The Correspondence Between Magnetic Resonance Images and the Clinical and Intraoperative Status of Patients with Spinal Tumors.
Surgical treatment of tumors, particularly metastases to the spine, has become increasingly common owing to the progress in anesthesiology and spinal surgery and greater detectability. The patients qualified for surgeries are those with mechanical pain, fracture or at risk of vertebral fracture or neurological complications. The basis for qualification for different types of surgeries is clinical and imaging examination, particularly MRI and CT. Qualification should always be multidisciplinary and requires understanding and knowledge of its most essential aspects. When carrying out imaging examinations, it is necessary to assess the size and the type of the tumor, taking into account of differential diagnosis. One should also consider the factors indicating spinal instability or the onset of neurological deficits. The criteria developed by Kostiuk-Weinstain and Taneichi are used for that purpose. The aim of the present study was to evaluate the correspondence between the most essential elements of clinical and MRI examination of the spine and the intraoperative status of patients with spinal tumors. We carried out prospective examination assessing the correspondence between the clinical status and MR images and the intraoperative spine. We introduced algorithm to describe the morphology of neoplastic lesions within the spine. The information obtained from the clinical examination and the intraoperative status of the spine corresponded with the MRI examination with the exception of the assessment of neoplastic infiltration to soft tissues, dura mater and nerve roots. It was also found that there are no clear-cut MRI features allowing differentiation of metastatic lesions from primary tumors and osteitis. Furthermore, MRI examination does not allow for the assessment of the quality of bone tissue in the vicinity of the tumor.


Dental students' experiences with and attitudes toward people with mental retardation.
People with mental retardation have limited access to oral health care. Dental school administrators reported minimal training in U.S. dental schools for these patients. As a result, students and practitioners may not be prepared to provide needed services. The authors surveyed 295 third- and fourth-year students at five dental schools about their didactic and clinical preparation for, attitudes toward and comfort levels with treating people with mental retardation, as well as whether their experiences affect their willingness to treat people with mental retardation. The authors analyzed data using previously developed statistical software. A little more than 68 percent of respondents reported receiving five hours or less of instruction devoted to how to care for people with mental retardation, and 50.8 percent reported having no clinical training in this area. Nearly 60 percent reported that they had little to no confidence in providing care, while 74.6 percent reported they had little to no preparation in providing care. Students who had experience working with people with mental retardation attributed greater capabilities to such people than did students who had no such experience. Many U.S. dental students are prepared inadequately to provide services for people with mental retardation. Spending time with these patients provides a more positive understanding of the capabilities of these people. Increasing numbers of people with mental retardation no longer live in institutions, and they are dependent on dentists in private practice for care. Increased dental school training and continuing education programs are needed to meet this need.


Meiobenthos provides a food resource for young cyprinids.
Young individuals of the bottom-biting (i.e. sediment-ingesting) common carp Cyprinus carpio and gudgeon Gobio gobio consumed significant amounts of nematodes in laboratory experiments, whereas the selective-feeding roach Rutilus rutilus did not. In mesocosm enclosure experiments in the field, C. carpio strongly decreased the nematode abundance within 4 days, whereas the bottom-biting bream Abramis brama did not affect the abundance until after 14 days. In controlled experiments with a known number of prey, C. carpio but not A. brama significantly reduced the number of nematodes, and G. gobio reduced the nematode abundance dependent on the size of the fish, with smaller fish causing a greater reduction. Cyprinus carpio consumed the nematodes and did not just mechanically kill them in the sediment, as shown by dissection of the fish intestine. Morphometric analysis of the branchial baskets indicated that the mesh width of C. carpio, but not of A. brama, is suitable for consuming meiobenthos. The results indicate that the meiobenthos is a food resource for certain bottom-feeding freshwater fishes.


