Successful surgical repair and recovery in a 2-week-old infant after birth-related cervical fracture dislocation.
Cervical spine injuries are the most common spine injuries in the pediatric population. The authors present the youngest known patient who underwent cervical spine fusion to repair birth trauma-induced cervical fracture dislocation, resulting in spondyloptosis and spinal cord injury. A 2-week-old boy was found to have spondyloptosis and spinal cord injury after concerns arose from reduced movement of the extremities. The patient's birth was complicated by undiagnosed abdominal dystocia, which led to cervical distraction injury. At 15 days of age, the boy underwent successful C-5 corpectomy, with anterior C4-6 and posterior C2-7 arthrodesis, using an autologous rib graft for a C-5 fracture dislocation. MRI performed 2 weeks postoperatively revealed significant improvement in the alignment of the spinal canal. The patient was discharged from the hospital in a custom Minerva brace and underwent close follow-up in addition to occupational therapy and physical therapy. At the latest follow-up 4.5 years later, the patient was able to walk and ride a tricycle by himself. The authors describe the patient's surgery and the challenges faced in achieving successful repair and cervical spine stabilization in such a young patient. The authors suggest that significant neurological recovery after spinal cord injury in infants is possible with appropriate, timely, and interdisciplinary management.


Alcohol promotes mammary tumor development via the estrogen pathway in estrogen receptor alpha-negative HER2/neu mice.
Alcohol consumption is an established risk factor for breast cancer. Yet, the mechanism by which alcohol affects breast cancer development remains unresolved. The transition from the premenopausal to the postmenopausal phase is associated with a drastic reduction in systemic estrogen levels. It is not clear whether the risk of breast cancer attributable to alcohol consumption is modified by the different levels of estrogen found in pre- and postmenopausal women. The objective of this study is to determine whether the effects of alcohol on mammary tumor development are dependent on the presence of ovarian estrogen. As a model of breast cancer, we used mouse mammary tumor virus (MMTV)-neu transgenic mice that overexpress the human epidermal growth factor receptor 2 (HER2/neu) in the mammary epithelium, resulting in the development of estrogen receptor alpha (ERα)-negative mammary tumors. The mammary tumorigenesis process in these mice is similar to that of patients with HER2 breast cancer. Nonovariectomized (NOVX) and ovariectomized (OVX) MMTV-neu mice were exposed to 0, 5, and 20% ethanol in the drinking water. Breast cancer development and progression were determined alongside the effects of alcohol on estrogen availability and signaling. Our data show that 20% alcohol consumption promoted tumor development in MMTV-neu mice only in the presence of ovarian hormones. Tumor promotion was associated with increased systemic estrogen levels, increased expression of aromatase (the rate-limiting enzyme in estrogen synthesis), and increased expression of ERα in the tumors of 20% alcohol-consuming MMTV-neu mice. Additionally, we show that ovariectomy (removal of the ovaries and ovarian hormone production) blocked the effects of 20% alcohol on tumor development. Our results support the notion that alcohol consumption promotes HER2 breast cancer development via the estrogen signaling pathway. Additionally, they suggest that the effects of alcohol on breast cancer may be prevented by blocking estrogen signaling.


Desmoplastic fibroma with malignant transformation.
Desmoplastic fibroma (DF) is a rare neoplasm of bone, showing infiltrative and locally aggressive nature. Here, we report a case of DF with an unusual histology arising in a 41-year-old female in the left distal femur, which was detected by plain x-ray as an osteolytic lesion and by magnetic resonance imaging as a well-demarcated mass with endosteal scalloping. Pathologically, the tumor was composed mainly of bland-looking spindle cells in abundant collagenous stroma, accompanied with areas of myxofibrosarcomatous and malignant fibrous histiocytomatous components. These histologically different areas were admixed with each other. The array-based comparative genomic hybridization study on the histologically different areas showed some specific gained or lost loci according to their histologic features. The specific genetic events and the histologic features of this case might represent the malignant transformation of DF.


Combination therapy of lymphatic drug delivery and total body irradiation in a metastatic lymph node and lung mouse model.
Chemotherapy using a lymphatic drug delivery system (LDDS) targeting lymph nodes (LNs) in the early stage of metastasis has a superior antitumor effect to systemic chemotherapy. An LDDS produces a higher drug retention rate and tissue selectivity in LNs. To expand the therapeutic coverage of LDDS from local treatment of metastatic LNs to prevention of distant metastases, the combination of treatment with therapies that enhance systemic tumor immune effects is an important therapeutic strategy. Recently, total body irradiation (TBI) has been shown to activate immune responses and alter the tumor microenvironment. Here we show that combination therapy with TBI and LDDS improves the antitumor effect of metastatic LNs and lung metastasis. Tumor cells were inoculated into the subiliac LN (SiLN) to induce metastasis into the proper axillary LN (PALN) and lung in a mouse model. TBI was carried out on day 4 after inoculation using a gamma irradiator. Lymphatic drug delivery into the accessory axillary LN was used to treat PALN. In vivo bioluminescence imaging, high-frequency ultrasound, and histology showed that combination therapy using TBI (total dose 1.0 Gy once) and the LDDS suppressed tumor growth in LNs and lung metastases and was more effective than using LDDS or TBI alone. Quantitative RT-PCR of spleens after combination therapy revealed increased expression of CD4, CD8, and IL-12b, indicating an activated immune response. The results show that combination therapy with TBI and LDDS is a method to improve the efficacy of LN metastases and distant metastases therapy and is a promising novel approach to treat cancer patients.


Luteal-phase ovarian stimulation is feasible for producing competent oocytes in women undergoing in vitro fertilization/intracytoplasmic sperm injection treatment, with optimal pregnancy outcomes in frozen-thawed embryo transfer cycles.
To explore the feasibility of luteal-phase ovarian stimulation using hMG and letrozole in terms of ovarian response and pregnancy outcome using frozen-thawed embryo transfer. A prospective cohort study. Academic tertiary-care medical center. Two hundred forty-two female patients undergoing IVF/intracytoplasmic sperm injection (ICSI) treatment. Ovarian stimulation was initiated with hMG 225 IU and letrozole 2.5 mg daily after spontaneous ovulation. Letrozole administration was stopped when the dominant follicles reached diameters of 12 mm. Ovulation was induced with a GnRH agonist 100 μg when at least three follicles reached diameters of 18 mm or one dominant follicle reached 20 mm. The highest quality embryos were extracted and cryopreserved for later transfer. The primary outcome measured was the number of oocytes retrieved. Secondary outcomes were the clinical pregnancy rate, ongoing pregnancy rate, and implantation rate after frozen embryo transfer (FET) cycles. Of the 242 women enrolled in the study, all participants succeeded in producing oocytes and 227 women had highest-quality embryos to cryopreserve. The average number of oocytes retrieved was 13.1, producing an average of 4.8 highest quality embryos. Moreover, no cases experienced a premature LH surge or moderate/severe ovarian hyperstimulation syndrome during the stimulation cycles. In FETs, the clinical pregnancy rate, ongoing pregnancy rate, and implantation rate were 55.46% (127/229), 48.91% (112/229), and 40.37% (174/431), respectively. Of all the pregnancies in the study, 68 resulted in live births and 44 were ongoing. Luteal-phase ovarian stimulation is feasible for producing competent oocytes/embryos in women undergoing IVF/ICSI treatments, with optimal pregnancy outcomes in FET cycles.


Inhibition of extracellular matrix production and remodeling by doxycycline in smooth muscle cells.
Alterations in the extracellular matrix (ECM) production and remodeling of smooth muscle cells (SMCs) have been implicated in processes related to the differentiation in atherosclerosis. Due to the anti-atherosclerotic properties of the tetracyclines, we aimed to investigate whether cholesterol supplementation changes the effect of doxycycline over the ECM proteins synthesis and whether isoprenylated proteins and Rho A protein activation are affected. SMC primary culture isolated from chicks exposed to atherogenic factors in vivo (a cholesterol-rich diet, SMC-Ch), comparing it with control cultures isolated after a standard diet (SMC-C). After treatment with 20 nM doxycycline, [H3]-proline and [H3]-mevalonate incorporation were used to measure the synthesis of collagen and isoprenylated proteins, respectively. Real-time PCR was assessed to determine col1a2, col2a1, col3a1, fibronectin, and mmp2 gene expression and the pull-down technique was applied to determine the Rho A activation state. A higher synthesis of collagens and isoprenylated proteins in SMC-Ch than in SMC-C was determined showing that doxycycline inhibits ECM production and remodeling in both SMC types of cultures. Moreover, preliminary results about the effect of doxycycline on protein isoprenylation and Rho A protein activation led us to discuss the possibility that membrane G-protein activation pathways could mediate the molecular mechanism.


En Bloc Resection of Tumors of the Lumbar Spine: A Systematic Review of Outcomes and Complications.
The literature on total en bloc spondylectomy (TES) of bone tumors of the lumbar spine is sparse and heterogeneous. Therefore, the aim was to systematically pool the data from the published studies to quantitatively summarize the morbidity and mortality and to identify factors associated with favorable outcomes and complications. A systematic literature search for studies with individual patient-level data was conducted using specific medical subject heading(MeSH) terms. The outcome measures assessed included complications, tumor recurrence, survival, and function. Individual patient data were pooled from all the studies and quantitatively analyzed to assess the association of different factors with outcomes and complications. Twelve studies were included in this review with a total of 145 TES cases. Of all patients, 50% had at least 1 reported complication post surgery and this was associated with advancing age (OR 1.04, P < 0.001), metastatic disease (OR 5.61, P < 0.001), and adjuvant chemo and/or radiotherapy (OR 20.3, P = 0.001). Intralesional excision (OR 5.2, P = 0.01) and primary malignant tumors (OR 3.3, P = 0.02) were associated with a high recurrence rate. However, the surgical approach was not associated with differences in survival (P = 0.874) or recurrence (P = 0.525) rates. L5 tumor resection was associated with excessive bleeding. Postoperatively, there was an overall improvement in the Frankel grades in most patients. TES is associated with high rates of complications especially in association with primary malignant and metastatic diseases. However, the number of publications on this topic remain scarce and heterogeneous. Hence, there is a need for standardization in the reporting of the outcomes and complications to help with decision-making and consenting for this procedure.


