case of osteophyte excision and arthroscopic arthrodesis for tarsal tunnel syndrome with traumatic osteoarthritis of the ankle.
There are some reports of tarsal tunnel syndrome (TTS) entrapment/impingement from bony factors, including exostosis and fragment, but there are no reports on TTS with traumatic osteoarthritis of the ankle that were treated with osteophyte excision for TTS and arthroscopic arthrodesis for osteoarthritis of the ankle. A 61-year-old woman with left trimalleolar fracture had undergone surgery 3 years earlier and was referred to our hospital for further investigation of persistent left ankle pain and numbness around the left medial malleolus and plantar aspect of the foot. Clinical examination demonstrated plantar hypesthesia and a positive Tinel's sign at the tarsal tunnel. Imaging showed severe osteoarthritic change in the ankle and an osteophyte of the posteromedial distal tibia that appeared to be impinging on the tibial nerve. We performed arthroscopic ankle arthrodesis, which is less invasive than the open procedure, with removal of the osteophyte as the cause of TTS. Tarsal tunnel exploration revealed a large osteophyte pushing on the tibial nerve, and the osteophyte was removed. About 8 weeks after surgery, bony union was achieved. At the 2-year follow-up visit, the patient could perform daily activities with almost no pain or numbness. This case offers further insight into the management of TTS with traumatic osteoarthritis of the ankle. We report here successful treatment of a rare case of tarsal tunnel syndrome (TTS) accompanied with traumatic osteoarthritis of the ankle, treated with osteophyte excision for the TTS and arthroscopic for the osteoarthritis.


Relationship between biofeedback and oxidative stress in patients with chronic migraine.
Chronic migraine (1.5.1) is burdened with headache-related disability. During noxious stimulation, changes of cerebral blood flow enhance the release of oxygen free radicals that react with nitric oxide (NO). We investigated the role of biofeedback in limiting migraine disability by influencing oxidative stress. Peroxides, NO and superoxide dismutase (SOD) were analysed in 20 female subjects with chronic migraine and in 20 female healthy controls before and after biofeedback sessions. NO(x) levels (23.7 +/- 4.2 vs. 34.9 +/- 4.6 microm; P < 0.05) and SOD activity (6.5 +/- 1.0 vs. 8.0 +/- 0.7 U/ml; P < 0.05) were lower in migraine sufferers before treatment than in healthy controls, whereas peroxide levels (145.8 +/- 40.3 vs. 78.0 +/- 20.0 microm; P < 0.05) were higher in migraine sufferers before treatment than in healthy controls. In migraine sufferers NO(x) levels (23.7 +/- 4.2 vs. 31.3 +/- 7.1 microm; P < 0.05) and SOD activity (6.5 +/- 1.0 vs. 7.9 +/- 0.9 U/ml; P < 0.05) were lower before than after treatment, whereas peroxide levels (145.8 +/- 40.3 vs. 82.4 +/- 21.1 microm; P < 0.05) were higher before than after treatment. SOD serum activity correlated positively with NO(x) serum levels and negatively with peroxide serum levels in healthy controls and in chronic migraine sufferers before and after biofeedback. The mean Migraine Disability Assessment Score before biofeedback sessions was higher than after treatment (36.9 +/- 13.9 vs. 18.8 +/- 10.4; P < 0.001). The effectiveness of biofeedback in limiting chronic migraine may be related to muscular relaxation associated with decreased oxidative stress accompanied by psychological well-being.


Thermal and mechanical characterization of composite materials from industrial plastic wastes and recycled nylon fibers for floor paving tiles application.
Industrial plastic waste is growing globally at an alarming rate and environmental pollution from traditional landfill disposal and incineration treatments are of great concern. As a strategy to reduce plastic pollution, value-added composite materials from industrial plastic wastes reinforced with recycled nylon fibers for use in floor paving tile applications were developed. This is to address the disadvantages of existing ceramic tiles which are relatively heavy, brittle, and expensive. The plastic waste composite structures were produced via compression molding technique at an optimized randomly oriented constant fiber volume fraction of 50 wt% after the initial sorting, cleaning, drying, pulverizing, and melt-mixing. The molding temperature, pressure, and time for the composite's structures were 220 ℃, 65 kg.cm-3, and 5 min respectively. The composites' thermal, mechanical, and microstructural properties were characterized in accordance with appropriate ASTM standards. From the results obtained, the differential scanning calorimetry (DSC) of mixed plastic wastes and nylon fiber wastes showed a processing temperature range of 130-180 ℃, and 250 ℃ respectively. Thermal degradation temperature (TGA) of the plastic and nylon fiber waste composites were stable above 400 ℃ with maximum bending strength, however, the reinforced plastic waste sandwiched composite structures had outstanding mechanical properties indicating unique characteristics suitable for floor paving tiles. Hence, the current research has developed tough and lightweight tiles composites that are economically viable, and their application will contribute to the development of the building and construction sectors thereby reducing about 10-15% of annual plastic waste generation and a sustainable environment.


[Neoadjuvant therapy for tumors of the upper gastrointestinal tract : Complication management].
Recent studies could demonstrate that neoadjuvant chemotherapy and radiochemotherapy for esophageal and gastric cancer do not significantly increase the risk of postoperative morbidity and mortality as compared to surgery alone. With respect to patient safety and effectiveness of neoadjuvant concepts, quality assured performance of each treatment modality and close interdisciplinary cooperation play an important role. The majority of potential side effects and complications, which might occur during neoadjuvant therapy can be adequately controlled by correct prophylaxis and professional medical complication management. Complications before, during and after neoadjuvant therapy of upper gastrointestinal tract tumors can also be caused by the tumor itself or by medicinal therapy. These comprise bleeding, fistulas, perforations and stenoses. Modern endoscopic techniques are the therapy of choice in these situations. Preoperative conditioning during the period of neoadjuvant therapy opens the possibility of reduced postoperative complications to patients with tumors of the upper gastrointestinal tract.


Norepinephrine Modulates Pyramidal Cell Synaptic Properties in the Anterior Piriform Cortex of Mice: Age-Dependent Effects of β-adrenoceptors.
Early odor preference learning in rodents occurs within a sensitive period [≤postnatal day (P)10-12], during which pups show a heightened ability to form an odor preference when a novel odor is paired with a tactile stimulation (e.g., stroking). Norepinephrine (NE) release from the locus coeruleus during stroking mediates this learning. However, in older pups, stroking loses its ability to induce learning. The cellular and circuitry mechanisms underpinning the sensitive period for odor preference learning is not well understood. We first established the sensitive period learning model in mice - odor paired with stroking induced odor preference in P8 but not P14 mice. This learning was dependent on NE-β-adrenoceptors as it was prevented by propranolol injection prior to training. We then tested whether there are developmental changes in pyramidal cell excitability and NE responsiveness in the anterior piriform cortex (aPC) in mouse pups. Although significant differences of pyramidal cell intrinsic properties were found in two age groups (P8-11 and P14+), NE at two concentrations (0.1 and 10 μM) did not alter intrinsic properties in either group. In contrast, in P8-11 pups, NE at 0.1 μM presynaptically decreased miniature IPSC and increased miniature EPSC frequencies. These effects were reversed with a higher dose of NE (10 μM), suggesting involvement of different adrenoceptor subtypes. In P14+ pups, NE at higher doses (1 and 10 μM) acted both pre- and postsynaptically to promote inhibition. These results suggest that enhanced synaptic excitation and reduced inhibition by NE in the aPC network may underlie the sensitive period.


Interrupting apoptosis in neurodegenerative disease: potential for effective therapy?
Current treatment options for neurodegenerative diseases are limited and mainly affect only the symptoms of disease. Because of the unknown and probably multiple causes of these diseases, they cannot be readily targeted. However, it has been established that apoptosis contributes to neuronal loss in most neurodegenerative diseases. A possible treatment option is to interrupt the signaling networks that link neuronal damage to apoptotic degradation in neurodegeneration. The viability of this option depends upon the extent to which apoptosis accounts for neuron loss, whether or not interruption of apoptosis signaling results in recovery of neurological function and whether or not there are significant downsides to targeting apoptosis. Several compounds acting at different sites in known apoptotic signaling networks are currently in development and a few are in clinical trial. If an apoptosis-targeted compound succeeds in slowing or halting neurological dysfunction in one or more neurodegenerative diseases, a new era in the treatment of neurodegenerative diseases will begin.


Maternal micronutrients and omega 3 fatty acids affect placental fatty acid desaturases and transport proteins in Wistar rats.
Adequate supply of LCPUFA from maternal plasma is crucial for fetal normal growth and development. The present study examines the effect of maternal micronutrients (folic acid and vitamin B12) and omega 3 fatty acids on placental mRNA levels of fatty acid desaturases (Δ5 and Δ6) and transport proteins. Pregnant female rats were divided into 6 groups at 2 levels of folic acid both in the presence and absence of vitamin B12. Both the vitamin B12 deficient groups were supplemented with omega 3 fatty acid. Maternal vitamin B12 deficiency reduced placental mRNA and protein levels of Δ5 desaturase, mRNA levels of FATP1 and FATP4 (p<0.05 for all) as compared to control while omega 3 fatty acid supplementation normalized the levels. Our data for the first time indicates that altered maternal micronutrients and omega 3 fatty acids play a key role in regulating fatty acid desaturase and transport protein expression in placenta.