Wound repair and anti-inflammatory potential of Lonicera japonica in excision wound-induced rats.
Lonicera japonica Thunb. (Caprifoliaceae), a widely used traditional Chinese medicinal plant, is used to treat some infectious diseases and it may have uses as a healthy food and applications in cosmetics and as an ornamental groundcover. The ethanol extract of the flowering aerial parts of L. japonica (LJEE) was investigated for its healing efficiency in a rat excision wound model. Excision wounds were inflicted upon three groups of eight rats each. Healing was assessed by the rate of wound contraction in skin wound sites in rats treated with simple ointment base, 10% (w/w) LJEE ointment, or the reference standard drug, 0.2% (w/w) nitrofurazone ointment. The effects of LJEE on the contents of hydroxyproline and hexosamine during healing were estimated. The antimicrobial activity of LJEE against microorganisms was also assessed. The in vivo anti-inflammatory activity of LJEE was investigated to understand the mechanism of wound healing. LJEE exhibited significant antimicrobial activity against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Candida albicans, and Candida tropicalis. The ointment formulation prepared with 10% (w/w) LJEE exhibited potent wound healing capacity as evidenced by the wound contraction in the excision wound model. The contents of hydroxyproline and hexosamine also correlated with the observed healing pattern. These findings were supported by the histopathological characteristics of healed wound sections, as greater tissue regeneration, more fibroblasts, and angiogenesis were observed in the 10% (w/w) LJEE ointment-treated group. The results also indicated that LJEE possesses potent anti-inflammatory activity, as it enhanced the production of anti-inflammatory cytokines that suppress proinflammatory cytokine production. The results suggest that the antimicrobial and anti-inflammatory activities of LJEE act synergistically to accelerate wound repair.


Death of american ground sloths.
Organic remains, especially dung, of extinct ground sloths provide ideal material for radiocarbon dating. Rampart Cave, Arizona, revealed periodic occupation at intervals by the Shasta ground sloth from before 40,000 years ago until 11,000 years ago. Dates from other caves in the arid Southwest indicate that the Shasta ground sloth disappeared at very soon after the time of Clovis big game hunters. Ground sloth remains in South America are slightly younger. The timing of ground sloth extinction is in accord with the model of explosive overkill.


High-throughput microRNAome analysis in human germ cell tumours.
Testicular germ cell tumours (GCTs) of adolescents and adults can be subdivided into seminomas (referred to as dysgerminomas of the ovary) and non-seminomas, all referred to as type II GCTs. They originate from carcinoma in situ (CIS), being the malignant counterparts of primordial germ cells (PGCs)/gonocytes. The invasive components mimic embryogenesis, including the stem cell component embryonal carcinoma (EC), the somatic lineage teratoma (TE), and the extra-embryonic tissues yolk sac tumour (YST) and choriocarcinoma (CH). The other type is the so-called spermatocytic seminomas (SS, type III GCT), composed of neoplastic primary spermatocytes. We reported previously that the miRNAs hsa-miR 371-373 cluster is involved in overruling cellular senescence induced by oncogenic stress, allowing cells to become malignant. Here we report the first high-throughput screen of 156 microRNAs in a series of type II and III GCTs (n = 69, in duplicate) using a quantitative PCR-based approach. After normalization to allow inter-sample analysis, the technical replicates clustered together, and the previous hsa-miRNA 371-373 cluster finding was confirmed. Unsupervised cluster analysis demonstrated that the cell lines are different from the in vivo samples. The in vivo samples, both normal and malignant, clustered predominantly based on their maturation status. This parallels normal embryogenesis, rather than chromosomal anomalies in the tumours. miRNAs within a single cluster showed a similar expression pattern, implying common regulatory mechanisms. Normal testicular tissue expressed most discriminating miRNAs at a higher level than SE and SS. Moreover, differentiated non-seminomas showed overexpression of discriminating miRNAs. These results support the model that miRNAs are involved in regulating differentiation of stem cells, retained in GCTs.


Striatal action-value neurons reconsidered.
It is generally believed that during economic decisions, striatal neurons represent the values associated with different actions. This hypothesis is based on studies, in which the activity of striatal neurons was measured while the subject was learning to prefer the more rewarding action. Here we show that these publications are subject to at least one of two critical confounds. First, we show that even weak temporal correlations in the neuronal data may result in an erroneous identification of action-value representations. Second, we show that experiments and analyses designed to dissociate action-value representation from the representation of other decision variables cannot do so. We suggest solutions to identifying action-value representation that are not subject to these confounds. Applying one solution to previously identified action-value neurons in the basal ganglia we fail to detect action-value representations. We conclude that the claim that striatal neurons encode action-values must await new experiments and analyses.