[X-ray crystallographic analysis of picrates].
Picric acid forms stable picrates with various organic molecules through pi- bonding or ionic bonding, and such picrates have been very useful for identification and qualitative analysis. As it seemed desirable to determine the crystal structures and the bonding mode of picrates of basic organic compounds, we have investigated the crystal structures of aromatic hydrocarbons, aromatic amino compounds, heterocyclic compounds and so on. A series of our studies on the crystal structure of basic organic compounds have shown that the complexes of picric acid and aromatic hydrocarbons are formed through pi-bonding, and those of aromatic heterocyclic compounds are formed through ionic and hydrogen bonding; in addition, some of them also have pi-bonding.


Regional Lymph Node Metastasis on Prostate Specific Membrane Antigen Positron Emission Tomography Correlates with Decreased Biochemical Recurrence-Free and Therapy-Free Survival after Radical Prostatectomy: A Retrospective Single-Center Single-Arm Observational Study.
We sought to address the impact of preoperative prostate specific membrane antigen (PSMA) positron emission tomography (PET) findings prior to radical prostatectomy and pelvic lymph node dissection on biochemical recurrence and time to adjuvant or salvage treatment. Between 2013 and 2017, 64 intermediate and 166 high risk (230) prostate cancer patients received 68Ga-PSMA-11 PET followed by radical prostatectomy and pelvic lymph node dissection. Biochemical recurrence-free and therapy-free survivalwere determined. For all time-to-event analyses, univariable and multivariable Cox proportional hazards models and univariable Kaplan-Meier analyses were applied, with a significance threshold of p <0.05. The overall sensitivity, specificity, positive predictive value and negative predictive value of PSMA PET for pN1 disease was 48.5%, 95.7%, 82.1% and 82.2%, respectively. Median followup was 30.2 months. Biochemical recurrence occurred in 50.4% (116) of patients and adjuvant or salvage treatment was performed in 46.5% (107). Worst biochemical recurrence-free and therapy-free survival was observed in pN1 patients who also exhibited PSMA PET positive lymph node, followed by pN1 patients without PSMA PET positive lymph node and patients without evidence of lymph node metastasis on histology and PSMA PET (median biochemical recurrence-free survival 1.7 vs. 7.5 vs. >36 months, median therapy-free survival 2.6 vs. 8.9 vs. >36 months). Patients with positive lymph node on PSMA PET prior to radical prostatectomy have to expect early biochemical recurrence and adjuvant/salvage therapy, despite thorough pelvic lymph node dissection. Therefore, results from PSMA PET can be used for patients' consultation and more stringent followup as well as for planning of neoadjuvant/adjuvant therapy.


The significance of bronchus-associated lymphoid tissue in human lung transplantation: is there an association with acute and chronic rejection?
In animal models of acute rejection in lung allografts, bronchus-associated lymphoid tissue (BALT) plays a major role in the induction and persistence of the alloreactive response. We undertook a study of the clinical and histologic associations with BALT identified on transbronchial biopsy in human lung allograft recipients. Transbronchial biopsies of patients receiving single lung, double lung, and combined heart-lung transplantation from 1984 to 1997 at the University of Pittsburgh Medical Center were reviewed. Seventy-seven patients had transbronchial biopsies demonstrating BALT. We examined all pathologic reports and slides, and graded rejection utilizing the Revised Working Formulation for the Classification of Pulmonary Allograft Rejection. Twenty-nine of 77 patients were selected at random to evaluate the distribution of BALT lymphocyte subsets immunohistochemically. There was no relationship between native disease or the transplant procedure and the identification of BALT. BALT was found from 9 days to 2431 days after transplant (average: 440 days; median: 157 days) in association with clinically insignificant acute cellular rejection (A0, A1) in 75% of cases. Bronchiolitis obliterans developed in 29% of patients with a BALT-positive biopsy, a percentage not different from that of our overall lung transplant population. Immunohistochemical examination of BALT showed helper T cells predominated over cytotoxic T cells in zones surrounding B cell-rich follicular center cells. The association of BALT with high-grade acute cellular rejection and with the development of bronchiolitis obliterans could not be confirmed in human lung allografts. BALT most often accompanied A0 or A1 rejection. This raises the possibility that the presence of BALT on transbronchial biopsy may be part of the evolution of immunologic tolerance in human pulmonary allografts.


[Is rituximab effective for induction of remission in lupus nephritis?].
The combination of cyclophosphamide and steroids constitutes the standard treatment in lupus nephritis requiring immunosuppressive therapy. However, it is associated with important adverse effects, so there is interest in alternative immunosuppressors such as rituximab. Searching in Epistemonikos database, which is maintained by screening 19 databases, we identified 5 systematic reviews including 24 studies. We combined the evidence using summary of findings tables following the GRADE approach and concluded there is uncertainty about the effects of rituximab in lupus nephritis because the certainty of the evidence is very low, probably leads to important adverse effects, and has high cost. Rituximab should not be used outside the context of a clinical trial, or only in cases where other treatments have failed and there are no resource constraints.


[THE HUMORAL, NEUROHORMONAL VEGETATIVE AND HYDRAULIC REGULATION OF METABOLISM. THE DISTAL AND PROXIMAL SECTIONS OF ARTERIAL BLOODSTREAM. THE FATTY ACIDS AND METABOLIC ARTERIAL HYPERTENSION (A LECTURE)].
The regulation of metabolism formed sequentially in phylogenesis at three levels separately: autocrine level--in cell; in paracrin cell cenosis--structural and functional units of organs; at organism level. The interrelated variants of regulation: humoral; neurohumoral; neurohormonal; vegetative-sympathetic; parasympathetic--conduction of nervous impulse is to be evaluated in consequence of becoming of stages of phylogenesis. The becoming of hydrodynamic regulation is early even. The impact by pressure (blood flow) in paracrin cell cenosis is implemented by local peristaltic pumps in open-ended system of lymph and blood circulation. In closed system of circulation occurred separation of arterial flow on two functional sections. Phylogenetically early distal with regulation of hydrodynamic pressure by arterioles of muscular type in paracrin cell cenosis and compensation of disorders of biological reaction metabolism-micro-circulation (M<-->M). In later proximal section, arteries of elastic type arterial pressure forms heart as a central pump under sympathetic innervation at level of organism from vasomotor center. The physical factor--pressure--became regulator of reaction M <--> M. Increasing of arterial pressure in proximal systemically increases blood pressure in distal and all paracrin cell cenosises compensating alteration of reaction M <--> M. The systemic non-optimal increasing of hydrodynamic pressure invoke negative reaction of organs controlling hydrodynamics in local pools of intercellular medium: kidneys with pool of primary urine; brain with spinal fluid; lungs with pulmonary circulation; placenta with pool of amniotic medium. All of them tend to decrease blood flow in organs. The activation of synthesis of angiotensin-II forms pathologic compensation and their secondary damage as organs-targets. The sympathetic stimulation of heart forces it to work at full capacity. No humoral mediator or internal organ can regulate arterial pressure.


Antiangiogenic, bioreductive and gene therapy approaches to the treatment of hypoxic tumours.
Quinone based bioreductive drugs have, potentially, a very versatile use in cancer chemotherapy. They can be activated by DT-diaphorase and hence can be used to target tumour types rich in this (O2)-independent reductase enzyme. Small molecular modifications can substantially reduce specificity for DT-diaphorase and under these circumstances the quinones become much less toxic in air but retain their potent cytotoxic effects under hypoxic conditions. Our understanding of the reductive (bio) chemistry of indolequinones, in particular, has subsequently allowed us to develop a platform technology where almost any therapeutic entity can potentially be delivered, selectively, to hypoxic tumours. Antiangiogenic approaches are currently receiving a substantial amount of attention and this review brings their development into context in view of the hypoxia dependence for neovascularization. Lastly, the use of bioreductive drugs when combined with hypoxia-mediated gene therapy is described. Such an approach provides a unique dual level of specificity for targeting hypoxic tumours and potentially can provide substantial therapeutic benefit.


Vagal afferent input determines the volume dependence of rat esophageal motility patterns.
The volume dependence of balloon distension-evoked esophageal rhythmic motor responses and their neural correlates was investigated in 72 urethane-anesthetized rats. With increasing balloon volume (75--200 microl), distal esophageal rhythmic contractions decreased in rate and became tonic in the range of 150--250 microl. This change in motor pattern involved only the striated musculature of the esophageal body and persisted after acute transection of the spinal cord at C(2). Impulse frequency in single vagal afferents of the distal esophagus increased with intraluminal pressure over the entire range of balloon volumes tested (50--300 microl). Distension-responsive neurons in the nucleus tractus solitarii showed rhythmic burst activity (type I), tonic excitation (type II), or inhibition followed by off bursts (type III). Increasing strength of stimulation changed type I responses to nonrhythmic but intensified type II and III responses. We conclude that load-dependent changes in distal esophagus motility pattern are encoded by vagal afferents alone and do not involve a spinal afferent input even at near-noxious stimulus strengths.


The effect of theory - Based educational intervention on consumption of smokeless tobacco products by merchants' guilds.
Smokeless tobacco (SLT) products are highly addictive and contain at least 28 carcinogenic chemicals. The purpose of this study was to determine the effect of theory-based on the Transtheoretical Model of Behavior Change on consumption of SLT products by Merchants' Guilds in 2018. The present quasi-experimental research was conducted over one intervention group. The research population consisted of all consumers of the SLT products among the merchants' guilds in Chabahar City, Iran in 2018. Data were gathered from 320 individuals by simple random sampling using a valid and reliable researcher-made questionnaire. The intervention program was designed based on the Transtheoretical Model of Behavior Change cognitive processes and lasted 6 months. After the intervention, the same questionnaires were administered among the participants. The data were analyzed by SPSS version 20 using the descriptive and analytical tests. In the preintervention phase, the participants' mean scores of the cognitive processes at the precontemplation, contemplation, and preparation stages were 29.16 ± 4.63, 25.07 ± 3.84, and 12.12 ± 1.63, respectively. At the postintervention phase, mean scores of the precontemplation, contemplation, and preparation stages reached to 40.5 ± 5.96, 38.8 ± 5.03, and 35.5 ± 4.23, respectively. Furthermore, the participants' mean sores at the action and maintenance stages were 36.4 ± 4.57 and 43.3 ± 3.29, respectively. According to the ANOVA, a significant relationship was found between cognitive processes at the preintervention phase and stages of change (P < 0.001). Individuals can improve from the precontemplation, contemplation, and preparation phases to the action and maintenance stages by attending based on Transtheoretical Model of Behavior Change educational interventions. It is suggested that the structure of this model be used to reduce high-risk behaviors in other occupations.