Automated water recycle (AWR) method for dust removal from rooftop photovoltaic (PV) at Johor, Malaysia.
Wet dust on the Photovoltaic (PV) surface is a persistent problem that is merely considered for rooftop based PV cleaning under a high humid climate like Malaysia. This paper proposes an Automated Water Recycle (AWR) method encompassing a water recycling unit for rooftop PV cleaning with the aim to enhance the electrical performance. This study makes a major contribution by developing a new model to correlate output power ( P out ) and dust-fall factor. For model validation, we conducted an experiment of taking one set of Monocrystalline PV (mono) on a 340 W m 2 of medium luminance day. One mono module was cleaned by AWR - pressurized water sprayed through 11 small holes over its front surface, while the other module was left with no-cleaning. The dust-contaminated water was filtered and collected back to the tank for recycling process. The water loss per cleaning cycle was achieved 0.32%, which was normalized to net loss of 28.8% at a frequency of 1 cycle/day for 90 days of operation. We observed that P out of no-cleaning PV was decreased by 29.44% than that of AWR method. From this experimental data also, a unique and more accurate model is created for P out prediction, which is much simpler compared to multivariables equation. Our investigation offers important insights into the accuracy of this regression model demonstrated by R 2 = 0.744 or a strong negative quadratic relationship between P out and dust-fall. The cleaning of PV modules is expected to save significant energy to reduce the payback period. An automated water recycle method for cleaning dust-fall in rooftop photovoltaic module is proposed.Both simulation and experimental models are developed to predict output power of the photovoltaic module.Proposed method can produce 24.40% more output power than a no-cleaning system with a mere water loss of 0.32%/cycle.


Three new species of penicillium.
Three new species of microfungi belonging to the genus Penicillium Link ex Fries are described and illustrated. All but one have been isolated from the atmosphere of las Palmas, capital city of the island of Gran Canaria (Canary Islands, Spain). They clearly differ from all species of the genus described so far and are, therefore, described and proposed as new species: Penicillium hispanicum sp. nov., Penicillium grancanariae sp. nov., and Penicillium palmensis sp. nov.


Capsular phimosis with complete occlusion of the anterior capsular opening after intact continuous curvilinear capsulorrhexis.
Shrinkage and whitening of the anterior capsule opening - capsular contraction syndrome - is a well-known complication after continuous curvilinear capsulorrhexis. A 72-year-old women underwent continuous curvilinear capsulorrhexis, phacoemulsification, and implantation of posterior chamber intraocular lens with polymethylmethacrylate haptics. Four months postoperatively, the patient reported deterioration in visual acuity that was resulted due to complete occlusion of anterior capsular opening by fibrotic tissue. The fibrous membrane was excised surgically in capsulorrhexis fashion.


Acquired mutations in phage lambda genes O or P that enable constitutive expression of a cryptic lambdaN+cI[Ts]cro- prophage in E. coli cells shifted from 30 degreesC to 42 degreesC, accompanied by loss of immlambda and Rex+ phenotypes and emergence of a non-immune exclusion-state.
The majority of bacteria, which carry the N+-cI857[Ts]-cro--O+-P+ fragment of lambda genome, are killed when derepressed by shifting from 30 degreesC to 42 degreesC. Among rare survivors, we observed a proportion of colony-forming units (cfu) that retained the typical immlambda-immunity phenotype when grown at 30 degreesC; however, when shifted from 30 degreesC to 42 degreesC, they lost lambda immunity and acquired a non-immune exclusion-state (Nie phenotype). We also found that the immlambda survivor cfu quickly lost their Rex+ exclusion phenotype (as measured by T4rII plating inhibition) when shifted from 30 degreesC to 42 degreesC, even though they produced CII, which stimulates pE-cI-rexA-rexB transcription. The Nie phenotype was characterized by an inhibition of plating of the homoimmune phage, lambdawt, and the heteroimmune phage, lambdaimm434. However, lambdavir and spontaneous mutants of lambdawt (lambdase mutations localized within oR) escaped the Nie exclusion-state and plated efficiently on lawns of Nie cfu at 42 degreesC. Thus, we examined the scope of the Nie exclusion-state toward lambda mutants blocked for lysogeny, and lambda hybrids substituted for immunity or replication genes. Phage like lambdawt, competent for lysogeny, were severely excluded compared to some mutants of lambda defective for lysogeny. Among this latter type, there was high variance in the Nie exclusion of various cI mutants; some of which were not excluded. The Nie exclusion-state was attributed to the constitutive expression of the defective lambda fragment in the survivor cfu, made possible by the acquired replication defect(s). We characterized, both genetically and physically, the mutations in the defective integrated lambda prophage that permitted growth of the survivor cfu at 42 degreesC. In five of seven survivor cfu, we identified IS2 insertions within lambda genes O and P that can block replication initiation from the lambda fragment. The remaining survivor cfu had multiple base substitutions within the C-terminal end of O and N-terminal half of P, the majority of which were silent. In some of these mutants, either an ochre nonsense mutation or a single-base frameshift deletion inactivated P.


Drug Discovery and Development Asia-Pacific Conference 2005. Strategies and case studies of successful alliances, licensing and outsourcing partnerships.
Delegates gathered at the conference to hear speakers presenting talks from a business and strategic viewpoint. This report highlights selected presentations relating to promotional alliances, globalization of R and D and successful collaborations.


Developmental changes of gangliosides of the rat stomach. Appearance of a blood group B-active ganglioside.
Rat stomach gangliosides were purified and their distribution in the different tissue compartments was established. Three major monosialogangliosides were found: GM3, GM1, and a ganglioheptaosylceramide carrying a blood group B determinant. This latter structure was characterized by exoglycosidase degradation, immunostaining with a monoclonal anti-blood group B antibody on thin layer chromatogram, permethylation analysis, electron-impact mass spectrometry of the permethylated-reduced and trimethylsilylated molecule, and 1H NMR spectroscopy of the native ganglioside. It was found to be (Formula: see text) i.e. a GM1 structure substituted with the blood group B determinant and was called B-GM1. A similar structure has been previously identified in precancerous rat liver and chemically induced rat hepatoma (Holmes, E. H., and Hakomori, S. (1982) J. Biol. Chem. 257, 7698-7703). Fucosyl-GM1 was also detected as a minor ganglioside in rat gastric mucosa. The ganglioside profile was modified during the postnatal development. The contribution of GM3 and GD3, which accounted for 95% of the ganglioside sialic acid at birth, decreased during the first 3 weeks of life. GM1, fucosyl-GM1, and B-GM1 were not detected at birth. The concentration of the fucogangliosides increased during the 2nd and 3rd weeks after birth, was stable during the 4th week and then decreased, whereas that of GM1 increased steadily between 6 days and 2 months of age. B-GM1, which has been defined as a tumor-associated ganglioside in the rat liver, was found to be a developmentally regulated antigen of the normal rat stomach.


Evaluation of synergistic approach of spinel cadmium-copper nanoferrites as magnetic catalysts for promoting wastewater decontamination: Impact of Ag ions doping.
Metal substitution is an efficient strategy to improve the catalytic activity of ferrite-based catalysts. In this study, Cd0.5Cu0.5-xAgxFe2O4 (where 0 ≤ x ≤ 0.5) ferrites were fabricated via a simple co-precipitation method. The influence of the silver ions on the structural, magnetic, and catalytic characteristics of the spinel nanoparticles, as well as on their morphology, was examined. X-ray diffractograms revealed a crystalline cubic spinel structure with crystallite sizes in the nanoregime (7-15 nm). The saturation magnetization reduced from 29.8 to 2.80 emu as the Ag+ doping increased. Two prominent absorption bands were visible in Fourier-transform infrared spectra at 600 cm-1 and 400 cm-1, respectively, and they belonged to the tetrahedral (A) and octahedral (B) sites. The samples were then used as catalysts for the oxidative breakdown of the typical organic contaminant indigo carmine dye (IC). The catalytic process followed the first-order kinetic model, and the rate constant increased from 0.007 to 0.023 min-1 with increasing of Ag+ doping. Cd0.5Cu0.5-xAgxFe2O4 exhibited excellent catalytic performance in the pH range of 2-11, which means that they are promising efficient and stable materials for Fenton-based alkaline wastewater treatment. Finally, the pathway includes, HO•, HO2-•, and O2-• as oxidants resulted from the synergistic effects of Fe3+, Cu2+, and Ag+, with H2O2 and surface hydroxyl groups have been proposed.