Evidence assessment of management of acute otitis media: I. The role of antibiotics in treatment of uncomplicated acute otitis media.
In 1995, >5 million episodes of acute otitis media (AOM) accounted for $3 billion in health care expenditures. To synthesize the literature on the natural history of AOM, the effectiveness of antibiotic treatment in uncomplicated AOM, and the relative effectiveness of specific antibiotic regimens. Seven electronic databases for articles published between 1966 and March 1999 and reference lists in proceedings, published articles, reports, and guidelines. Two physicians independently assessed each article. Studies addressing AOM in children 4 weeks to 18 years old were included; those addressing children with immunodeficiencies or craniofacial abnormalities were excluded. Randomized, controlled trials (RCTs) were used to assess antibiotic effectiveness, and RCTs and cohort studies were used to assess the natural history of AOM. Among the 3491 citations identified, 80 (2.3%) met our inclusion criteria. Two physicians independently abstracted data and assessed the quality of studies using a validated scale for RCTs and 8 quality components for cohort studies. Random-effects estimates of pooled absolute rate differences of outcomes were derived, and heterogeneity of both the rates and rate differences was assessed. Children with AOM not treated with antibiotics experienced a 1- to 7-day clinical failure rate of 19% (95% confidence interval: 0.10-0.28) and few suppurative complications. When patients were treated with amoxicillin, the 2- to 7-day clinical failure rate was reduced to 7%, a 12% (95% confidence interval: 0.04-0.20) reduction. Adverse effects, primarily gastrointestinal, were more common among children on cefixime than among those on ampicillin or amoxicillin. They were also more common among children on amoxicillin-clavulanate than among those on azithromycin. The majority of uncomplicated cases of AOM resolve spontaneously without apparent suppurative complications. Ampicillin or amoxicillin confers a limited therapeutic benefit. There is no evidence to support any particular antibiotic regimens as more effective at relieving symptoms. Certain antibiotics are more likely than others to cause diarrhea and other adverse events.


Allelic variation in the Helicobacter pylori flagellin genes flaA and flaB: its consequences for strain typing schemes and population structure.
Extensive DNA sequence diversity was noted in Helicobacter pylori flagellin genes flaA and flaB. PCR amplified sequences from 49 isolates were digested with AluI, HindIII, MboI or MspI, the resultant patterns were compared between the different isolates and these used to differentiate the isolates from each other. Evidence that the extensive diversity that was found in these genes is the result of reassortment of sequences between strains in the bacterial population is presented, such that a comparatively small number of individual sequence mutations can recombine together in random combinations to form a greater number of distinct alleles. Geographical differences in the predominant patterns in the flaA alleles were also observed and could reflect regional differences either in the human host population or in the bacterial population. In view of the genetic complexity of this species, molecular typing schemes designed to identify related strains may falsely associate strains if the methods do not characterize sufficient genetic sites to exclude chance associations of genetic markers in strains which are actually not closely related to each other.


Biological effects of the PINK1 c.1366C>T mutation: implications in Parkinson disease pathogenesis.
PINK1 gene mutations are a cause of recessively inherited, early-onset Parkinson's disease. In some patients, a single heterozygous mutation has been identified, including the recurrent c.1366C>T transition. The interpretation of this finding remains controversial. Furthermore, the c.1366C>T mutation is associated with lower levels of PINK1 transcript, raising the question of whether mRNA levels correlate with the clinical status. We sequenced genomic DNA and copy DNA (cDNA) from 20 subjects carrying the c.1366C>T mutation in the homozygous (n = 5) or heterozygous (n = 15) state. In 17 mutation carriers, messenger RNA (mRNA) was quantified by real-time PCR using four different assays (PINK1 exon 5-6 or exon 7-8 relative to control genes SDHA or YWHAZ). Genomic sequencing confirmed the presence and zygosity of PINK1 mutations. cDNA sequencing in heterozygous mutation carriers revealed a strong wild-type and a much weaker or almost absent mutant signal, whereas in the homozygous patients, only the mutant signal was detected. Homozygous and heterozygous carriers showed PINK1 mRNA levels relative to a reference gene in the range of 0.1-0.2 and 0.5-0.6, respectively, compared with values of 0.9-1.0 in mutation-negative individuals. Treatment of lymphoblasts from a heterozygous mutation carrier with cycloheximide markedly increased the mutant transcript signal. We conclude that the recurrent PINK1 c.1366C>T mutation exerts a major effect at the mRNA level (80-90% reduction), most likely via nonsense-mediated mRNA decay. The absence of correlation between PINK1 mRNA levels and clinical status in heterozygous mutation carriers suggests that other genetic or environmental factors play a role in determining the phenotypic variability associated with the c.1366C>T mutation.