Ascorbate-Dependent Peroxidase (APX) from Leishmania amazonensis Is a Reactive Oxygen Species-Induced Essential Enzyme That Regulates Virulence.
The molecular mechanisms underlying biological differences between two Leishmania species that cause cutaneous disease, L. major and L. amazonensis, are poorly understood. In L. amazonensis, reactive oxygen species (ROS) signaling drives differentiation of nonvirulent promastigotes into forms capable of infecting host macrophages. Tight spatial and temporal regulation of H2O2 is key to this signaling mechanism, suggesting a role for ascorbate-dependent peroxidase (APX), which degrades mitochondrial H2O2 Earlier studies showed that APX-null L. major parasites are viable, accumulate higher levels of H2O2, generate a greater yield of infective metacyclic promastigotes, and have increased virulence. In contrast, we found that in L. amazonensis, the ROS-inducible APX is essential for survival of all life cycle stages. APX-null promastigotes could not be generated, and parasites carrying a single APX allele were impaired in their ability to infect macrophages and induce cutaneous lesions in mice. Similar to what was reported for L. major, APX depletion in L. amazonensis enhanced differentiation of metacyclic promastigotes and amastigotes, but the parasites failed to replicate after infecting macrophages. APX expression restored APX single-knockout infectivity, while expression of catalytically inactive APX drastically reduced virulence. APX overexpression in wild-type promastigotes reduced metacyclogenesis, but enhanced intracellular survival following macrophage infection or inoculation into mice. Collectively, our data support a role for APX-regulated mitochondrial H2O2 in promoting differentiation of virulent forms in both L. major and L. amazonensis Our results also uncover a unique requirement for APX-mediated control of ROS levels for survival and successful intracellular replication of L. amazonensis.


Familial hypercholesterolaemia and coronary risk factors among patients with angiogram-proven premature coronary artery disease in an Asian cohort.
Familial hypercholesterolaemia (FH) patients have elevated levels of low-density lipoprotein cholesterol, rendering them at high risk of premature coronary artery disease (PCAD). However, the FH prevalence among angiogram-proven PCAD (AP-PCAD) patients and their status of coronary risk factors (CRFs) have not been reported in the Asian population. This study aimed to (1) determine the prevalence of clinically diagnosed FH among AP-PCAD patients, (2) compare CRFs between AP-PCAD patients with control groups, and (3) identify the independent predictors of PCAD. AP-PCAD patients and FH patients without PCAD were recruited from Cardiology and Specialist Lipid Clinics. Subjects were divided into AP-PCAD with FH (G1), AP-PCAD without FH (G2), FH without PCAD (G3) and normal controls (G4). Medical records were collected from the clinic database and standardised questionnaires. FH was clinically diagnosed using Dutch Lipid Clinic Network Criteria. A total of 572 subjects were recruited (males:86.4%; mean±SD age: 55.6±8.5years). The prevalence of Definite, Potential and All FH among AP-PCAD patients were 6%(19/319), 16% (51/319) and 45.5% (145/319) respectively. G1 had higher central obesity, family history of PCAD and family history of hypercholesterolaemia compared to other groups. Among all subjects, diabetes [OR(95% CI): 4.7(2.9,7.7)], hypertension [OR(95% CI): 14.1(7.8,25.6)], FH [OR(95% CI): 2.9(1.5,5.5)] and Potential (Definite and Probable) FH [OR(95% CI): 4.5(2.1,9.6)] were independent predictors for PCAD. Among FH patients, family history of PCAD [OR(95% CI): 3.0(1.4,6.3)] and Definite FH [OR(95% CI): 7.1(1.9,27.4)] were independent predictors for PCAD. Potential FH is common among AP-PCAD patients and contributes greatly to the AP-PCAD. FH-PCAD subjects have greater proportions of various risk factors compared to other groups. Presence of FH, diabetes, hypertension, obesity and family history of PCAD are independent predictors of PCAD. FH with PCAD is in very-high-risk category, hence, early management of modifiable CRFs in these patients are warranted.


Effects of organochlorine chemicals on the reproductive outcome of humans who consumed contaminated Great Lakes fish: an epidemiologic consideration.
Three sets of studies of the impacts of human exposure to PCB contaminated fish from the Great Lakes basin--the Michigan Sports Fisherman Cohort, the Michigan Maternal/Infant Cohort, and the Wisconsin Maternal/Infant Cohort-were evaluated using the epidemiologic criteria of Susser (1986). The studies were compared against each other, and against comparable data from other geographic locales. A total of seven major categories of exposure sequelae were evaluated. These ranged from the effects of primary exposure to contaminants upon maternal health status, to effects from secondary intrauterine fetal exposure, including alterations in birth size and gestational age, changes in neonatal health status, and effects persisting into early infancy. Results of the evaluations suggest that the causal hypothesis may be strongly affirmed for the relationship between PCB exposure and alterations in both neonatal health status and in health status in early infancy may be affirmed with reasonable certainty. While the evidence from the Michigan Maternal/Infant Cohort related to maternal exposure to PCB and infant size at birth and gestational age affirms the causal hypothesis, studies from other geographic locales tend only to be supportive. Analytic differences are likely responsible for this variation, but epidemiologically, the composite rating must be regarded as indeterminate. The relationship with observed alterations in maternal health status, composite activity ranking, and McCarthy Memory Scale deficits were also classified as indeterminate. No evidences of obvious negation were seen, although one portion of a study was disqualified because of incoherence.


Wide-ranging collaborative drives improvement in patient safety.
Access to instant information about medications can help reduce errors. Use of safety culture assessment tool highlights opportunities for improvement. Collaborative model enables hospitals to share successes, failures.


[Combinations of mezlocillin with other antibiotics. A review of in vitro laboratory studies (author's transl)].
Thirteen publications concerning combinations of mezlocillin with other antibiotics are reviewed, with special attention to antibiotics at present available in France. A fairly large number of different methods were used by the authors, making a comparative study extremely difficult. Most studies dealt with mezlocillin-aminoglycoside combinations against enterobacteriacaea and Pseudomonas aeruginosa : the effect was predominantly synergistic, but a few antagonistic effects are reported. The results on other groups of bacteria and with other antibiotics are more scattered. It was sometimes useful to combine mezlocillin with a cephalosporin. A synergistic effect with fosfomycin was found against Serratia.


Fertility drugs and the risk of breast cancer: a meta-analysis and review.
The risk of breast cancer has been associated with reproductive history. The purpose of this study was to determine the relationship between fertility drugs used in assisted reproductive procedures and the risk of breast cancer. We performed a literature search using the MEDLINE, the COCHRANE Library, and Scopus to identify studies linking breast cancer to fertility drugs. We excluded case series, case reports, and review articles from our analysis. The study populations included women who were treated for infertility with clomiphene, gonadotropins, gonadotropin-releasing hormones, or other unspecified fertility agents. We extracted information on study design, sample size, type of fertility drugs and number of treatment cycles, breast cancer incidence, and follow-up time from these studies. Eight case-control studies and fifteen cohort studies were included in the quantitative analyses. The Newcastle-Ottawa Quality Assessment Scales were used. Two investigators independently extracted study methods, sources of bias, and outcomes. We found that the risk of breast cancer was not significantly associated with fertility drug treatment. The follow-up periods were short in some of the studies analyzed in our study; however, we proceeded to test the trend in risk estimates across different durations of follow-up and found a trend for association using the nonparametric test; this was interpreted with caution in view of the lack of adjustment with other confounding factors. The current published data do not suggest higher risk of breast cancer in women who receive fertility treatment, but the lack of long-term follow up and the inherent weaknesses in some of the published studies have to be cautiously taken into account.


A Novel Diabetes Healthcare Disease Prediction Framework Using Machine Learning Techniques.
Diabetes is a chronic disease that continues to be a significant and global concern since it affects the entire population's health. It is a metabolic disorder that leads to high blood sugar levels and many other problems such as stroke, kidney failure, and heart and nerve problems. Several researchers have attempted to construct an accurate diabetes prediction model over the years. However, this subject still faces significant open research issues due to a lack of appropriate data sets and prediction approaches, which pushes researchers to use big data analytics and machine learning (ML)-based methods. Applying four different machine learning methods, the research tries to overcome the problems and investigate healthcare predictive analytics. The study's primary goal was to see how big data analytics and machine learning-based techniques may be used in diabetes. The examination of the results shows that the suggested ML-based framework may achieve a score of 86. Health experts and other stakeholders are working to develop categorization models that will aid in the prediction of diabetes and the formulation of preventative initiatives. The authors perform a review of the literature on machine models and suggest an intelligent framework for diabetes prediction based on their findings. Machine learning models are critically examined, and an intelligent machine learning-based architecture for diabetes prediction is proposed and evaluated by the authors. In this study, the authors utilize our framework to develop and assess decision tree (DT)-based random forest (RF) and support vector machine (SVM) learning models for diabetes prediction, which are the most widely used techniques in the literature at the time of writing. It is proposed in this study that a unique intelligent diabetes mellitus prediction framework (IDMPF) is developed using machine learning. According to the framework, it was developed after conducting a rigorous review of existing prediction models in the literature and examining their applicability to diabetes. Using the framework, the authors describe the training procedures, model assessment strategies, and issues associated with diabetes prediction, as well as solutions they provide. The findings of this study may be utilized by health professionals, stakeholders, students, and researchers who are involved in diabetes prediction research and development. The proposed work gives 83% accuracy with the minimum error rate.


Cloning of two distinct hemolysin genes from Porphyromonas (Bacteroides) gingivalis in Escherichia coli.
Hemolysin is considered a potent virulence factor in a large number of Gram-positive and Gram-negative bacterial pathogens. The hemolysin produced by the oral pathogen Porphyromonas gingivalis functions to provide the cell with its required heme-containing molecules for growth in the periodontal pocket. Two distinct P. gingivalis genes, each of which confers a hemolytic phenotype in Escherichia coli, were isolated by screening genomic DNA libraries of P. gingivalis on sheep blood agar plates. The results obtained from physical maps and Southern blots indicated a considerable degree of divergence in the nucleotide sequences of these two genes. Maxicell analyses of the recombinant plasmids in E. coli suggested that plasmid pPGH5 encoded a polypeptide of molecular weight 48 kDa, while an 18-kDa polypeptide was obtained with pPGH1 and pPGH7. When E. coli harboring these hemolysin genes were subjected to iron starvation, the levels of hemolysin activity increased. Biochemical characterization of hemolytic activities indicated that the activity of both hemolysins was inhibited by Mg2+ and Ca2+; but not by EDTA. Elevated levels of hemolytic activity were obtained from the E. coli recombinant strains in the presence of glutathione, DTT and 2-mercaptoethanol. Cholesterol inhibited the activity.