Comparison of Overall Survival Between De Novo and Secondary Acute Lymphoblastic Leukemia Patients of Different Ages.
To compare the overall survival (OS) between de novo and secondary acute lymphoblastic leukemia (ALL) patients in different age groups after chemotherapy. Data from 8305 ALL patients undergoing chemotherapy from the Surveillance, Epidemiology, and End Results (SEER) database during 1975 to 2015 were included in this study, of which 7454 (80.11%) were in the de novo ALL group, and 851 (19.89%) were in the secondary ALL (sALL) group. Propensity matching was used before comparison of OS between the two groups. Female ALL patients had a lower risk of death than male (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.88-0.98; P < .01). The mortality of black patients was higher than in white patients (HR, 1.29; 95% CI, 1.18-1.42; P < .001). Patients aged 45-75 years (HR, 1.82; 95% CI, 1.72-1.94; P < .001) and ≥ 75 years (HR, 3.85; 95% CI, 3.52-4.23; P < .001) had a higher risk of death. Separated/divorced (HR, 1.21; 95% CI, 1.10-1.34; P < .001) and widowed (HR, 1.35; 95% CI, 1.21-1.51; P < .001) patients had a higher risk of death than single patients. sALL patients had a higher risk of death than de novo ALL patients (HR, 1.21; 95% CI, 1.12-1.30; P < .001). The mean age of the de novo ALL group was lower than in the sALL group (51.05 vs. 60.25; P < .001) after the propensity score was matched, and the 1-, 2-, 3-, 4-, and 5-year OS of the de novo ALL group were higher than that of the sALL group aged 18-75 years (P < .001). The survival rate of ALL decreased with increased age. Patients with sALL had poorer OS than de novo patients aged 18-75 years.


Comparative efficacy of levamisole, thiabendazole and fenbendazole against cattle gastrointestinal nematodes.
Efficacy of two older anthelmintics, levamisole and thiabendazole, was compared with a newer benzimidazole, fenbendazole, against naturally acquired gastrointestinal nematode infections in cattle superimposed with experimental infections of Bunostomum phlebotomum and Dictyocaulus viviparus. Twenty-four crossbred beef heifers of 7-9 months of age and 152 kg in average weight were randomly allocated to four groups of six calves. The cattle grazed on pastures contaminated with larvae of gastrointestinal nematodes and the lungworm for 2 months prior to Day 0. Treatment groups were as follows: Group 1--levamisole, topical at 10 mg kg-1; Group 2--thiabendazole paste at 110 mg kg-1; Group 3--fenbendazole paste at 10 mg kg-1; Group 4--untreated controls. All calves were necropsied for worm recovery between 8 and 10 days after treatment. Fecal egg/larval per gram counts at 18 and 42 h post-treatment indicated greatest reductions in Groups 1 and 2. By 7 days post-treatment, reduction in counts for all treated groups ranged from 99.1 to 100%, except for the 66.7% reduction of B. phlebotomum in Group 2. Seven nematode species were present in a sufficient number of untreated controls for valid efficacy assessment at necropsy. Efficacy of fenbendazole was 100% against all species, including Cooperia spp. L4 and immature (E5) D. viviparus. The overall efficacy of levamisole and thiabendazole was generally high (93.0-100% against Haemonchus placei adults, Cooperia punctata and C. spatulata adult males, Cooperia spp. adult females, Oesophogastomum radiatum, B. phlebotomum, and D. viviparus adults).(ABSTRACT TRUNCATED AT 250 WORDS)


Localization of zinc-enriched neurons in the mouse peripheral sympathetic system.
Growing evidence supports the notion that zinc ions located in the synaptic vesicles of zinc-enriched neurons (ZEN) play important physiological roles and are involved in certain pathological changes in the central nervous system. Here we present data revealing the distribution of zinc ions and the co-localization of zinc transporter 3 (ZnT3) and tyrosine hydroxylase (TH) in crush-operated sciatic nerves and lumbar sympathetic ganglia of mice, using zinc selenide autometallography (ZnSe(AMG)) and ZnT3 immunofluorescence combined with confocal scanning microscopy, respectively. Six hours after the crush operation, ZnSe(AMG) grains and ZnT3 immunoreactivity were predominantly present in a subpopulation of thin unmyelinated sciatic nerve axons. In order to identify the type(s) of ZEN axons involved, double labeling with ZnT3 and (1) TH, (2) vesicular acetylcholine transporter (VAChT), (3) calcitonin gene-related peptide (CGRP), and (4) neuropeptide Y (NPY) was performed. Confocal microscopic observations showed that ZnT3 was located in a subpopulation of sciatic axons in distended parts proximal and distal to the crush site. Most, if not all, ZnT3-positive axons contained TH immunofluorescence, a few showed co-localization of ZnT3 and VAChT with very weak immunostaining, while no congruence was observed between ZnT3 and CGRP or NPY. Studies of the lumbar sympathetic ganglia showed that not more than 5% of the neurons were ZnT3-positive and that almost all of these were TH-positive. Furthermore, approximately 5% of total lumbar sympathetic ganglionic cells were ZnSe(AMG) positive, 48 h after a local injection of sodium selenide into the sciatic nerve. The present data support the notion that a subgroup of mouse sympathetic postganglionic neurons are ZEN neurons.


Ojigi tying spatula: a newly developed movable spatula for laparoscopic ligation.
We developed a new type of movable tying spatula for ligation of the cystic duct and artery in laparoscopic cholecystectomy. This spatula can be used to ligate any vascular or ductal structure before laparoscopic resection. This instrument should give strong support to surgeons performing laparoscopic procedures and eventually will replace the expensive clips and Endoloops.


Patterns of practice of palliative radiotherapy in Africa, Part 1: Bone and brain metastases.
To provide data on the pattern of practice of palliative radiotherapy (RT) on the African continent. A questionnaire was distributed to participants in a regional training course of the International Atomic Energy Agency in palliative cancer care and sent by e-mail to other institutions in Africa. Requested information included both infrastructure and human resources available and the pattern of RT practice for metastatic and locally advanced cancers. Of 35 centers contacted, 24 (68%) completed the questionnaire. Although RT is used by most centers for most metastatic cancers, liver and lung metastases are treated with chemotherapy. Of 23 centers, 14 (61%) had a single RT regimen as an institutional policy for treating painful bone metastases, but only 5 centers (23%) of 23 used 8 Gy in 1 fraction. Brain metastases were being treated by RT to the whole brain to 30 Gy in 10 fractions, either exclusively (n=13, 56%) or in addition to the use of 20 Gy in 5 fractions (n=3, 14%). Radiotherapy is a major component of treatment of cancer patients in African countries. There is consensus among few centers for treatment schedules for almost all sites regarding time and dose-fractionation characteristics of RT regimens used and/or indications for the use of RT in this setting.


Meandering Rivers: How Important is Lateral Variability for Species Persistence?
Models for population dynamics in rivers and streams have highlighted the importance of spatial and temporal variations for population persistence. We present a novel model that considers the longitudinal variation as introduced by the sinuosity of a meandering river where a main channel is laterally extended to point bars in bends. These regions offer different habitat conditions for aquatic populations and therefore may enhance population persistence. Our model is a nonstandard reaction-advection-diffusion model where the domain of definition consists of the real line (representing the main channel) with periodically added intervals (representing the point bars). We give an existence and uniqueness proof for solutions of the equations. We then study population persistence as the (in-) stability of the trivial solution and population spread as the minimal wave speed of traveling periodic waves. We conduct a sensitivity analysis to highlight the importance of each parameter on the model outcome. We find that sinuosity can enhance species persistence.


Prolonged and multiple immobilizations of the southern elephant seal using ketamine hydrochloride-xylazine hydrochloride or ketamine hydrochloride-diazepam combinations.
Thirty seven southern elephant seals (Mirounga leonina) were singularly or repeatedly immobilized with combinations of ketamine hydrochloride (HCl) and xylazine HCl or ketamine HCl and diazepam. Atropine sulphate was included in the drug combinations. To permit experimental procedures the seals were immobilized for periods of 30-330 min. The mean induction dose of ketamine HCl was 8.71 +/- 0.25 mg/kg (mean +/- SE). The mean induction time was 16.02 +/- 2.62 min. For the elephant seals immobilized for periods in excess of 180 min, the mean dose of ketamine HCl used per hr was 3.31 +/- 0.13 mg/kg/hr and the mean dose of ketamine HCl used per hr postinduction was 1.31 +/- 0.15 mg/kg/hr. The mean dose of diazepam used was 0.09 +/- 0.01 mg/kg and the mean dose of xylazine HCl was 0.41 +/- 0.01 mg/kg. Elephant seals were weighed on 20 occasions (weight range: 897-1,932 kg) and the relationship between standard length and weight was found to be: Weight = 9.98 length - 2,317.63 (r2 = 0.724). Adverse reactions to seals immobilized only once or twice were not observed. Two seals immobilized on three occasions developed abscesses at the site of injection.


A clinic-based system for monitoring the quality of techniques for the diagnosis of gonorrhea.
The author describes a clinic-based system that monitors the quality of techniques for diagnosis of gonorrhea by continuous comparison of the results of gram-strained smears of urethral and cervical specimens with the corresponding cultures. Discrepant results are immediately reviewed. During a two-year period, the system detected two defects in culture incubation, visual defects in a laboratory technician, and three unexplained reductions in cultural sensitivity. The system motivates clinicians and laboratory technicians to maintain a high level of quality control. In 11,474 comparisons of urethral smear and culture results, there was agreement in 96.9% while the smear alone was positive in 1.6% and the culture alone in 1.5%. Review of positive-smear-negative-culture discrepancies indicated that most smears judged "false-positive" were so classified on the basis of false-negative cultures. In study of 1,331 women, the endocervical smeras identified 60% (273/455) of those with positive culture discrepancies. Many of these may have represented false-negative cultures.