Endogenous cortisol production in response to knee arthroscopy and total knee arthroplasty.
There is controversy about whether patients who take exogenous glucocorticoids, such as prednisone, require supplemental (exogenous) glucocorticoids in order to meet the physiological demands of surgery. In this study, we sought to define the magnitude of the surgical stress response in normal patients undergoing major and minor elective orthopaedic surgery. A prospective, observational study of thirty patients who had not taken exogenous glucocorticoids and who underwent either elective knee arthroscopy or elective unilateral total knee arthroplasty was performed. Regional anesthesia was used for all patients, and all patients treated with total knee arthroplasty had continuous epidural anesthesia for forty-eight hours after the surgery. The stress response was assessed on the basis of serum and twenty-four-hour urine cortisol levels; comparisons of the urine values were made after correcting for renal function by calculating the cortisol-to-creatinine clearance ratio. Preoperatively, patients undergoing arthroscopy and total knee arthroplasty had similar cortisol-to-creatinine clearance ratios. Patients treated with total knee arthroplasty had a significant (p < 0.001) surgical stress response on the day of the surgery, compared with baseline, whereas patients treated with arthroscopy did not. The mean cortisol-to-creatinine clearance ratio in patients treated with total knee arthroplasty was highest on the day of the surgery and decreased on the third postoperative day. However, on the third postoperative day, the cortisol-to-creatinine clearance ratio still was significantly higher than the baseline value (p < 0.001). Significant differences in the serum cortisol levels also were detected between the patients treated with arthroscopy and those treated with total knee replacement. Patients undergoing total knee arthroplasty had a significant surgical stress response (a seventeenfold increase in the cortisol-to-creatinine clearance ratio); patients treated with arthroscopy did not. Additional studies, including a prospective trial of patients taking exogenous glucocorticoids, are warranted. Until they are performed, the significantly increased cortisol production observed in non-steroid-dependent patients following total knee arthroplasty leaves open the possibility that steroid-dependent patients undergoing this procedure could benefit from perioperative glucocorticoid supplementation. Since the non-steroid-dependent patients in the present series did not mount a substantial stress response to knee arthroscopy, our results do not support the use of supplemental steroids for that less-invasive procedure.


Reinvestigation of electric field-induced optical activity in α-quartz: application of a polarimeter with four photoelastic modulators.
Linear electrogyration (electric field-induced optical activity) and electro-optic effects in x-cut and z-cut right-handed (RH) α-quartz were measured using a complete Mueller matrix polarimeter. The polarimeter used in the analysis was equipped with four photoelastic modulators operating at different frequencies. This configuration is especially sensitive due to the fidelity of the modulators and the fact that all the Mueller matrix elements can be delivered without any moving optical elements. The linear electrogyration coefficient γ11 as a function of the wavelength of incident light was remeasured. The coefficient γ33 , required by symmetry to be zero, was evaluated as a control. γ11 was much smaller than values obtained previously using devices dependent on mechanical light modulation. Electrogyration measurements have often been confounded by the much larger linear electro-optic effect. The Mueller calculus used herein is well suited to the separation of the competing changes to the polarization state of light. Quadratic electrogyration associated with elements β(11) and β(33) was not detectable.