Bacillus methylotrophicus Strain NKG-1, Isolated from Changbai Mountain, China, Has Potential Applications as a Biofertilizer or Biocontrol Agent.
Chemical pesticides are widely used in agriculture, which endangers both environmental health and food safety. Biocontrol is an environmentally-friendly and cost-effective green technique in environmental protection and agricultural production; it generally uses selected bioresources, including beneficial microorganisms. We isolated a novel bacterial strain (NKG-1) from the rare dormant volcanic soils of Changbai Mountain in China's Jilin Province. The strain was identified as Bacillus methylotrophicus using morphological, biochemical, physiological, and phylogenetic 16S rDNA sequencing data. This strain was able to suppress mycelial growth and conidial germination of numerous plant pathogenic fungi on solid media. A greenhouse experiment showed that application of NKG-1 fermentation broth prior to inoculation of Botrytis cinerea, the cause of gray tomato mold, inhibited growth of the mold by 60%. Furthermore, application of a 100× dilution of NKG-1 fermentation broth to tomato seedlings yielded a significant increase in seedling fresh weight (27.4%), seedling length (12.5%), and root length (57.7%) compared to the control. When the same dosage was applied in the field, we observed increases in tomato plant height (14.7%), stem diameter (12.7%), crown width (16.3%), and maximum fruit diameter (11.5%). These results suggest that NKG-1 has potential commercial application as a biofertilizer or biocontrol agent.


Adaptive processing of visual motion.
Three studies relating perception of motion to stimulus uncertainty are reported. Generally, detectability declines when the observer is uncertain about the direction in which a target will move, but the visibility loss associated with direction uncertainty can be attenuated if the observer has adequate practice. This attenuation seems to depend upon the observer's ability to switch among directionally selective visual mechanisms in an adaptive fashion. The implications of these findings for models of motion detection are discussed.


Gallstone formation in obese women treated by a low-calorie diet.
This study assessed the incidence of gallstone formation in 47 obese women who consumed a low-calorie diet (LCD) for the first 16 weeks of a 26-week weight loss program. The LCD consisted of four daily servings of a liquid diet combined with an evening meal of a pre-packaged dinner entrée and provided approximately 925 kcal/d. Six of the 47 patients (12.8%) displayed gallstones at week 17, as determined by sonography. Five patients were asymptomatic when followed for up to 48 weeks. The sixth, however, reported severe abdominal pain 30 weeks after beginning treatment and required a cholecystectomy. Patients who developed gallstones, as compared with those who did not, had significantly higher baseline triglyceride and total cholesterol levels and had a significantly greater rate of weight loss. Results of this study indicate that an increased risk of gallstones is not limited to very-low-calorie diets and that the incidence of this complication should be assessed in persons who consume popular over-the-counter meal replacement plans.


N-Terminal 5-Mer Peptide Analog P165 of Amyloid Precursor Protein Repairs Skin Photodamage Induced by UVB through the Nrf2 Signaling Pathway.
Acute photodamage is an acute inflammatory reaction of the skin after ultraviolet (UV) irradiation. Many drugs have been successfully used for the treatment and prevention of photodamage. To evaluate the molecular mechanism of N-terminal 5-mer peptide analog P165 of amyloid precursor protein in repairing photodamaged rat skin. We establish a rat model of acute UVB photodamage. The ratskin was treated with or without 250, 500, and, 1000 μM P165. Histological analysis was performed by hematoxylin and eosin staining. Apoptotic cells were analyzed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The kits were used to measure the levels of protein carbonyl (PC), malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH). Western blotting was used to measure Nrf2. P165 repaired UVB-induced cutaneous erythema and edema, and reduced apoptosis of skin cells. The levels of PC, MDA, and 8-OHdG in 250 and 500 μM P165 groups were all lower than those in the solvent group. Activities of SOD, CAT, and GPx, and the level of GSH in P165 groups were higher than those in the solvent group. Nrf2 expression in the solvent group was higher than that in the negative group, whereas in the 500 μM P165 group was higher than in the solvent group. Our findings suggest that P165 repairs the rat skin with acute photodamage by reducing oxidative stress. These activities may be mediated by promoting the Nrf2 signaling pathway. Thus, P165 may be a promising agent for the treatment of acute photodamage, which may be used in cosmetics and postsun repair.


Clinical significance of molecular diagnosis for gastric cancer lymph node micrometastasis.
Advances in molecular diagnostic tools have allowed the identification of lymph node micrometastasis (LNM), including isolated tumor cells, in cancer patients. While immunohistochemistry and reverse transcription-polymerase chain reaction have been used to identify LNM in patients with gastric cancer, the clinical significance of this finding remains unclear. Recently, minimally invasive treatments, such as endoscopic submucosal dissection and laparoscopic surgery, are widely performed to help improve postsurgical quality of life (QOL). However, it is important to maintain the balance between QOL and curability when making treatments decision for patients with gastric cancer. If minimally invasive surgery based on accurate intraoperative LNM diagnosis was established, it could be performed safely. Therefore, we reviewed the clinical significance of LNM detected by molecular techniques as an important target for treatment decision making with gastric cancer patients.


Oxygen fixation into hydroxyproline in etiolated maize seedlings : verification by tandem mass spectrometry.
Etiolated maize (Zea mays L.) seedlings were grown in the dark for 5 days in an atmosphere enriched with 10.0 atom% (18)O(2). Hydroxyproline was isolated from root and shoot tissues, purified, and methylated. It was not possible to determine (18)O incorporation into hydroxyproline by conventional mass spectrometry because the final product was not sufficiently pure. The final product was analyzed successfully by tandem mass spectrometry. The (18)O content of the hydroxyl oxygen atom was 10 +/- 0.7 atom%. This result demonstrates that the hydroxyl oxygen atom in hydroxyproline was derived exclusively from molecular oxygen.


Identification of Aging-Related Genes Associated with Prognostic Value and Immune Microenvironment Characteristics in Diffuse Large B-Cell Lymphoma.
Diffuse large B-cell lymphoma (DLBCL) is a complex invasive tumour that occurs mainly among the elderly. Therefore, we analysed the relationship between ageing-related genes (AG) and DLBCL prognosis. Datasets related to DLBCL and human AGs were downloaded and screened from the Gene Expression Omnibus (GEO) database and HAGR website, respectively. LASSO and Cox regression were used to analyse AGs in the dataset and construct an AG predictive model related to DLBCL prognosis. Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes enrichment were used to analyse the function of the AG predictive model. The immune microenvironment and immune cell infiltration in DLBCL and their relationship with the AG prediction model were also analysed. After the analysis, 118 AGs were identified as genes related to DLBCL prognosis. Using the LASSO and Cox regression analyses, 9 AGs (PLAU, IL7R, MYC, S100B, IGFBP3, NR3C1, PTK2, TBP, and CLOCK) were used to construct an AG prognostic model. In the training and verification sets, this model exhibited excellent predictive ability for the prognosis of patients with DLBCL who have different clinical characteristics. Further analysis revealed that the high- and low-risk groups of the AG prognostic model were significantly correlated with immune cell infiltration and tumour microenvironment in DLBCL. Functional enrichment analysis also showed that the genes in the AG model were associated with immune-related functions and pathways. In conclusion, we constructed an AG model with a strong predictive function in DLBCL, with the ability to predict the prognosis of patients with different clinical features. This model provides new ideas and potential therapeutic targets for the study of the pathogenesis of DLBCL.


Intracellular recording from posterior cricoarytenoid motoneurons in the rat.
The ability to maintain coordinated vocal cord abduction and upper airway patency is dependent on the integrity of the posterior cricoarytenoid (PCA) motoneurons and their multiple neural connections. Study of the PCA motoneurons represents the initial step in understanding the complex mechanisms responsible for coordinated vocal cord abduction and may provide an insight into the possible pathological processes underlying the various clinical presentations of vocal cord dysfunction. Intracellular recordings were made from 11 PCA motoneurons in Sprague-Dawley rats, which all showed an inspiratory augmenting discharge pattern that is also characteristic of phrenic nerve activity. The resting membrane potential was -56+/-11 mV. Two PCA motoneurons were injected with Neurobiotin to demonstrate neuronal morphology, which was found to be similar to that obtained by retrograde labeling with cholera toxin B subunit. The technique described for intracellular recording of PCA motoneurons should allow more detailed morphological, electrophysiological, and immunohistochemical information to be obtained, to thereby identify some of the factors responsible for maintaining normal function of the PCA muscle.


Impact of atrial fibrillation on the accuracy of oscillometric blood pressure monitoring.
The introduction of automated oscillometric blood pressure monitors was the basis for today's widespread use of blood pressure self-measurement. However, in atrial fibrillation, there is a controversial debate on the use of oscillometry because there is a high variability of heart rate and stroke volume. To date, the accuracy of oscillometric blood pressure monitoring in atrial fibrillation has only been investigated using auscultatory sphygmomanometry as reference method, which may be biased by arrhythmia as well. We performed a cross-sectional study in 102 patients (52 sinus rhythm, 50 atrial fibrillation) assessing the accuracy of an automated and validated oscillometric upper arm (M5 Professional, Omron) and wrist device (R5 Professional, Omron) to invasively assessed arterial pressure. Blood pressure values were calculated as the mean of 3 consecutive measurements. Systolic and diastolic blood pressure did not significantly differ in patients with sinus rhythm and atrial fibrillation, independent of the method of measurement (P>0.05 each). The within-subject variability of the oscillometric measurements was higher in patients with atrial fibrillation compared with sinus rhythm (P<0.01 each). The biases of systolic and diastolic blood pressure, however, did not significantly differ in presence or absence of atrial fibrillation in Bland-Altmann analysis (P>0.05 each). In conclusion, atrial fibrillation did not significantly affect the accuracy of oscillometric measurements, if 3 repeated measurements were performed.