The antitumour agent 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide (DTIC) inhibits rat liver cAMP phosphodiesterase and amplifies hormone effects in hepatocytes and hepatoma cells.
The antitumour agent 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC) was found to inhibit competitively the low-Km cyclic AMP phosphodiesterase activity in an ammonium-sulphate-precipitable fraction of the 2,000g supernatant of rat liver. With substrate concentration at 0.25 microM, I50 was 790 microM for DTIC and 350 microM for theophylline. DTIC at 2 mM more than doubled the cAMP response to glucagon in hepatocytes and to adrenaline in MH1C1 hepatoma cells, indicating that it also exerts its inhibitory effect on the phosphodiesterase in intact cells. The possible contribution of the phosphodiesterase inhibition to the growth-inhibitory and cytotoxic effects of DTIC is discussed.


Prostate cancer brachytherapy: SFRO guidelines 2021.
Prostate brachytherapy techniques are described, concerning both permanent seed implant and high dose rate brachytherapy. The following guidelines are presented: brachytherapy indications, implant procedure for permanent low dose rate implants and high dose rate with source projector, as well as dose and dose-constraints objectives, immediate postoperative management, post-treatment evaluation, and long-term follow-up.


Assessment of pollution impact on biological activity and structure of seabed bacterial communities in the Port of Livorno (Italy).
The main objective of this study was to assess the impact of pollution on seabed bacterial diversity, structure and activity in the Port of Livorno. Samples of seabed sediments taken from five selected sites within the port were subjected to chemical analyses, enzymatic activity detection, bacterial count and biomolecular analysis. Five different statistics were used to correlate the level of contamination with the detected biological indicators. The results showed that the port is mainly contaminated by variable levels of petroleum hydrocarbons and heavy metals, which affect the structure and activity of the bacterial population. Irrespective of pollution levels, the bacterial diversity did not diverge significantly among the assessed sites and samples, and no dominance was observed. The type of impact of hydrocarbons and heavy metals was controversial, thus enforcing the supposition that the structure of the bacterial community is mainly driven by the levels of nutrients. The combined use of chemical and biological essays resulted in an in-depth observation and analysis of the existing links between pollution macro-indicators and biological response of seabed bacterial communities.


Study of mandibular growth in patients treated with Fränkel's functional regulator (1b).
The purpose of this study was to assess mandibular growth in patients with Class II division 1 malocclusions when treated with Fränkel's functional regulator 1b. The treatment group was made up of 43 patients that were divided into two groups: prepubescent (n:28), and pubescent (n:15). The control group included 40 patients who did not receive any kind of treatment and were likewise divided into a prepubescent group (n:19), and a pubescent group (n:21). A computerized cephalometric study was carried out and superimpositions were done in order to assess the antero-posterior, vertical and rotational movements of the mandible. A two-way ANOVA with interaction was done to compare the changes between the control group and the treatment group, while the Student t for independent samples was used to compare each age group. The Gnathion and Gonion points showed significant differences in the whole sample (p<0.001) as well as in the prepubescent (p<0.001) and pubescent groups (p<0.05). Rotational changes of the mandible measured using the facial axis and mandibular plane showed no statistical differences between both groups (p>0.05). The results show that the FR produces vertical orthopedic growth in the mandible but not horizontal growth compared to non-treated Class II-type I malocclusion patients. No rotational changes were found in the mandible, but we did record mandibular growth along the inclination of the facial axis.


Improved lactate control with dichloroacetate in a case with severe neonatal lactic acidosis due to MTFMT mitochondrial translation disorder.
Mitochondrial methionyl-tRNA formyltransferase (MTFMT) is a nuclear-encoded gene that produces a protein involved in mitochondrial translation. MTFMT formylates a portion of Met-tRNAMet, which allows for translation initiation of mitochondrial mRNA. Mutations in this gene have been shown to result in decreased mitochondrial translation with reduction function of the electron transport chain complexes I, III, IV, and V, thus affecting cellular energy production. Our patient presented with severe lactic acidosis in the neonatal period, and was found to be homozygous for the pathogenic mutation c.994C > T, p.(Arg332*). Her blood lactate levels normalized and her cardiomyopathy reversed after initiation of dichloroacetate (30 mg/kg/day). After two years of follow-up, she continues to show long-term lactate stability, continues to make developmental gains, and is in overall good general health. This is the first report using dichloroacetate in a patient with MTFMT deficiency, which may be a potential therapeutic option that warrants further study.


Dedicator of Cytokinesis 2 (DOCK2) Silencing Protects Against Cerebral Ischemia/Reperfusion by Modulating Microglia Polarization via the Activation of the STAT6 Signaling Pathway.
Cerebral ischemia/reperfusion is the major pathophysiological process in stroke and could lead to severe and permanent disability. The current study aimed to investigate the effects of dedicator of cytokinesis 2 (DOCK2) on cerebral ischemia/reperfusion-induced cerebral injury. We established a mouse middle cerebral artery occlusion (MCAO) model with suture-occluded method in vivo. Then, BV-2 cells were conducted to oxygen-glucose deprivation and re-oxygenation (OGD/R) in vitro. The results showed that DOCK2 was highly expressed in ischemic brain following MCAO and in BV-2 cells induced by OGD/R. DOCK2 depletion protected against MCAO-induced brain infarcts and neuron degeneration. DOCK2 downregulation improved long-term neurological function, which was assessed by the Morris water-maze test. Moreover, silencing of DOCK2 promoted M2 polarization (anti-inflammation) and repressed M1 polarization (pro-inflammation) of microglia both in vivo and in vitro. Subsequently, we found that the loss of DOCK2 upregulated the expression of p-STAT6. DOCK2 knockdown-induced microglial cell polarization towards M2 phenotype was partly abrogated by the STAT6 inhibitor AS1517499. In conclusion, DOCK2 downregulation protected against cerebral ischemia/reperfusion by modulating microglia polarization via the activation of the STAT6 signaling pathway.


Epithelial Na⁺ channel activity in human airway epithelial cells: the role of serum and glucocorticoid-inducible kinase 1.
Glucocorticoids appear to control Na⁺ absorption in pulmonary epithelial cells via a mechanism dependent upon serum and glucocorticoid-inducible kinase 1 (SGK1), a kinase that allows control over the surface abundance of epithelial Na⁺ channel subunits (α-, β- and γ-ENaC). However, not all data support this model and the present study re-evaluates this hypothesis in order to clarify the mechanism that allows glucocorticoids to control ENaC activity. Electrophysiological studies explored the effects of agents that suppress SGK1 activity upon glucocorticoid-induced ENaC activity in H441 human airway epithelial cells, whilst analyses of extracted proteins explored the associated changes to the activities of endogenous protein kinase substrates and the overall/surface expression of ENaC subunits. Although dexamethasone-induced (24 h) ENaC activity was dependent upon SGK1, prolonged exposure to this glucocorticoid did not cause sustained activation of this kinase and neither did it induce a coordinated increase in the surface abundance of α-, β- and γ-ENaC. Brief (3 h) exposure to dexamethasone, on the other hand, did not evoke Na⁺ current but did activate SGK1 and cause SGK1-dependent increases in the surface abundance of α-, β- and γ-ENaC. Although glucocorticoids activated SGK1 and increased the surface abundance of α-, β- and γ-ENaC, these responses were transient and could not account for the sustained activation of ENaC. The maintenance of ENaC activity did, however, depend upon SGK1 and this protein kinase must therefore play an important but permissive role in glucocorticoid-induced ENaC activation.


Position of the American Dietetic Association: fortification and nutritional supplements.
It is the position of the American Dietetic Association (ADA) that the best nutritional strategy for promoting optimal health and reducing the risk of chronic disease is to wisely choose a wide variety of foods. Additional nutrients from fortified foods and/or supplements can help some people meet their nutritional needs as specified by science-based nutrition standards such as the Dietary Reference Intakes. Dietetics professionals are trained to assess dietary adequacy as well as the need for dietary modification. This position paper addresses increasing the nutrient density of foods or diets through fortification or supplementation when diets fail to deliver consistently adequate amounts of vitamins and minerals. The discussion presents points to consider that relate to both public health and individual applications. Many resources may be used to help guide the dietetics professional to determine responsible, evidence-based recommendations relating to nutrient fortification or supplementation.