Effect of sample preparation techniques on the concentrations and distributions of elements in biological tissues using µSRXRF: a comparative study.
Routine tissue sample preparation using chemical fixatives is known to preserve the morphology of the tissue being studied. A competitive method, cryofixation followed by freeze drying, involves no chemical agents and maintains the biological function of the tissue. The possible effects of both sample preparation techniques in terms of the distribution of bio-metals (calcium (Ca), copper (Cu) zinc (Zn), and iron (Fe) specifically) in human skin tissue samples was investigated. Micro synchrotron radiation x-ray fluorescence (μSRXRF) was used to map bio-metal distribution in epidermal and dermal layers of human skin samples from various locations of the body that have been prepared using both techniques. For Ca, Cu and Zn, there were statistically significant differences between the epidermis and dermis using the freeze drying technique (p = 0.02, p < 0.01, and p < 0.01, respectively). Also using the formalin fixed, paraffin embedded technique the levels of Ca, Cu and Zn, were significantly different between the epidermis and dermis layers (p = 0.03, p < 0.01, and p < 0.01, respectively). However, the difference in levels of Fe between the epidermis and dermis was unclear and further analysis was required. The epidermis was further divided into two sub-layers, one mainly composed of the stratum corneum and the other deeper layer, the stratum basale. It was found that the difference between the distribution of Fe in the two epidermal layers using the freeze drying technique resulted in a statistically significant difference (p = 0.012). This same region also showed a difference in Fe using the formalin fixed, paraffin embedded technique (p < 0.01). The formalin fixed, paraffin embedded technique also showed a difference between the deeper epidermal layer and the dermis (p < 0.01). It can be concluded that studies involving Ca, Cu and Zn might show similar results using both sample preparation techniques, however studies involving Fe would need more special attention.


Reducing replacement donors in Sub-Saharan Africa: challenges and affordability.
In 1975, the World Health Assembly recommended that blood for transfusion should come from voluntary, non-remunerated donors; yet, in Africa, 75-80% of blood for transfusion still comes from hospital-based replacement donors. Although comprehensive economic data are scarce, evidence indicates that blood from voluntary donors recruited and screened at centralized transfusion centres, costs four to eight times as much as blood from a hospital-based, replacement donor system. Donor recruitment, quality assurance systems and distribution mechanisms in the centralized system are major reasons for the cost difference. There are concerns about the sustainability of centralized voluntary donor systems and their compatibility with the levels of health care that exist in many poor countries yet burdening patients' families with the responsibility of finding replacement blood donors will exacerbate poverty and reduce the safety of the blood supply. There are measures that can be introduced into hospital-based systems to improve safe blood supply in Africa but their effectiveness in different contexts needs to be evaluated.


Fibroblast growth factor-2 autofeedback regulation in pituitary folliculostellate TtT/GF cells.
To investigate paracrine regulation of pituitary cell growth, we tested fibroblast growth factor (FGF) regulation of TtT/GF folliculostellate (FS) cells. FGF-2, and FGF-4 markedly induced cell proliferation, evidenced by induction of pituitary tumor transforming gene-1 (Pttg1) mRNA expression and percentage of cells in S phase. Signaling for FGF-2-induced FS cell proliferation was explored by specific pharmacological inhibition. A potent inhibitory effect on FGF-2 action was observed by blocking of Src tyrosine kinase with 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d] pyrimidine (>or=0.1 microm), followed by protein kinase C (PKC) inhibition with GF109203X. Treatment with FGF-2 (30 ng/ml; 10 min) activated phosphorylation of signal transducer and activator of transcription-3, ERK, stress-activated protein kinase/c-Jun N-terminal kinase, Akt, and focal adhesion kinase. Src inhibition with 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d] pyrimidine suppressed FGF-2-induced Akt and focal adhesion kinase, indicating effects downstream of FGF-2-induced Src activation. FGF-2 also markedly induced its own mRNA expression, peaking at 2-4 h, and this effect was suppressed by Src tyrosine kinase inhibition. The PKC inhibitor GF109203X abolished FGF-2 autoinduction, indicating PKC as the primary pathway involved in FGF-2 autoregulation in these cells. In addition to pituitary FGF-2 paracrine activity on hormonally active cells, these results show an autofeedback mechanism for FGF-2 in non-hormone-secreting pituitary FS cells, inducing cell growth and its own gene expression, and mediated by Src/PKC signaling.