Short- and long-term effects of melatonin on myocardial post-ischemic recovery.
Melatonin, the chief secretory product of the pineal gland, has been shown to protect the heart against ischemia-reperfusion injury. This was attributed to its free radical scavenging and broad-spectrum antioxidant properties. The possibility that melatonin may act via its receptor and intracellular signaling, has not yet been addressed in this regard. In all previous studies, only the acute effects of melatonin on the heart, were evaluated. The aims of the present study were to: (i) compare the acute and long-term effects of melatonin on infarct size and functional recovery of the ischemic heart, and (ii) evaluate the role of the melatonin receptor in cardioprotection. For evaluation of the short-term effects of melatonin on contractile recovery and infarct size, the isolated perfused working rat heart was subjected to 20 min global ischemia or 35 min regional ischemia respectively, and melatonin (25-50 microm) administered either before and during reperfusion, or before ischemia or during reperfusion after ischemia. The melatonin receptor was manipulated using luzindole and N-acetyltryptamine. The long-term effects of melatonin were evaluated 24 hr after melatonin administration (2.5 or 5.0 mg/kg, i.p.) or after oral administration for 7 days (20 or 40 microg/mL). Infarct size and mechanical recovery during reperfusion of the working heart were used as endpoints. Melatonin (50 microm), when administered either before and during reperfusion after ischemia or during reperfusion only, significantly improved cardiac output and work performance and reduced infarct size compared with untreated controls. Luzindole (5 microm), a melatonin receptor antagonist, abolished these cardioprotective effects. Long-term administration of melatonin (i.p. or orally for 7 days) caused a significant reduction in infarct size of hearts subjected to 35 min regional ischemia. The cardioprotection persisted for 2-4 days after discontinuation of treatment. In summary, the results obtained suggest that melatonin induces short- as well as long-term protection and that the melatonin receptor is also involved in its cardioprotective actions.


Generation of Ramped Current Profiles in Relativistic Electron Beams Using Wakefields in Dielectric Structures.
Temporal pulse tailoring of charged-particle beams is essential to optimize efficiency in collinear wakefield acceleration schemes. In this Letter, we demonstrate a novel phase space manipulation method that employs a beam wakefield interaction in a dielectric structure, followed by bunch compression in a permanent magnet chicane, to longitudinally tailor the pulse shape of an electron beam. This compact, passive, approach was used to generate a nearly linearly ramped current profile in a relativistic electron beam experiment carried out at the Brookhaven National Laboratory Accelerator Test Facility. Here, we report on these experimental results including beam and wakefield diagnostics and pulse profile reconstruction techniques.


Are Operating Rooms With Laminar Airflow a Risk for Inadvertent Perioperative Hypothermia During Ureterorenoscopic Lithotripsy Under Spinal Anesthesia? A Prospective Randomized Clinical Trial.
Inadvertent perioperative hypothermia (IPH), defined as a core temperature <36°C, is common during a surgical procedure and is associated with high morbidity and mortality. Laminar (LAS) and conventional airflow systems (CAS) are used frequently for clean microenvironmental surgical areas in operating rooms. In LAS, the cold airflow is directed toward the patient, unlike CAS. Does this airflow in LAS cause heat loss from the patient by convection more than CAS? We aimed to compare the IPH frequencies of these airflow systems on patients who underwent ureterorenoscopic lithotripsy (ureterorenoscopic surgery) under spinal anesthesia. The study was a prospective, parallel-group, randomized trial. A total of 246 volunteers were included in the study and divided into group LAS (n = 123) and group CAS (n = 123). Randomization of patients was performed using the closed-envelope method (as 1:1).The tympanic membrane temperature of patients was measured before spinal anesthesia ( T0 ) and then every 15 minutes ( T n ) during the procedure. The IPH ratio and the change of the tympanic temperatures (Δ T ) were recorded (clinical trial number: IRCT20180324039145N5). In total, there were no statistical differences between the IPH ratios of group LAS and group CAS (61.2% [71 of 116] versus 49.6% [57 of 115], respectively; P = 0.075). The IPH ratio was 55.4% (128 of 231). The tympanic temperatures of patients decreased about 0.64°C (0.45°C) at the 30th minute. In both groups, Δ 30 was similar (0.62; 95% confidence interval, 0.52-0.72 [ P = 0.65]; 95% confidence interval, 0.55-0.74 [ P = 0.236], respectively). The risk for IPH of both LAS and CAS in the operating room is similar during ureterorenoscopic surgery.


Isolated Kaposi Sarcoma in two HIV negative patients.
Kaposi sarcoma (KS) is a neoplasm of the endothelial cells. It often manifests with multiple vascular nodules on the skin and other organs. It is a systemic, malignant and multifactorial disease and has a variable course. There are four types: classic, endemic, iatrogenic and HIV-associated. The primary presentation on the penis and face is uncommon and is mainly observed in HIV-positive patients. Multiple treatment modalities are used including surgery, cryotherapy, electrosurgery, laser and radiation therapy. The authors present two cases of isolated Kaposi sarcoma in HIV negative, human herpes virus 8 (HHV-8) positive non immunocompromised patients. One case with facial KS and the other one with penile KS. Both were treated surgically with no recurrence in the following 6 months of the follow up period. Kaposi sarcoma is rare in HIV negative patients and is associated with HHV-8 infection. Lesions are usually solitary and can be treated surgically. It should be included in the differential diagnoses of penile and facial lesions that are clinically suspecious and resistent to therapy.


Paraneoplastic cerebellar degeneration caused by ovarian clear-cell carcinoma.
Paraneoplastic cerebellar degeneration is a paraneoplastic neurological syndrome caused by the remote effect of certain systemic cancers and is characterized by subacute cerebellar symptoms. A 62-year-old woman suffering from unidentified cerebellar symptoms was admitted to our hospital. Paraneoplastic cerebellar degeneration was suspected and ovarian cancer was detected after the systemic examination for malignancy. The symptoms of vertigo and dysarthria were improved a little after surgical operation and treatments of γ-globulin, steroid pulse and tacrolimus hydrate. The cerebellar symptoms of paraneoplastic cerebellar degeneration are often evident prior to detection of malignancy. It is important to perform systemic examination for malignancy in case of unidentified cerebellar symptoms.


Improving the management of iron deficiency in ambulatory heart failure patients.
Based on clinical trial data patients with heart failure (HF) and evidence of iron deficiency should be offered intravenous (iv) iron with the aim of improving exercise capacity and symptoms. Baseline measurement in outpatient HF clinics demonstrated that only 50% of patients who may be eligible for iv iron were investigated with iron studies. Our aim was to make sure that 90% of the patients attending our heart failure clinics who were symptomatic and had an ejection fraction (EF) ≤45% should have their iron studies checked within the last six months. In an effort to increase the proportion of suitable patients in whom iron studies are requested, we carried out three plan-do-study-act (PDSA) cycles each with a different intervention. These interventions included a presentation of the clinical trial evidence at a HF multidisciplinary meeting, email reminders prior to clinic and stickers in the patient notes (repeated twice). The effect of each intervention was measured with the outcome being the proportion of eligible patients in whom iron studies were documented within the previous 6 months. The interventions increased the number of suitable patients who had iron studies checked, to as high as 100%, however this effect was not sustained. Root cause analysis revealed that clinicians were unenthusiastic to continue performing iron studies due to inefficiency in the process of admitting patients and giving them iv iron. For example median in-hospital stay of seven hours for an infusion that is given over 15 minutes. In an attempt to improve patient and physician satisfaction we piloted an ambulatory outpatient service to deliver iv iron. We demonstrated that this service was feasible and more efficient as less time was required waiting for a bed or spent in hospital and was less costly. In summary we have demonstrated interventions which can increase the identification of patients who would benefit from iv iron and piloted a new time and cost efficient system of administration of iv iron.


Tomographic particle image velocimetry for the validation of hemodynamic simulations in an intracranial aneurysm.
Image-based blood flow simulations can provide detailed hemodynamic information in diseased vessels such as intracranial aneurysms. However, validation is essential to evaluate the accuracy of these computations and further improve their acceptance among physicians. In this regard, tomographic particle image velocimetry was used to measure the flow characteristics in a patient specific aneurysm phantom model. Additionally, computational fluid dynamics (CFD) simulations were carried out using a well accepted commercial software package and a clinical research prototype, respectively. The comparison between in-vitro measurement and in-silico computations reveals a good qualitative agreement. Further, computations based on classical CFD agreed well with results from a clinical research prototype. Hence, the results of this study demonstrate the usability of numerical methods to obtain realistic blood flow predictions in a clinical context.


The effect of UGT1A1 promoter polymorphism on bilirubin response to hydroxyurea therapy in hemoglobinopathies.
Hydroxyurea is known to reduce ineffective erythropoiesis and thereby hemolysis leading to a reduction in bilirubin levels in patients with hemoglobinopathies. However, the effect of hydroxyurea on hyperbilirubinemia in relation to the UGT1A1 gene promoter polymorphism is not known in Indian patients with different hemoglobinopathies. We studied 112 patients (77 sickle cell anemia, 22 β-thalassemia intermedia and 13 HbE-β-thalassemia) who were on hydroxyurea therapy for 2 years for their response towards hyperbilirubinemia associated with UGT1A1 promoter polymorphism. The patients with (TA)(7)/(TA)(7) repeats had significantly higher serum bilirubin levels than those with (TA)(6)/(TA)(6) repeats in all the groups and the reduction in serum bilirubin after hydroxyurea therapy was still higher among patients with (TA)(7)/(TA)(7) repeats when compared with (TA)(6)/(TA)(6) repeats. Higher bilirubin levels were associated with the (TA)(7)/(TA)(7) sequence however they did not come down to normal levels after hydroxyurea therapy.


Evaluation of virus recovery methods and efficiency of tannin-derived coagulants in removing total coliforms, E. coli and enteric viruses in effluents of a domestic sewage treatment plant.
In the present study, nine coagulants having potential to be used for sewage treatment were compared to assess their efficiency in removing total coliform bacteria, Escherichia coli and adenovirus. The coagulants tested were metallic and organic and their efficiency was compared when treating samples of raw and treated sewage (activated sludge). Before the efficiency tests of the coagulants, viral concentration methods were compared. Coagulation tests were carried out by using the jar-test system and the doses used ranged from 100 ppm to 1,000 ppm. Viral DNA was extracted and subjected to real-time polymerase chain reaction (qPCR) using primers for the gene of AdV hexon. Aluminum sulfate (1,000 ppm) presented the best results for raw sewage among metal coagulants whereas Acquapol® C118 and WW (1,000 ppm) had the most satisfactory results among organic coagulants, both reducing up to 7 logs for coliforms and 4 logs for virus. For the treated effluent, FeCl2 (1,000 ppm) presented best results for metal coagulants, whereas, from organic coagulants, the best removal rates were for Acquapol® 893/11 (1,000 ppm), both reducing up to 3 logs for coliforms and 4 logs for virus.