N-acetylglucosamine inhibits T-helper 1 (Th1)/T-helper 17 (Th17) cell responses and treats experimental autoimmune encephalomyelitis.
Current treatments and emerging oral therapies for multiple sclerosis (MS) are limited by effectiveness, cost, and/or toxicity. Genetic and environmental factors that alter the branching of Asn (N)-linked glycans result in T cell hyperactivity, promote spontaneous inflammatory demyelination and neurodegeneration in mice, and converge to regulate the risk of MS. The sugar N-acetylglucosamine (GlcNAc) enhances N-glycan branching and inhibits T cell activity and adoptive transfer experimental autoimmune encephalomyelitis (EAE). Here, we report that oral GlcNAc inhibits T-helper 1 (Th1) and T-helper 17 (Th17) responses and attenuates the clinical severity of myelin oligodendrocyte glycoprotein (MOG)-induced EAE when administered after disease onset. Oral GlcNAc increased expression of branched N-glycans in T cells in vivo as shown by high pH anion exchange chromatography, MALDI-TOF mass spectroscopy and FACS analysis with the plant lectin l-phytohemagglutinin. Initiating oral GlcNAc treatment on the second day of clinical disease inhibited MOG-induced EAE as well as secretion of interferon-γ, tumor necrosis factor-α, interleukin-17, and interleukin-22. In the more severe 2D2 T cell receptor transgenic EAE model, oral GlcNAc initiated after disease onset also inhibits clinical disease, except for those with rapid lethal progression. These data suggest that oral GlcNAc may provide an inexpensive and nontoxic oral therapeutic agent for MS that directly targets an underlying molecular mechanism causal of disease.


A coordinated attempt for prevention of child abuse at the antenatal care level.
The authors report the preliminary result of an integrated approach to the primary prevention of the child abuse syndrome. The problem has been approached through a new concept of prenatal and postnatal care, the obstetrical team working in close cooperation with the child psychiatrist of the department of pediatrics. The obstetrical team followed 91 patients during their pregnancy; they were all discussed at supervisory sessions. This permitted a gynaecologist and a social nurse to develop a therapeutic plan for 72 patients. For the 19 more problematic cases, the child psychiatrist intervened immediately in the surroundings of the antenatal clinic. Short, specific psychotherapeutic interventions based on the alleviation of a family crisis have remedied important stress situations. The favourable influence of this new methodology has led to: (1) reduction of a potentially high expected prematurity rate; (2) improved integration of out-patient and in-patient care; (3) improved adaptation of the health staff to this type of situation. A case example to illustrate the functioning of both teams is given.


Effect of transauricular electroacupuncture on stress-induced changes in cognitive function and erosions of the gastric mucosa in rats.
Transauricular electroacupuncture prevented stress-induced increase in the degree of anxiety and suppression of exploratory activity in rats. This procedure significantly accelerated decision-making process during acute stress in both control and prestressed rats. Transauricular electroacupuncture decreased the number and area of erosions by producing a pronounced antistress effect at the central and peripheral levels.


Localization and signaling patterns of vascular endothelial growth factors and receptors in human periapical lesions.
Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are key players in vasculogenesis and are also involved in pathologic conditions with bone destruction. Vasculogenesis is critical for disease progression, and bone resorption is a hallmark of apical periodontitis. However, the localization of VEGFs and VEGFRs and their gene signaling pathways in human apical periodontitis have not been thoroughly investigated. The aim of this study was to localize VEGFs and VEGFRs and analyze their gene expression as well as signaling pathways in human periapical lesions. Tissue was collected after endodontic surgery from patients diagnosed with chronic apical periodontitis. Periodontal ligament samples from extracted healthy wisdom teeth was also collected and used as control tissue. In lesion cryosections, VEGFs/VEGFRs were identified by immunohistochemistry/double immunofluorescence by using specific antibodies. A human VEGF signaling polymerase chain reaction array system was used for gene expression analysis comparing lesions with periodontal ligament samples. The histologic evaluation revealed heterogeneous morphology of the periapical lesions with various degrees of inflammatory infiltrates. In the lesions, all investigated factors and receptors were identified in blood vessels and various immune cells. No lymphatic vessels were detected. Gene expression analysis revealed up-regulation of VEGF-A and VEGFR-3, although not significant. Phosphatidylinositol-3-kinases, protein kinase C, mitogen-activated protein kinases, and phospholipases, all known to be involved in VEGF-mediated angiogenic activity, were significantly up-regulated. The cellular and vascular expressions of VEGFs and VEGFRs in chronic apical periodontitis, along with significant alterations of genes mediating VEGF-induced angiogenic responses, suggest ongoing vascular remodeling in established chronic periapical lesions.


Risk factors for early death or euthanasia within 100 days of diagnosis in dogs with meningoencephalitis of unknown origin.
Meningoencephalitis of unknown origin (MUO) in the dog is an inflammatory condition of the central nervous system with variable short- and long-term prognosis. Previous studies have attempted to identify risk factors for early death; however, the findings were inconsistent and prognostication and treatment selection remain difficult for cases of MUO. The aim of this study was to compare the influence of putative prognostic factors on early survival in dogs with MUO. Logistic regression was used to analyse the effect of clinical and magnetic resonance imaging (MRI) features at diagnosis and type of immune-suppressive treatment received on survival at three-time points; 7 days, 30 days, and 100 days post-diagnosis. Ninety eight dogs were included. Dogs that were obtunded at presentation had a 6.6 times increased odds of death in the first 7 days after diagnosis, a 2.1 times increased risk of death 8-30 days after diagnosis, and a 1.9 times increased risk of death 31-100 days after diagnosis. No other clinical, MRI feature, or treatment was found to have a significant influence on survival. Obtundation at presentation was found to increase risk of early euthanasia in dogs with MUO, while the addition of an IV infusion of cytarabine to immune-suppressive corticosteroid therapy (prednisolone and/or dexamethasone) at initial treatment did not improve the odds of survival at 7, 30, or 100 days after diagnosis.


[Choice of surgical technic in cancer of the stomach. Results in 999 cases].
Authors analyze 999 of stomach cancer, as well as 865 operated patients (86,58%). Choice of operative method depends concert tumor localisation, its growth, methastasis, general condition and age of patient.


Role of miR-19b and its target mRNAs in 5-fluorouracil resistance in colon cancer cells.
Drug resistance in colorectal cancers is assumed to be mediated by changes in the expression of microRNAs, but the specific identities and roles of microRNAs are largely unclear. We examined the effect of 5-fluorouracil (5-FU) resistance on microRNA expression. Two types of 5-FU-resistant colon cancer cells were derived from the DLD-1 and KM12C cell lines. The expressions of microRNAs were profiled with a microarray containing 723 microRNAs and validated by quantitative real-time polymerase chain reaction (qRT-PCR). To survey the downstream mediators of microRNA, we used a microRNA:mRNA immunoprecipitation (RIP)-Chip and pathway analysis tool to identify potential direct targets of microRNA. In response to 5-FU, miR-19b and miR-21 were over-expressed in 5-FU-resistant cells. Of note, miR-19b was up-regulated 3.47-fold in the DLD-1 resistant cells, which exhibited no alteration in cell cycle profiles despite exposure to 5-FU. After transfection of miR-19b, specific mRNAs were recruited to microRNA:mRNA complexes isolated with Ago2 antibody and subjected to whole-genome transcriptional analysis. In this analysis, 66 target mRNAs were enriched by at least 5.0-fold in the microRNA:mRNA complexes from DLD-1 resistant cells. Ingenuity pathway analysis of mRNA targets significantly (P < 0.05) indicated the category "Cell Cycle" as a probable area of the molecular and cellular function related with 5-FU resistance. Among candidate mRNA targets, SFPQ and MYBL2 have been linked to cell cycle functions. We revealed up-regulation of miR-19b in response to 5-FU and potential targets of miR-19b mediating the cell cycle under treatment with 5-FU. Our study provides an important insight into the mechanism of 5-FU resistance in colorectal cancers.


Impact of non-clinical community-based promotional campaigns on bowel cancer screening engagement: An integrative literature review.
This paper reviewed the relationship between non-clinical, client-oriented promotional campaigns to raise bowel cancer awareness and screening engagement. An integrative literature review using predefined search terms was conducted to summarise the accumulated knowledge. Data was analysed by coding and categorising, then synthesized through development of themes. Eighteen of 116 studies met inclusion criteria. Promotional campaigns had varying impact on screening uptake for bowel cancer. Mass media was found to moderately increase screening, predominately amongst "worried well". Small media used in conjunction with other promotional activities, thus its effect on screening behaviours was unclear. One-on-one education was less effective and less feasible than group education in increasing intention to screen. Financial support was ineffective in increasing screening rates when compared to other promotional activities. Screening engagement increased because of special events and celebrity endorsement. Non-clinical promotional campaigns did impact uptake of bowel cancer screening engagement. However, little is evident on the effect of single types of promotion and most research is based on clinician-directed campaigns. Cancer awareness and screening promotions should be implemented at community and clinical level to maximize effectiveness. Such an approach will ensure promotional activities are targeting consumers, thus strengthening screening engagement.


Symptomatic leiomyoma of the adrenal.
Small leiomyomas of the adrenal gland are pathologic curiosities, usually discovered incidentally at autopsy, and thought to arise from smooth muscle of the adrenal vasculature. We report the clinical, radiologic and pathologic features of a symptomatic adrenal leiomyoma, which, to our knowledge, represents the first recorded example.