Traditional botanical knowledge of artisanal fishers in southern Brazil.
This study characterized the botanical knowledge of artisanal fishers of the Lami community, Porto Alegre, southern Brazil based on answers to the following question: Is the local botanical knowledge of the artisanal fishers of the rural-urban district of Lami still active, even since the district's insertion into the metropolitan region of Porto Alegre? This region, which contains a mosaic of urban and rural areas, hosts the Lami Biological Reserve (LBR) and a community of 13 artisanal fisher families. Semi-structured interviews were conducted with 15 fishers, complemented by participatory observation techniques and free-lists; in these interviews, the species of plants used by the community and their indicated uses were identified. A total of 111 species belonging to 50 families were identified. No significant differences between the diversities of native and exotic species were found. Seven use categories were reported: medicinal (49%), human food (23.2%), fishing (12.3%), condiments (8%), firewood (5%), mystical purposes (1.45%), and animal food (0.72%). The medicinal species with the highest level of agreement regarding their main uses (AMUs) were Aloe arborescens Mill., Plectranthus barbatus Andrews, Dodonaea viscosa Jacq., Plectranthus ornatus Codd, Eugenia uniflora L., and Foeniculum vulgare Mill. For illness and diseases, most plants were used for problems with the digestive system (20 species), followed by the respiratory system (16 species). This community possesses a wide botanical knowledge, especially of medicinal plants, comparable to observations made in other studies with fishing communities in coastal areas of the Atlantic Forest of Brazil. Ethnobotanical studies in rural-urban areas contribute to preserving local knowledge and provide information that aids in conserving the remaining ecosystems in the region.


Lixisenatide Versus Insulin Glulisine on Fasting and Postbreakfast Systemic Hemodynamics in Type 2 Diabetes Mellitus Patients.
The prolonged treatment effects of a short-acting GLP-1RA (glucagon-like peptide-1 receptor agonist), such as lixisenatide, on fasting and postprandial systemic hemodynamics in type 2 diabetes mellitus patients are unknown. In this secondary analysis, we included 34 overweight insulin glargine-treated type 2 diabetes mellitus patients (mean±SD age, 62±7 years; HbA1c, 8.0±0.9%; systolic blood pressure [BP], 133.9±16.1 mm Hg; diastolic BP, 75.4±8.39 mm Hg) that were randomized to once-daily lixisenatide 20 μg or once-daily titrated insulin glulisine for 8 weeks. Systemic hemodynamics (oscillometric device and finger photoplethysmography), arterial stiffness (applanation tonometry), and cardiac sympathovagal balance (heart rate variability) were measured in the fasting state and repetitively (up to minute 175) after a standardized mixed breakfast. Acetaminophen was given orally to estimate gastric emptying rate. Lixisenatide did not affect fasting systemic hemodynamics compared with insulin glulisine from baseline to week 8. Postbreakfast overall, lixisenatide compared with insulin glulisine tended to increase systolic BP by 5.2±2.9 mm Hg (P=0.087) and increased diastolic BP by 5.4±1.4 mm Hg (P<0.001), with respective maximal differences of +10.2±3.7 mm Hg (P=0.007) and +7.2±1.5 mm Hg (P<0.001). Lixisenatide increased systemic vascular resistance (P<0.001) and arterial stiffness (P=0.007). No between-group differences in overall postbreakfast heart rate, cardiac output, or cardiac sympathovagal balance, and circulating catecholamines, angiotensin II, or aldosterone were observed. Both treatments lowered HbA1c similarly, whereas lixisenatide achieved greater reductions in postbreakfast plasma glucose excursions. Lixisenatide slowed gastric emptying rate, which statistically explained changes in postbreakfast BP. Lixisenatide compared with once-daily titrated insulin glulisine for 8 weeks does not affect fasting but increases postbreakfast BP in insulin glargine-treated type 2 diabetes mellitus patients. This effect could, at least in part, be explained by reduced passage rate of nutrients and water and activation of the gastrovascular reflex.