Mycoplasma pneumoniae and Legionella pneumophila in community-acquired lower respiratory tract infections among hospitalized children: diagnosis by real time PCR.
Mycoplasma pneumoniae and Legionella pneumophila are increasingly recognized as important agents of community-acquired lower respiratory tract infections (LRTI). Mycoplasma pneumoniae has been also recognized as a cause of nosocomial infections. The aim of this study was to investigate the role of real time polymerase chain reaction (PCR) for the rapid diagnosis of these infections among hospitalized children with community-acquired LRTI. During 2001, 65 children were prospectively studied. Microbiological investigation consisted of capillary PCR with a LightCycler for M. pneumoniae and L. pneumophila in induced sputum or throat swab specimens, IgM enzyme immunoassay for M. pneumoniae and immunofluorescence for L. pneumophila in paired sera. Serology testing showed acute M. pneumoniae infection in 18 (27.5%) patients and L. pneumophila in 1 (1.5%). M. pneumoniae was also detected in sputum specimen by capillary PCR in 9 (50%) serologically diagnosed cases, including 4 (22%) with non-diagnostic IgM levels in the acute phase. Capillary PCR and IgM enzyme immunoassay diagnosed together 15 (83%) M. pneumoniae cases in the acute phase. It is concluded that M. pneumoniae is an important cause of LRTI necessitating hospitalization among children in Greece. Capillary PCR in sputum may diagnose M. pneumoniae LRTI in the acute setting and direct therapy and isolation of patients.


Mib1 contributes to persistent directional cell migration by regulating the Ctnnd1-Rac1 pathway.
Persistent directional cell migration is involved in animal development and diseases. The small GTPase Rac1 is involved in F-actin and focal adhesion dynamics. Local Rac1 activity is required for persistent directional migration, whereas global, hyperactivated Rac1 enhances random cell migration. Therefore, precise control of Rac1 activity is important for proper directional cell migration. However, the molecular mechanism underlying the regulation of Rac1 activity in persistent directional cell migration is not fully understood. Here, we show that the ubiquitin ligase mind bomb 1 (Mib1) is involved in persistent directional cell migration. We found that knockdown of MIB1 led to an increase in random cell migration in HeLa cells in a wound-closure assay. Furthermore, we explored novel Mib1 substrates for cell migration and found that Mib1 ubiquitinates Ctnnd1. Mib1-mediated ubiquitination of Ctnnd1 K547 attenuated Rac1 activation in cultured cells. In addition, we found that posterior lateral line primordium cells in the zebrafish mib1ta52b mutant showed increased random migration and loss of directional F-actin-based protrusion formation. Knockdown of Ctnnd1 partially rescued posterior lateral line primordium cell migration defects in the mib1ta52b mutant. Taken together, our data suggest that Mib1 plays an important role in cell migration and that persistent directional cell migration is regulated, at least in part, by the Mib1-Ctnnd1-Rac1 pathway.


Influence of acute and chronic ethanol treatment on interferon production in mice.
The effect of acute (single dose) and long-term ethanol treatment of Swiss Albino and C3H/He mice on IFN production stimulated in vitro by NDV, PHA and ConA was examined. Liver organ cultures and spleen cells of mice which received intraperitoneally a single dose (2 g/kg of body weight) of ethanol (II group) or were drinking ethanol solutions instead of water for 4 weeks (III group) or for 8 weeks (IV group), and cells of control mice not treated with ethanol (I group) were cultivated in vitro. Some of the cultures were treated with 0.4% (w/v) ethanol or several IFN inducers NDV-R, PHA and ConA or incubated without any stimulators. The titers of IFN in supernatant fluids were measured. The results showed that cells from mice, which received a single ethanol injection, produced IFN spontaneously and this production was enhanced in the presence of 0.4% ethanol in culture medium. When spleen cell cultures of acute treated mice were induced with PHA and ConA, IFN titers lower than in cells of the control mice were produced. In contrast to these results, liver and spleen cells of mice after long term ethanol consumption produced significantly lower IFN titers than controls after NDV-R induction. Also spleen cells responded poorly both to PHA and ConA induction. These results demonstrate that long-term ethanol treatment can destroy IFN response to viral infection and can impair mitogen-induced IFN production. This suppression of IFN production by long term ethanol was similar in both strains of the mice examined.


Ceramic foam plates: a new tool for processing fresh radical prostatectomy specimens.
Procurement of fresh tissue of prostate cancer is critical for biobanking and generation of xenograft models as an important preclinical step towards new therapeutic strategies in advanced prostate cancer. However, handling of fresh radical prostatectomy specimens has been notoriously challenging given the distinctive physical properties of prostate tissue and the difficulty to identify cancer foci on gross examination. Here, we have developed a novel approach using ceramic foam plates for processing freshly cut whole mount sections from radical prostatectomy specimens without compromising further diagnostic assessment. Forty-nine radical prostatectomy specimens were processed and sectioned from the apex to the base in whole mount slices. Putative carcinoma foci were morphologically verified by frozen section analysis. The fresh whole mount slices were then laid between two ceramic foam plates and fixed overnight. To test tissue preservation after this procedure, formalin-fixed and paraffin-embedded whole mount sections were stained with hematoxylin and eosin (H&E) and analyzed by immunohistochemistry, fluorescence, and silver in situ hybridization (FISH and SISH, respectively). There were no morphological artifacts on H&E stained whole mount sections from slices that had been fixed between two plates of ceramic foam, and the histological architecture was fully retained. The quality of immunohistochemistry, FISH, and SISH was excellent. Fixing whole mount tissue slices between ceramic foam plates after frozen section examination is an excellent method for processing fresh radical prostatectomy specimens, allowing for a precise identification and collection of fresh tumor tissue without compromising further diagnostic analysis.


Flow Cytometric Assessment of the Morphological and Physiological Changes of Listeria monocytogenes and Escherichia coli in Response to Natural Antimicrobial Exposure.
Essential oils (EOs) or their components represent one of the most promising natural, safe, and feasible alternatives to prevent the growth of food-borne pathogens like Listeria monocytogenes and Escherichia coli in food matrices. Although antimicrobial properties of EOs and their components are well-documented, limited and fragmented information is available on the changes induced by these compounds, even at sub-lethal concentrations, in the physiological properties of microbial cells. The aim of this study was to explore the morpho-physiological changes of L. monocytogenes Scott A and E. coli MG 1655 induced after 1 h exposure to different sub-lethal and lethal concentrations of citral, carvacrol, (E)-2-hexenal, and thyme EO. For this purpose, different cell viability parameters such as membrane integrity, esterase activity, and cytoplasmic cell membrane potential were measured by flow cytometry. Flow cytometric data revealed specific response patterns in relation to the strain, the natural antimicrobial and its concentrations. Both the target microbial strains showed an increased cell membrane permeabilization without a loss of esterase activity and cell membrane potential with increasing citral, carvacrol and thyme EO concentrations. By contrast, (E)-2-hexenal did not significantly affect the measured physiological properties of L. monocytogenes Scott A and E. coli MG 1655. The used approach allowed identifying the most effective natural antimicrobials in relation to the microbial target.


The role of in vitro methods as alternatives to animals in toxicity testing.
It is accepted that animal testing should be reduced, refined or replaced as far as it is practicably possible. There are also a wide variety of in vitro models, which are used as screening studies and mechanistic investigations. The ability of an in vitro assay to be reliable, biomedically, is essential in pharmaceutical development. Furthermore, it is necessary that cells used in in vitro testing mimic the phenotype of cells within the human target tissue. The focus of this review article is to identify the key points of in vitro assays. In doing so, the authors take into account the chemical agents that are assessed and the integrated in vitro testing strategies. There is a transfer of toxicological data from primary in vivo animal studies to in vitro assays. The key element for designing an integrated in vitro testing strategy is summarized as follows: exposure modeling of chemical agents for in vitro testing; data gathering, sharing and read-across for testing a class of chemical; a battery of tests to assemble a broad spectrum of data on different mechanisms of action to predict toxic effects; and applicability of the test and the integrated in vitro testing strategies and flexibility to adjust the integrated in vitro testing strategies to test substance. While these methods will be invaluable if effective, more studies must be done to ensure reliability and suitability of these tests for humans.


Outcome of patients hospitalized for COVID-19 and exposure to angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers in France: results of the ACE-CoV study.
Data are lacking on the impact of ACEI/ARB exposure on unfavorable outcome in the population of patients hospitalized for COVID-19 with hypertension/cardiovascular disease, particularly in Europe. The ACE-CoV study was designed to assess this question. The study was conducted in the Covid-Clinic-Toul cohort, which contains data about all patients hospitalized at Toulouse University hospital, France with a SARS-CoV-2 infection since March, 2020. We selected the patients with a history of cardiovascular disease (heart failure or coronary disease) and/or arterial hypertension. We conducted a subgroup analysis in patients with arterial hypertension. ACEI/ARB exposures at admission were assessed. The outcome was composite: admission to intensive care unit, need of mechanical ventilation or death during the 14 days after admission to hospital. We used logistic regression models with propensity scores (PS) weighted by overlap weighting (OW) and inverse probability of treatment weighting (IPTW). Between March 2020 and April 20, 2020, the Covid-Clinic-Toul included 263 patients. Among them, 111 were included in the ACE-CoV study population. In OW-PS-adjusted analyses, the association of exposure to ACEIs or ARBs with outcome occurrence was OR: 1.56 (95% CI: 0.73-3.33). It was 0.99 (95% CI: 0.68-1.45) for ACEIs and 1.64 (95% CI: 0.77-3.50) for ARBs. Analyses with weighting by the IPTW-PS method gave similar results. Results were similar when considering the subgroup of patients with arterial hypertension. The ACE-CoV study found no association between exposure to ACEIs or ARBs and unfavorable outcome in hospitalized patients for COVID-19 with a history of cardiovascular disease/arterial hypertension.


hnRNP A1 antagonizes cellular senescence and senescence-associated secretory phenotype via regulation of SIRT1 mRNA stability.
Senescent cells display a senescence-associated secretory phenotype (SASP) which contributes to tumor suppression, aging, and cancer. However, the underlying mechanisms for SASP regulation are not fully elucidated. SIRT1, a nicotinamide adenosine dinucleotide-dependent deacetylase, plays multiple roles in metabolism, inflammatory response, and longevity, etc. However, its posttranscriptional regulation and its roles in cellular senescence and SASP regulation are still elusive. Here, we identify the RNA-binding protein hnRNP A1 as a posttranscriptional regulator of SIRT1, as well as cell senescence and SASP regulator. hnRNP A1 directly interacts with the 3' untranslated region of SIRT1 mRNA, promotes its stability, and increases SIRT1 expression. hnRNP A1 delays replicative cellular senescence and prevents from Ras OIS via upregulation of SIRT1 expression to deacetylate NF-κB, thus blunting its transcriptional activity and subsequent IL-6/IL-8 induction. hnRNP A1 overexpression promotes cell transformation and tumorigenesis in a SIRT1-dependent manner. Together, our findings unveil a novel posttranscriptional regulation of SIRT1 by hnRNP A1 and uncover a critical role of hnRNP A1-SIRT1-NF-κB pathway in regulating cellular senescence and SASP expression.