[Not Available].
Knowledge about the contamination of cereals with mycotoxins produced by the fungusAlternaria is rare in Germany. With regard to the fact thatAlternaria spp. were detected in the leaves and in the ears of winter wheat in high frequency and high numbers a monitoring program was started in order to get more information about the actual contamination of winter wheat with the three importantAlternaria-mycotoxins: Alternariol (AOH), alternariol monomethyl ether (AME) and tenuazonic acid (TeA). In 2000 and 2001 the occurrence ofAlternaria spp and their toxins in kernels and straw of winter wheat harvested in the state of Brandenburg (Germany) was investigated. First, for the sensitive determination of theAlternaria mycotoxins a HPLC method has been developed. Sample preparation included the extraction with acetonitrile/KCI and the purification by a liquid/liquid partition step. The toxins were analysed by HPLC with fluorescence (AOH, AME) or UV/VIS (TeA) detection after separation through a C18 column using methanol + water + zinc sulphate as eluent. AME and TeA were only detected in few kernel probes in concentrations of 45-83 ppb (AME) and 44-105 ppb (TeA), respectively. 50% of the straw probes were highly contaminated with TeA (300 ppb-75 ppm).


Do financial incentives of introducing case mix reimbursement increase feeding tube use in nursing home residents?
To determine whether adoption of Medicaid case mix reimbursement is associated with greater prevalence of feeding tube use in nursing home (NH) residents. Secondary analysis of longitudinal administrative data about the prevalence of feeding tube insertion and surveys of states' adoption of case mix reimbursement. NHs in the United States. NH residents at the time of NH inspection between 1993 and 2004. Facility prevalence of feeding tubes reported at the state inspection of NHs reported in the Online Survey, Certification and Reporting database and interviews with state policy makers regarding the adoption of case mix reimbursement. Between 1993 and 2004, 16 states adopted Resource Utilization Group case mix reimbursement. States varied in the prevalence of feeding tubes in their NHs. Although the use of feeding tube increased substantially over the years of the study, once temporal trends and facility fixed effects were accounted for, case mix reimbursement was not associated with greater prevalence of feeding tube use. The adoption of Medicaid case mix reimbursement was not associated with an increase in the prevalence of feeding tube use.


Single-sitting, fiber-reinforced fixed bridges for the missing lateral or central incisors in adolescent patients.
Many materials, methods, and techniques for the reinforcing of composites to bond a pontic onto abutment teeth have been tried and promoted. In this article, the author examines the use of fiber reinforcement in fixed bridges, describing the various steps performed by the dentist during the procedure.


Transabdominal chorionic villus sampling for fetal genetic diagnosis. Technical and obstetrical evaluation of 100 cases.
First trimester fetal diagnosis was established in 100 pregnancies at risk by transabdominal chorionic villus sampling (TA-CVS). Forty-eight per cent of the women were 35 years or more at the time of sampling. Using the double needle technique, both the aspiration and the diagnostic success rate were 100 per cent. The mean amount of villi aspirated was 28.2 mg (10-50 mg). The mean needle time was 3 min. Vaginal spotting appeared in 2 per cent of the women. Four women had therapeutic abortion due to abnormal findings and one for social reasons. Three fetuses with normal karyotypes were lost. Excluding the therapeutic abortions, the fetal loss rate was 3.2 per cent. The fetal loss rate in the amniocentesis control group (n = 200) was 3.6 per cent. The cytogenetic diagnosis was carried out by the direct preparation technique as well as by chorion villus cultivation. All karyotypes were confirmed by lymphocyte cultures from umbilical cord blood or heel blood from the newborn or from aborted fetal tissue. Transabdominal CVS is deemed a safe and easy tool for achieving chorionic villi in the first trimester.


Handling characteristics of gallium alloy for dental restoration.
The handling characteristics of a gallium alloy (Gallium Alloy GF) were compared to those of a spherical high-copper amalgam (Tytin). Ten dentists each restored four identical MO preparations in acrylic typodont teeth (no. 30), two with amalgam and two with gallium alloy. Each restoration was evaluated immediately following completion by the operator for six clinically relevant criteria. Each criterion was scored between 1 and 5, where 1 = very poor, 2 = poor, 3 = fair, 4 = good, and 5 = very good. Three two-sided Mann-Whitney tests were used to compare the median scores for significant differences (P < 0.05). The first test indicated no significant difference between scores for the first- and second-placed restorations, within criteria and within alloy type (n = 10). The second test indicated a significant difference between amalgam and gallium alloy, within criteria and within restoration sequence (n = 10), for each criterion except resistance to fracture during removal of the matrix band. The third test indicated a significant difference between amalgam and gallium alloy, within each criteria, combining scores for first- and second-placed restorations (n = 20). During simulated clinical placement, amalgam was rated significantly higher than gallium alloy in each handling characteristic evaluated.


Efficient adsorption of methylene blue by xanthan gum derivative modified hydroxyapatite.
In this work, hydroxyapatite modified by xanthan gum (XG) derivative material (XMH) was prepared and applied to remove methylene blue (MB) from water. The physicochemical properties of XMH were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, X-Ray spectroscopy and thermogravimetric analysis. Results showed the operating variables (pH, ionic strength and adsorbent dosage) were related to the MB removal efficiency. Adsorption kinetic and adsorption isotherm were well fitted by the pseudo-second-order model and the Langmuir isotherm model, respectively. It indicated that the adsorption process was a monolayer layer adsorption and chemisorption process. Besides, the result of intra-particle diffusion model demonstrated that the intra-particle diffusion was not the only rate determining step. The maximum adsorption capability on MB was 769 mg/g. Thermodynamic parameters (ΔG0, ΔH0, and ΔS0) showed that the adsorption was a spontaneous and endothermic process. Adsorption mechanisms of MB on XMH might be governed by electrostatic attraction and hydrogen-bonding. Furthermore, XMH could be regenerated well and retained MB removal efficiency of 81% after five cycles of adsorption and desorption. Therefore, XMH is a promising adsorbent for the efficient removal of MB from aqueous solution due to its low cost, good thermal stability and excellent adsorption performance.


Intestinal atresia with segmental musculature and neural defect.
The aim of this study was to investigate the possible etiologic factors of small bowel atresia and to detect the prognostic role of adequate resection and tapering in postoperative morbidity and mortality. Intestinal resection specimens were obtained from 10 patients with jejunoileal atresia and 3 control subjects without any gastrointestinal disease. Intestinal specimens taken from 2-cm and 4-cm proximal sides of atresia, atretic segment, and 1-cm and 2-cm distal sides of atresia were stained with Masson trichrome and H&E. Immunohistochemical staining of the biopsy specimens with synaptophysin was also performed to ascertain the number, the intensity, and the morphology of ganglia. At the blind proximal end, there was segmental absence of muscular layers, presence of neural defects, and replacement of the muscular layers with fibrous tissue beside the relatively intact mucosa. Segmental defects in muscular and neural structures of the intestinal wall observed in both the antimesenteric and mesenteric sides of the atretic small bowel were considered to support the vascular insult theory as an etiologic factor. Adequate resection rather than tapering the dilated proximal atretic intestinal segment should be included in the surgical treatment of this pathology to avoid the intestinal dysmotility, which may result in gut-related sepsis and death in the postoperative period.


P2Y-purinoceptor regulation of surfactant secretion from rat isolated alveolar type II cells is associated with mobilization of intracellular calcium.
1 The effect of methylene, thio, and imido substituted analogues of adenosine 5'-triphosphate (ATP) on surfactant phospholipid secretion and calcium mobilization in rat isolated alveolar Type II cells was studied. 2 ATP was the most potent secretagogue of adenine nucleotides studied. The rank order of agonist potency for [3H]-phosphatidylcholine secretion was ATP greater than adenosine 5'-O-(3-thiotriphosphate) (gamma S-ATP) greater than beta, gamma-imido adenosine 5'-triphosphate (AMPPNP) greater than beta, gamma-methylene adenosine 5'-triphosphate (beta, gamma-CH2-ATP) greater than alpha, beta-methylene adenosine 5'-triphosphate (alpha, beta-CH2-ATP). The respective EC50S were 10(-6) M, 2 X 10(-6) M, 2 X 10(-5) M, and greater than 2.5 X 10(-4) M. 3 Exogenous ATP also induced a rapid mobilization of intracellular calcium monitored by changes in Fura 2 fluorescence. The rank order of agonist potency for calcium mobilization was similar to the rank order of agonist potency for surfactant secretion: ATP = gamma S-ATP greater than AMPPNP greater than alpha, beta-CH2-ATP. 4 There was no effect of EGTA on ATP-induced calcium mobilization, consistent with the hypothesis that exogenous ATP induces release of calcium from intracellular stores. 5 These data are consistent with a P2Y-purinoceptor regulating surfactant secretion from isolated Type II cells via mobilization of intracellular calcium, since: (a) non-hydrolyzed analogues of ATP are potent secretagogues, (b) beta, gamma-CH2-ATP was a more potent secretagogue than alpha, beta-CH2-ATP and (c) the rank orders of agonist potency for calcium mobilization and phospholipid secretion were the same.