Sex- and stress-dependent effects of a single injection of ketamine on open field and forced swim behavior.
Ketamine has emerged as a novel treatment for common psychiatric conditions such as Major Depressive Disorder (MDD) and anxiety disorders, many of which can be initiated and exacerbated by psychological stress. Sex differences in the frequency of both anxiety and depressive disorders are well known and could be due to sex differences in neuroendocrine responses to stress. Ketamine is known to modulate the hormonal response to stress, specifically corticosterone. It is not clear if the acute effect of ketamine on corticosterone differs by sex, or what role this could play in subsequent behavior. Here we test whether a single injection of (R,S)-ketamine (30 mg/kg, i.p.), administered either with or without unpredictable chronic stress (UCS), has different sustained effects on open field test (OFT), elevated zero maze (EZM) or forced swim test (FST) behavior in female versus male C57BL/6J mice. In the OFT (24 h post-injection), ketamine increased center square exploration in males but not females. In contrast, in the FST (72 h post-injection), females showed a trend toward a decrease in immobility after ketamine whereas males were not strongly modulated. These behavioral effects of ketamine were stronger in the presence of UCS than in unstressed animals. UCS animals also showed lower corticosterone after injection than unstressed animals, and in the presence of UCS ketamine increased corticosterone; these effects were similar in both sexes. Corticosterone post-injection did not predict subsequent behavior. These findings complement a growing preclinical literature suggesting both stress-dependency and sex differences in OFT and FST behavioral responses to ketamine.LAY SUMMARYIn humans, it is known that major depression and anxiety disorders, which can be caused or made worse by exposure to psychological stress, occur roughly twice as frequently in women than in men, but the underpinnings of these effects are not well characterized. In the current study, we explored how sex interacts with stress and ketamine (a rapidly acting antidepressant) by assessing both open field and forced swim behavior in mice after chronic mild stress. We report the novel finding that male mice exhibit greater exploration of the aversive center square in the open field after ketamine, whereas females trended toward lower immobility (often interpreted as an antidepressant-like effect) in the forced swim test after this drug, and these effects were amplified by prior stress exposure.


Proton Therapy Outcomes for Head and Neck Cutaneous Melanoma: Proton Collaborative Group Analysis.
Reports of proton beam therapy (PBT) utilization for cutaneous melanoma of the head and neck (HN) region is virtually non-existent. This study reports on the efficacy and acute toxicities of PBT for primary HN cutaneous melanoma. We queried the prospectively collected, multi-institutional Proton Collaborative Group registry for all consecutive patients with HN cutaneous melanoma receiving PBT from May 2010 to December 2019. Kaplan-Meier methods were used to estimate overall survival (OS), progression free survival (PFS), and local regional recurrence free survival (LRFS). Toxicity was reported per CTCAE version 4.0. A total of 8 patients were identified with a median age of 69 (range, 37-88). All patients (100%) underwent surgery followed with postoperative PBT. There were 3 patients (37.5%) with T3 or T4 disease and 4 (50%) with N2 or N3 disease. The median radiation dose was 46 GyRBE (range, 27-70) and median dose per fraction was 2.4 GyRBE (range, 2.0-6.0) with the most common dose fractionation being 44 or 48 GyRBE in 20 fractions (n = 4). At a median follow-up of 40.1 months (range, 1.6-62.4) the 1 and 3 year OS rates were 85.7% and 35.7%, respectively. The median PFS was 25.40 months (95% CI, 2.53-58.70) while PFS at 1 year and 3 years was 85.7% and 35.7%, respectively. LRFS was 100% at 1 year and 85.7% at 3 years. Five of the 8 patients developed distant metastases, of which 3 received immunotherapy. Acute G2+ and G3+ toxicities occurred in 5 of 8 patients and 2 of 8 patients, respectively. G3 toxicities included radiation dermatitis (n = 1) and immunotherapy-related rash (n = 1). No G4+ toxicities were reported. Single modality PBT for HN melanomas in the definitive setting provides effective and durable local control rates with tolerable acute toxicity. Distant failure remains the primary pattern of failure.


Asperity level characterization of abrasive wear using atomic force microscopy.
Using an atomic force microscope, a nanoscale wear characterization method has been applied to a commercial steel substrate AISI 52100, a common bearing material. Two wear mechanisms were observed by the presented method: atom attrition and elastoplastic ploughing. It is shown that not only friction can be used to classify the difference between these two mechanisms, but also the 'degree of wear'. Archard's Law of adhesion shows good conformity to experimental data at the nanoscale for the elastoplastic ploughing mechanism. However, there is a distinct discontinuity between the two identified mechanisms of wear and their relation to the load and the removed volume. The length-scale effect of the material's hardness property plays an integral role in the relationship between the 'degree of wear' and load. The transition between wear mechanisms is hardness-dependent, as below a load threshold limited plastic deformation in the form of pile up is exhibited. It is revealed that the presented method can be used as a rapid wear characterization technique, but additional work is necessary to project individual asperity interaction observations to macroscale contacts.


Inhibition of inducible nitric-oxide synthase expression by silymarin in lipopolysaccharide-stimulated macrophages.
Silymarin, a polyphenolic flavonoid antioxidant, is known to have anti-inflammatory, hepatoprotective, and anticarcinogenic effects. In the present study, we report the inhibitory effect of silymarin on nitric oxide production and inducible nitric-oxide synthase (iNOS) gene expression in macrophages. In vivo administration of silymarin attenuated nitric oxide production by peritoneal macrophages in lipopolysaccharide (LPS)-treated mice. Silymarin also dose dependently suppressed the LPS-induced production of nitric oxide in isolated mouse peritoneal macrophages and RAW 264.7, a murine macrophage-like cell line. Moreover, iNOS mRNA and its protein expression were completely abrogated by silymarin in LPS-stimulated RAW 264.7 cells. To further investigate the mechanism responsible for the inhibition of iNOS gene expression by silymarin, we examined the effect of silymarin on LPS-induced nuclear factor-kappaB (NF-kappaB)/Rel activation, which regulates various genes involved in immune and inflammatory response. In RAW 264.7 cells, the LPS-induced DNA binding activity of NF-kappaB/Rel was significantly inhibited by silymarin, and this effect was mediated through the inhibition of the degradation of inhibitory factor-kappaB. Silymarin also inhibited tumor necrosis factor-alpha-induced NF-kappaB/Rel activation, whereas okadaic acid-induced NF-kappaB/Rel activation was not affected. NF-kappaB/Rel-dependent reporter gene expression was also suppressed by silymarin in LPS-stimulated RAW 264.7 cells. Further study showed that silymarin suppressed the production of reactive oxygen species generated by H(2)O(2) in RAW 264.7 cells. Collectively, these results suggest that silymarin inhibits nitric oxide production and iNOS gene expression by inhibiting NF-kappaB/Rel activation. Furthermore, the radical-scavenging activity of silymarin may explain its inhibitory effect on NF-kappaB/Rel activation.


Boronate affinity-based surface molecularly imprinted polymers using glucose as fragment template for excellent recognition of glucosides.
Rapid and efficient extraction of bioactive glycosides from complex natural origins poses a difficult challenge, and then is often inherent bottleneck for their highly utilization. Herein, we propose a strategy to fabricate boronate affinity based surface molecularly imprinted polymers (MIPs) for excellent recognition of glucosides. d-glucose was used as fragment template. Boronic acid, dynamic covalent binding with d-glucose under different pH conditions, was selected as functional monomer to improve specificity. Fe3O4 solid core for surface imprinting using tetraethyl orthosilicate (TEOS) as crosslinker could control imprinted shell thickness for favorable adsorption capacity and satisfactory mass transfer rate, improve hydrophilicity, separate easily by a magnet. Model adsorption studies showed that the resulting MIPs show specific recognition of glucosides. The equilibrium data fitted well to Langmuir equation and the adsorption process could be described by pseudo-second order model. Furthermore, the MIPs were successfully applied for selective extraction of three flavonoid glucosides (daidzin, glycitin, and genistin) from soybean. Results indicated that selective extraction of glucosides from complex aqueous media based on the prepared MIPs is simple, rapid, efficient and specific. Moreover, this method opens up a universal route for imprinting saccharide with cis-diol group for glycosides recognition.


Signaling pathways in diabetic nephropathy.
Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD), however, specific treatment for DN has not yet been elucidated. Therefore, it is critically important to understand the molecular mechanism underlying DN to develop cause-related therapeutic strategy. To date, various factors such as hemodynamic changes and metabolic pathways have been shown to be involved in the pathogenesis of DN. Excessive glucose influx activates cellular signaling pathways, including the diacylglycerol (DAG)-protein kinase C (PKC) pathway, advanced glycation end-products (AGE), polyol pathway, hexosamine pathway and oxidative stress. These factors interact with one another, thereby facilitating inflammatory processes, leading to the development of glomerulosclerosis under diabetic conditions. In addition to metabolic pathways, Rho-kinase, an effector of small-GTPase binding protein Rho, has been implicated as an important factor in the pathogenesis of DN. A number of studies have demonstrated that Rho-kinase plays key roles in the development of DN by inducing endothelial dysfunction, mesangial excessive extracellular matrix (ECM) production, podocyte abnormality, and tubulointerstitial fibrosis. In this review article, we describe our current understanding of the signaling pathways in DN.