Distinguishing separable domains of cognition in human and animal studies: what separations are optimal for targeting interventions? A summary of recommendations from breakout group 2 at the measurement and treatment research to improve cognition in schizophrenia new approaches conference.
At the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) New Approaches Conference, a discussion group focused on directions for future research that are critical to enhancing our understanding of the distinctions among key cognitive domains that have relevance for the development of cognition-enhancing interventions. One set of recommendations emphasizes the need for examining and optimizing the psychometric properties of relevant measurement paradigms from cognitive psychology and cognitive neuroscience. This step is critical to translating many notable advances in these basic fields into measures that would be appropriate for clinical trials. A second set of recommendations focuses on key directions for the development and application of animal models of cognitive processes that would greatly aid the discovery and preclinical testing of potential cognition-enhancing agents. As part of this process, the group noted several existing animal paradigms that have particular promise as measures in the key cognitive domains in schizophrenia identified by the MATRICS Neurocognition Committee.


[Calculation of retention indices with the pocket calculator HP 65 (author's transl)].
An universal measuring system for retention datas in Gas Chromatography using retention indices (RI) by Kovats is well established. The meaning of RI is explained and a simple calculation by programmable pocket calculator is proposed.


The presence of interleukin-2 receptor alpha in the serum of colorectal cancer patients is unlikely to result only from T cell up-regulation.
It is unclear whether the presence of interleukin-2 soluble receptor alpha (IL-2 sRalpha) in the serum of colorectal cancer patients is solely due to T cell activation. In this study, we therefore investigated whether T cell activation, indicated by the up-regulation of the CD25 and HLA-DR markers, or cell-mediated immunity (CMI) were associated with increased serum levels of IL-2 sRalpha in patients with advanced colorectal carcinoma. The levels of serum IL-2 sRalpha and the proportion of T cells expressing HLA-DR (DR(+) T cells) were measured as markers for chronic activation. CMI was assessed by delayed-type hypersensitivity reaction (DTH) to intradermal injections of recall antigens. Eighty-seven colorectal liver metastases (CLM) patients and 23 'cancer-free' control subjects were studied. DR(+) T cells were found to be more prevalent ( P<0.0001) in CLM patients (median: 21.1%) than in controls (median: 3.4%), but DR(+) T cell up-regulation was not correlated with serum IL-2 sRalpha levels. CMI positivity was significantly reduced ( P=0.002) in CLM patients compared with controls, and this reduction was significantly associated ( P=0.05) with an increase in the number of DR(+) T cells. Although survival was significantly shorter ( P=0.0003) in patients with increased serum IL-2 sRalpha levels than in subjects with normal levels, no association was found between survival and DR(+) T cell up-regulation. These findings were consistent with the hypothesis of an additional source of serum IL-2 sRalpha other than T cell up-regulation in CLM patients -- either from other immune cells, or from tumour products.


Cryptosporidiosis and Cryptosporidium species in animals and humans: a thirty colour rainbow?
Parasites of the genus Cryptosporidium (Apicomplexa) cause cryptosporidiosis in humans and animals worldwide. The species names used for Cryptosporidium spp. are confusing for parasitologists and even more so for non-specialists. Here, 30 named species of the genus Cryptosporidium are reviewed and proposed as valid. Molecular and experimental evidence suggests that humans and cattle are the hosts for 14 and 13 out of 30 named species, respectively. Two, four and eight named species are considered of major, moderate and minor public health significance, respectively. There are at least nine named species that are shared between humans and cattle. The aim of this review is to outline available species information together with the most commonly used genetic markers enabling the identification of named Cryptosporidium spp. Currently, 28 of 30 named species can be identified using the complete or partial ssrRNA, serving as a retrospective 'barcode'. Currently, the ssrRNA satisfies the implicit assumption that the reference databases used for comparison are sufficiently complete and applicable across the whole genus. However, due to unreliable annotation in public DNA repositories, the reference nucleotide entries and alignment of named Cryptosporidium spp. has been compiled. Despite its known limitations, ssrRNA remains the optimal marker for species identification.


Is Immediate Radical Cystectomy Necessary for All Patients with Non-Muscle-Invasive Micropapillary Bladder Cancer?
We aim to review the outcomes of micropapillary urothelial carcinoma (MPUC) of the bladder from a single institution. The hypothesis is that non-muscle-invasive (NMI) MPUC may have a heterogeneous prognosis, and detailed pathological analysis may identify patients that could be managed without immediate cystectomy. This is a retrospective analysis of patients presenting with MPUC in a primary transurethral resection specimen (n = 40). The pattern of micropapillary (MP) differentiation [surface/non-invasive (sMP) or invasive (iMP)], extent of MP differentiation and lymphovascular invasion (LVI) were correlated with overall survival (OS), recurrence-free survival and upstaging at re-resection. Sixteen of 40 patients died after a median follow-up of 37 months. Tumour stage was strongly predictive of OS (p < 0.0001). LVI was associated with increased mortality (hazard ratio 12.4, 95% CI: 3.5-44.5, p = 0.0001), higher pathological stage (p = 0.001), lymph node involvement (p = 0.001) and iMP differentiation (p = 0.006). In NMI patients not undergoing cystectomy (n = 17), NMI-sMP compared with NMI-iMP differentiation was associated with an improved OS when compared with iMP (63 vs. 47 months, p = 0.05). MPUC is an aggressive variant of urothelial carcinoma (UC). Similar to conventional UC, LVI associated with MPUC is an adverse prognostic indicator. iMP is a morphological marker for LVI. Histopathological reports should distinguish between sMP and iMP differentiation.


Detection of polymolecular associations in hydrophobized chitosan derivatives using fluorescent probes.
The microenvironment formed by lauroyl and stearoyl derivatives of chitosan in solution has been studied using two fluorescent probes, pyrene and nabumetone. Existence or not of microdomains formed by polymolecular associations, the inherent hydrophobicity of them in aqueous solution, and the influence of degree of substitution (DS) of derivatives were investigated by emission properties of pyrene and strengthened by the photophysical behavior of nabumetone. Additionally, the ratio between the fluorescence intensities of first (approximately 372 nm) to the third (approximately 384 nm) bands of the emission spectrum of pyrene was used to determine the critical aggregation concentration (CAC). In a previous work, it was already reported the characterization of chitosan derivatives by three spectroscopic techniques ((13)C-NMR, (1)H-NMR and infrared), as well as data on the solubility and swelling-index of them. In addition of that, the new results show that the investigated lauroyl and stearoyl derivatives of chitosan are expected to be potential models for applications in the medical field.


Techniques for incorporation of attachments in implant-retained overdentures with unsplinted abutments.
A variety of techniques have been reported in the literature for the incorporation of attachments in implant-retained partial and complete overdentures with unsplinted or individual abutments. Three important elements that are necessary in describing any technique for incorporation of attachments are the type of final impression method (tissue-level impression, abutment-level impression, or implant-level impression), stage of overdenture fabrication (record base stage, denture-processing stage, or denture insertion stage) and nature of technique (direct or indirect). This article reviews 7 different techniques for the incorporation of attachments in implant-retained complete and partial overdentures. Discussion of indications, contraindications, advantages, and disadvantages of each technique is provided to aid the clinician in making an appropriate choice.


B cell dysregulation in primary Sjögren's syndrome: A review.
Primary Sjögren's syndrome is a chronic autoimmune disorder of unknown etiology and is characterized by progressive focal lymphocytic infiltration of the lacrimal and salivary glands. Comparison of B cell subsets from the peripheral blood and salivary glands of patients with primary Sjögren's syndrome and those from healthy individuals shows dysregulation and derangement of B cell subsets in both peripheral circulation and in inflamed glandular tissues. This dysregulation is expressed as a decrease in the percentage of CD27+ memory B cells in peripheral blood and an increase in the CD27+ memory B cells in the affected glands. Further, the overall percentage of long-lived autoantibodies-producing plasma cells within the affected glands is increased. In the last two decades, several studies have shown growing evidences that B cells play multiple roles in primary Sjögren's syndrome pathophysiology, and that dysregulation of these cells may actually play a central role in the disease development.


Cardiac cobaltism: a rare complication after bilateral metal-on-metal total hip arthroplasty.
This is one of the first documented cases of metal-on-metal (MoM) total hip arthroplasty cobalt cardiac toxicity that has led to patient death. A 69-year-old female presented to our institution with cardiac failure secondary to cobalt toxicity resulting from bilateral MoM total hip arthroplasty. Her presenting metal ion levels were a cobalt level of 199 ppb and a chromium level of 77 ppb. She underwent bilateral femoral revisions to remove the source of cobalt. On postoperative day 7, the patient sustained a cerebral infarct and eventually expired because of the insult. This case represents one of the first documented fatalities related to MoM cobalt cardiac toxicity.


Combined imaging of molecular function and morphology with PET/CT and SPECT/CT: image fusion and motion correction.
Imaging of the cardiovascular system with a combination of positron emission tomography (PET) and computer tomography (CT) or with a combination of single-photon emission computerized tomography (SPECT) and CT holds great promise for the future. Owing to the movement of the heart and the great vessels due to heart contraction and respiration this is, however, not straightforward. This article provides an overview over the principles of combined PET/CT or SPECT/CT imaging. It points out technical challenges inherent in imaging of cardiovascular system and presents possible solutions that allow for optimal fusion and motion correction of the combined molecular, functional and morphological image data.