Auditory function in Alzheimer's disease.
The pattern of cerebral degeneration in Alzheimer's disease (AD) patients suggests that basic auditory capacities should be normal in AD, whereas progressively higher levels of auditory function should be increasingly impaired. To test this hypothesis, we administered tests of auditory capacities associated with primary auditory cortex (sound localization and perception of complex tones) and auditory association cortex (phoneme discrimination, timbre discrimination, and tonal memory) to 19 mildly to moderately demented AD patients, 21 elderly control subjects (ECS), and 14 young control subjects (YCS). The results showed significant differences between YCS and ECS on phoneme discrimination with synthetic speech and on tonal memory. The AD group differed from the ECS group on sound localization, one measure of synthetic speech discrimination, and timbre discrimination. Performance did not correlate with age, dementia severity, or duration of illness on any test condition. These findings indicate that although AD is accompanied by specific auditory deficits, the increase in neuropathologic change between primary auditory and auditory association cortices is not reflected in an increased impairment of functions that are mediated by these areas. Degraded aural language comprehension, which is characteristic of AD, likely reflects disruption of language processes, rather than dysfunction specific to auditory circuits.


Factors associated with caries increment: a longitudinal study from 18 months to 5 years of age.
Identifying the early determinants of risk for dental caries would be useful in its primary prevention. All children at the age of 18 months in one health care area were invited in the screening test for mutans streptococci (MS) and their caretakers interviewed for the study purposes. The 366 children who met the inclusion criteria were clinically examined after 42 months. At the age of 5 years ± 6 months, in 79 (21.6%) children the 42-month caries increment was >0. In the multivariate regression analysis, the strongest correlation was found with MS detected in the oral biofilm. Of the reported background factors the blue-collar occupation of the caretaker, child's sugar use, night feeding, use of other thirst quenchers than water and father's reported poor oral health were significantly correlated with the child's caries increment. The oral health of a child is strongly related to the lifestyle and the oral health habits of the caretakers during the first years.


Supraspinatus tendon thickness and subacromial impingement characteristics in younger and older adults.
Subacromial impingement (SAI) may be a cause of age-related rotator cuff abnormalities; therefore, the purpose of this study was to compare SAI characteristics between younger and older adults. In addition to the fact that thickened supraspinatus tendon (SST) indicates tendon abnormalities, SAI characteristics have been recognized as follows: greater SST thickness, reduced acromiohumeral distance (AHD), greater reduction of AHD (∆AHD) with arm elevation, and a higher percentage of SST within AHD (i.e., occupation ratio: OcAHD). Furthermore, we investigated the relationships between SST thickness and AHD, as well as SST thickness and ∆AHD to clarify the effect of SAI on rotator cuff abnormalities. Healthy younger (n = 18, 21-24-year-old) and older (n = 27, 45-80-year-old) adults without any shoulder symptoms participated in this study. We measured their SST thickness and AHD at rest and at arm elevation (30° and 60°) in the scapular plane using ultrasound, and calculated ∆AHD as the relative change expressed as a percentage of the baseline. OcAHD was expressed as the ratio of SST thickness at rest to AHD at rest and in elevated positions. The older subjects had approximately one mm thicker SST (P = 0.003, 95% Confidence interval [CI] = 0.410 to 1.895) and approximately 1.0 to 1.3 mm greater AHD than the younger subjects (P = 0.011, 95%CI = 0.284 to 2.068 at rest; P = 0.037, 95%CI = 0.082 to 2.609 for 30° of arm elevation; P = 0.032, 95%CI = 0.120 to 2.458 for 60° of arm elevation). However, there were no differences in ΔAHD and OcAHD between the groups. This study demonstrated that, compared with the younger subjects, the older subjects showed thicker supraspinatus tendon but no other SAI characteristics including decreases in AHD and increases in OcAHD. Thus, this study suggests that older subjects showed age-related SST abnormalities without SAI, although the magnitude of the differences in SST thickness is notably small and the clinical significance of this difference is unclear.


Animal models of polymicrobial pneumonia.
Pneumonia is one of the leading causes of severe and occasionally life-threatening infections. The physiopathology of pneumonia has been extensively studied, providing information for the development of new treatments for this condition. In addition to in vitro research, animal models have been largely used in the field of pneumonia. Several models have been described and have provided a better understanding of pneumonia under different settings and with various pathogens. However, the concept of one pathogen leading to one infection has been challenged, and recent flu epidemics suggest that some pathogens exhibit highly virulent potential. Although "two hits" animal models have been used to study infectious diseases, few of these models have been described in pneumonia. Therefore the aims of this review were to provide an overview of the available literature in this field, to describe well-studied and uncommon pathogen associations, and to summarize the major insights obtained from this information.


Global impairment of cardiac autonomic nervous activity late after repair of tetralogy of Fallot.
Sustained ventricular tachycardia (VT) and sudden cardiac death (SCD) remain devastating late complications after repair of Tetralogy of Fallot (ToF). Although heart rate variability (HRV) and baroreflex sensitivity (BRS) are recognized as independent markers of autonomic activity and strong predictors of SCD in major cardiovascular disease, little is known about their role in patients with tetralogy. We measured HRV and BRS in 45 ToF patients (27 male, age 35+/-12 years, 26+/-7 years after repair) and 45 matched healthy controls. Subjects underwent 20 minute of resting measurements of heart rate (ECG) and noninvasive beat-to-beat blood pressure recording (Finapres), with 5 minutes of 0.1Hz controlled breathing followed by cardiac MRI. BRS was computed by spectral analysis and the sequence and controlled breathing methods. All HRV time and frequency domain variables were measured. All BRS and HRV variables were significantly reduced in patients compared with controls (P<0.001 in all). HRV tended to increase with years from repair. BRS decreased with previous palliation and increasing patient age. Both HRV and BRS decreased with pulmonary regurgitation, elevated right ventricular end systolic volumes and reduced right and left ventricular ejection fraction. Finally, there was an inverse relation between QRS duration (predictor of sustained VT and SCD) and indices of HRV but no relation with indices of BRS. There is global impairment of autonomic nervous system regulation late after repair of tetralogy with marked reduction of BRS and HRV. This seems to relate to previous surgical intervention/s, their timing and current right and left-sided hemodynamics. Reduced HRV also related to markers of sustained VT and SCD, suggesting possible common pathogenic mechanisms. Further studies are required to examine the prognostic significance of impaired BRS and HRV in these patients.


Biology of attenuated modified vaccinia virus Ankara recombinant vector in mice: virus fate and activation of B- and T-cell immune responses in comparison with the Western Reserve strain and advantages as a vaccine.
The modified vaccinia virus Ankara (MVA) strain is a candidate vector for vaccination against pathogens and tumors, due to safety concerns and the proven ability of recombinants based on this vector to trigger protection against pathogens in animals. In this study we addressed the fate of the MVA vector in BALB/c mice after intraperitoneal inoculation in comparison with that of the replication-competent Western Reserve (WR) strain by measuring levels of expression of the reporter luciferase gene, the capability to infect target tissues from the site of inoculation, and the length of time of virus persistence. We evaluated the extent of humoral and cellular immune responses induced against the virus antigens and a recombinant product (beta-galactosidase). We found that MVA infects the same target tissues as the WR strain; surprisingly, within 6 h postinoculation the levels of expression of antigens were higher in tissues from MVA-infected mice than in tissues from mice infected with wild-type virus but at later times postinoculation were 2 to 4 log units higher in tissues from WR-infected mice. In spite of this, antibodies and cellular immune responses to viral vector antigens were considerably lower in MVA-inoculated mice than in WR virus-inoculated mice. In contrast, the cellular immune response to a foreign antigen expressed from MVA was similar to and even higher than that triggered by the recombinant WR virus. MVA elicited a Th1 type of immune response, and the main proinflammatory cytokines induced were interleukin-6 and tumor necrosis factor alpha. Our findings have defined the biological characteristics of MVA infection in tissues and the immune parameters activated in the course of virus infection. These results are of significance with respect to optimal use of MVA as a vaccine.


Dynamic susceptibility contrast magnetic resonance imaging in neuropsychiatry: present utility and future promise.
Dynamic susceptibility contrast magnetic resonance imaging (DSC MRI) provides a noninvasive means to create high resolution maps of the regional distribution of cerebral blood volume (CBV). Most DSC MRI studies conducted to date have focused on the evaluation of patients with cerebral neoplasms, ischemia or infarction, and epilepsy. However, preliminary work suggests that DSC MRI may also provide clinically important information for the evaluation of patients with neuropsychiatric disorders, especially dementia and schizophrenia. Additionally, with appropriate modification, DSC MRI may be used to reliably evaluate the effects of pharmacological challenges on cerebral hemodynamics. As pharmacotherapy is an important component in the treatment of a range of psychiatric disorders, the dynamic assessment of changes in cerebral perfusion associated with drug administration may ultimately lead to the development of "brain function tests" for a wide range of disorders.


PWHATSHAP: efficient haplotyping for future generation sequencing.
Haplotype phasing is an important problem in the analysis of genomics information. Given a set of DNA fragments of an individual, it consists of determining which one of the possible alleles (alternative forms of a gene) each fragment comes from. Haplotype information is relevant to gene regulation, epigenetics, genome-wide association studies, evolutionary and population studies, and the study of mutations. Haplotyping is currently addressed as an optimisation problem aiming at solutions that minimise, for instance, error correction costs, where costs are a measure of the confidence in the accuracy of the information acquired from DNA sequencing. Solutions have typically an exponential computational complexity. WHATSHAP is a recent optimal approach which moves computational complexity from DNA fragment length to fragment overlap, i.e., coverage, and is hence of particular interest when considering sequencing technology's current trends that are producing longer fragments. Given the potential relevance of efficient haplotyping in several analysis pipelines, we have designed and engineered PWHATSHAP, a parallel, high-performance version of WHATSHAP. PWHATSHAP is embedded in a toolkit developed in Python and supports genomics datasets in standard file formats. Building on WHATSHAP, PWHATSHAP exhibits the same complexity exploring a number of possible solutions which is exponential in the coverage of the dataset. The parallel implementation on multi-core architectures allows for a relevant reduction of the execution time for haplotyping, while the provided results enjoy the same high accuracy as that provided by WHATSHAP, which increases with coverage. Due to its structure and management of the large datasets, the parallelisation of WHATSHAP posed demanding technical challenges, which have been addressed exploiting a high-level parallel programming framework. The result, PWHATSHAP, is a freely available toolkit that improves the efficiency of the analysis of genomics information.