Transferrin Receptor is Associated with Sensitivity to Ferroptosis Inducers in Hepatocellular Carcinoma.
Transferrin receptor (TFR), a membrane protein that has a critical role in the transport of iron into cells, is known to be a ferroptosis-related marker. Although TFR is reported to be abundantly expressed in tumor cells, its relationship with ferroptosis inducers in hepatocellular carcinoma (HCC) remains unclear. The authors performed immunohistochemical staining of TFR and divided 350 HCC patients into two groups according to its expression. They analyzed the association between TFR expression and prognosis or clinicopathologic factors. In addition, the regulation of malignant activity and its effect on the efficacy of ferroptosis inducers were investigated in vitro. For this study, 350 patients were divided into TFR-positive (n =180, 51.4%) and TFR-negative (n = 170, 48.6%) groups. The TFR-positive group had more hepatitis B surface antigen (HBs-Ag) (p = 0.0230), higher α-fetoprotein (AFP) levels (p = 0.0023), higher des-gamma-carboxyprothrombin (DCP) levels (p = 0.0327), a larger tumor size (p = 0.0090), greater proportions of Barcelona Clinic Liver Cancer (BCLC) stage B or C (p = 0.0005), poor differentiation (p < 0.0001), and microscopic intrahepatic metastasis (p = 0.0066). In the multivariate analyses, TFR expression was an independent prognostic factor in disease-free survival (p = 0.0315). In vitro, TFRC knockdown decreased cell motility. In addition, TFRC knockdown abolished artesunate (AS)-, lenvatinib-, and sorafenib-induced ferroptosis in HCC cell lines. The study demonstrated that simultaneous treatment of AS with multi-kinase inhibitor augmented the ferroptosis-inducing effects of AS in HCC cell lines. TFR expression is a poor prognostic factor in HCC, but its expression increases sensitivity to ferroptosis-inducing agents.


Functional Therapeutic Target Validation Using Pediatric Zebrafish Xenograft Models.
The survival rate among children with relapsed tumors remains poor, due to tumor heterogeneity, lack of directly actionable tumor drivers and multidrug resistance. Novel personalized medicine approaches tailored to each tumor are urgently needed to improve cancer treatment. Current pediatric precision oncology platforms, such as the INFORM (INdividualized Therapy FOr Relapsed Malignancies in Childhood) study, reveal that molecular profiling of tumor tissue identifies targets associated with clinical benefit in a subgroup of patients only and should be complemented with functional drug testing. In such an approach, patient-derived tumor cells are exposed to a library of approved oncological drugs in a physiological setting, e.g., in the form of animal avatars injected with patient tumor cells. We used molecularly fully characterized tumor samples from the INFORM study to compare drug screen results of individual patient-derived cell models in functional assays: (i) patient-derived spheroid cultures within a few days after tumor dissociation; (ii) tumor cells reisolated from the corresponding mouse PDX; (iii) corresponding long-term organoid-like cultures and (iv) drug evaluation with the corresponding zebrafish PDX (zPDX) model. Each model had its advantage and complemented the others for drug hit and drug combination selection. Our results provide evidence that in vivo zPDX drug screening is a promising add-on to current functional drug screening in precision medicine platforms.


The effects of pH and temperature on fluorescent calcium indicators as determined with Chelex-100 and EDTA buffer systems.
A novel method of determining the apparent dissociation constants of fluorescent calcium indicators is described which utilizes Chelex-100 ion exchange resin and 45Ca. The affinity for calcium of indicators fluo-3, fura-2 and indo-1 measured at either 22 degrees or 37 degrees C decreases as pH is decreased from 7.4 to 5.5. These measurements agree with determinations made using EDTA-calcium buffers. The 1:1 calcium:indicator complex is maintained under all conditions. The necessity to correct dissociation constants during intracellular acidification to properly interpret fluorescence measurements is illustrated by indo-1 measurements in the ischemic rat heart.


Molecular phenotyping of circulating tumour cells in patients with prostate cancer: prediction of distant metastases.
What's known on the subject? and What does the study add? The role of circulating cancer cells in metastogenesis is generally accepted. Two forms of these cells have been reported in a number of studies, cancer cell clusters (CCCs) and individual epithelial cancer cells. Clusters appear at higher frequencies in the blood. CCCs have been reported to be rich in vimentin and poor in E-cadherin expression The resulting epithelial to mesenchymal transition, a prerequisite for metastasis formation, occurs in CCCs. We have developed a new set of biomarkers, namely the antioxidant genes GPX1, SOD2 and TXNRD1, specific to cell trafficking in the blood. Firstly, the study shows that diagnosis of distant metastases is feasible by applying molecular phenotyping with a five gene test that has 94% sensitivity and 81% accuracy. Again SOD2 and GPX1 showed the highest sensitivities. Secondly, the study shows the efficacy of palliative chemotherapy in clearing the blood of CCCs overexpressing diagnostic genes. Clinically the overall lifespan ranged from 5 to 99 months under taxotere. We aimed to investigate the molecular reasons and found that MDR1 overexpression worsened survival by 31%. To the best of our knowledge, this is the first study to show the clinical impact of drug targeting and the counter-effect of drug resistance in CCCs on overall survival. The findings may, therefore, add a novel tool for clinicians in tailoring therapies individually. • To find the molecular phenotype in circulating cancer cells from patients with prostate cancer (PCa) in order to predict distant metastases. • To determine genes affecting the study endpoints of overall survival and time to progression. • Twenty-five urologists in several clinics participated in the study, with 51 patients with metastatic and 77 with non-metastatic PCa. • Molecular analysis was carried out in two forms of circulating cancer cells, cancer cell clusters (CCCs) and individual epithelial cancer cells (CECs). • Gene expression was studied using real-time reverse-transcriptase PCR. • Cycle threshold values were normalized with glyceraldehyde 3-phosphate dehydrogenase in cancer cells and mononucleated cells, yielding comparative specific expression values from the relative quantification method with the help of the standard curve method for each patient and each gene locus. • Preclinical validation was performed using aggregated and non-aggregated SW480 cells showing the independence of CCCs and CECs. • Prediction of metastases was achieved with five genes showing the highest sensitivity, SOD2, GPX1, AR, cyclin B and bFGF. • The following results were obtained: 94% sensitivity, 65% specificity, 76% positive predictive value and 89% negative predictive value. The prevalence was 63%. Test accuracy was 81% with an odds ratio of 32 (P < 0.001). • Overall survival was worsened by preceding chemotherapies when leaving insufficient GPX1 clearance in blood. • Drug resistance genes were found to worsen the endpoints, among them MDR1 (P = 0.003; hazard ratio: 1.31; 95% CI: 1.09-1.58). • SOD2, GPX1 and AR represent a novel biomarker set for circulating cancer cells (clusters and scattered individual cells) in PCa. • The clinical usefulness of these biomarkers ranges from the prediction of clinical tumours to disease prognostication, therapy monitoring and therapy outcome prediction (hormonal therapies, chemotherapies). • The presence of CCCs and CECs after batch isolation allows the addition of genes for intensive studies, e.g. drug resistance.


Ex vivo treatment of proliferating human cord blood stem cells with stroma-derived factor-1 enhances their ability to engraft NOD/SCID mice.
Ex vivo proliferation of hematopoietic stem cells (HSCs) is important for cellular and gene therapy but is limited by the observation that HSCs do not engraft as they transit S/G(2)/M. Recently identified candidate inhibitors of human HSC cycling are transforming growth factor-beta(1) (TGF-beta(1)) and stroma-derived factor-1 (SDF-1). To determine the ability of these factors to alter the transplantability of human HSCs proliferating in vitro, lin(-) cord blood cells were first cultured for 96 hours in serum-free medium containing Flt3 ligand, Steel factor, interleukin-3, interleukin-6, and granulocyte colony-stimulating factor. These cells were then transferred to medium containing Steel factor and thrombopoietin with or without SDF-1 and/or TGF-beta(1) for 48 hours. Exposure to SDF-1 but not TGF-beta(1) significantly increased (> 2-fold) the recovery of HSCs able to repopulate nonobese diabetic/severe combined immunodeficiency mice. These results suggest new strategies for improving the engraftment activity of HSCs stimulated to proliferate ex vivo.


Isolation and characterization of DNA from Tritrichomonas foetus and Trichomonas vaginalis.
High molecular weight DNA samples free of contaminating proteins or RNA were obtained from Tritrichomonas foetus or Trichomonas vaginalis by lysing the cells in 4 M guanidinium thiocyanate before centrifuging in CsCl density gradient and then purifying the DNA band by NACS-37 column chromatography. The bulk DNA from either organism acted as a single component in ion-exchange chromatography, agarose gel electrophoresis, CsCl density gradient centrifugation and thermal denaturation. T. foetus DNA showed a melting temperature (Tm) of 82 degrees C corresponding to a 31% GC content whereas T. vaginalis DNA melted at 84 degrees C to suggest 36% GC. Both DNA samples demonstrated 35 to 42% hyperchromicity when fully melted. Cot analysis revealed the presence of repetitive sequences in both DNAs: approximately 46.7% in T. foetus DNA and 53.3% in T. vaginalis DNA. The unique sequences of these two protozoan DNAs are of a similar size of about 2.5 X 10(7) base pairs. Agarose gel electrophoresis of restriction fragments of the two purified DNA samples gave distinct banding patterns that were characteristic of the two species of protozoan parasites.