Confidence in health care at what cost? Results from the 1998 Health Confidence Survey.
This Issue Brief presents the findings from the 1998 Health Confidence Survey. It focuses on Americans' satisfaction with the health care system and their confidence in the system's future. Only 5 percent of Americans give an excellent rating to health care in America today. However, while just over one-half rate health care as excellent, very good, or good, almost one-half (46 percent) rate it as fair or poor. When asked what they consider to be the most critical issue in America today, 15 percent of Americans cite health care. Overall, Americans are not extremely confident about various aspects of health care in the next 10 years. Only 10 percent are extremely confident that they will be able to get the medical treatments they need during this period, while 22 percent are not confident. Americans are even less confident that they will have access to quality health care (26 percent not confident), that they will have enough freedom to choose their health care provider (36 percent not confident), and that they will be able to afford health care without suffering financial hardship (41 percent not confident). The nonelderly population is even less confident about health care once they become eligible for Medicare. Americans are clearly confused about the meaning of managed care and whether they are enrolled in a managed care plan. While 70 percent of those who were determined to be enrolled in a managed care plan label the plan correctly, only 21 percent report that they are currently enrolled in a managed care plan. Most American have opinions about managed care. However, only 28 percent of Americans form their opinions about managed care based on their own personal experience. Twenty-three percent base their opinion on what they learn from family and friends, and 29 percent base it on what they hear or see in the media. While few Americans give managed care an excellent rating, few give it a poor rating. Most Americans rate managed care somewhere in the middle. Americans are particularly concerned about health care costs. Over 30 percent are not satisfied with the cost of their health insurance over the last 2 years, and 37 percent are not satisfied with the health care costs that are not covered by their health plan. These numbers compare with higher satisfaction levels concerning choice of physician, quality of care received, treatments received, hospitals used, and benefits covered by health plans.


Pre-employment screening among trainee bakers.
To assess the prevalence of atopy in a vocational school so as to evaluate the feasibility of pre-employment screening. The prevalence of atopy by family diathesis, prick tests, immunoglobulin E (IgE) concentrations, and personal history of allergic respiratory diseases was investigated in 144 trainee bakers and 81 students on a graphic artists course (mean age 15.4 years). Skin sensitisation to wheat, rye, and barley flours, to alpha amylase, and to storage mites was also evaluated. Personal allergic symptoms were reported by 13.2% of the bakers and 14.7% of the graphic artists and there was a significant association between symptoms and atopy by prick tests (odds ratio (OR) 17.2; 95% confidence interval (95% CI) 5.27-56.4) and by family history (OR 3.11; 95% CI 1.02-9.53). When bakers were grouped according to the presence of allergic symptoms and results of immunological tests, 6.9% had asthma, 6.3% had rhinoconjunctivitis, and a high percentage (28.5%) were without symptoms but scored positive on prick tests or family symptoms. Skin sensitisation to storage mites had similar prevalences (16%) in the two groups of trainees and occurred nearly always in atopic people. Positive skin tests to wheat flour (3.5%), rye (0.7%), and alpha amylase (0.7%) were specific to bakers. Pre-employment screening is a useful source of medical information and allows for counseling. The presence of asthma, or of another allergic disease in a severe form, is suggested as a criterion for excluding students of a vocational school from training as bakers. Student bakers without allergic symptoms but atopic by other criteria should be informed about their risks of developing occupational asthma, and periodic check ups must be recommended. Screening studies in vocational school provide a better understanding of specificity of skin sensitisation to occupational allergens.


Genetic and environmental risks for specific language impairment in children.
Specific language impairment (SLI) is the term used to refer to unexplained difficulties in language acquisition in children. Over the past decade, there has been rapid growth of evidence indicating that genes play an important part in the aetiology of SLI. However, further progress in elucidating the role of genes in causing SLI is limited by our lack of understanding of the phenotype. Studies to date have been hampered by the fact that we do not know whether SLI should be treated as a discrete disorder or a continuous variable, let alone which measures should be used to identify cases, or how many subtypes there are. Recent research suggests that theoretically motivated measures of underlying processes may be better than conventional clinical diagnoses for identifying aetiologically distinct types of language impairment. There has been a tendency for researchers to embrace parsimony and look for a single cause of SLI-or in any event, to identify different subtypes, each with a different single cause. Research is reviewed that suggests that may not be a fruitful approach to SLI, and that an approach in terms of multiple risk and protective factors, which is widely adopted in medicine, is more realistic.


Hybrid molecules combining GABA-A and serotonin 5-HT6 receptors activity designed to tackle neuroinflammation associated with depression.
There is clear evidence that the presence of inflammatory factors and impaired GABA-ergic neurotransmission in depressed patients is associated with poor clinical outcome. We designed hybrid molecules, bearing the GABA molecule assembled with chemical fragments that interact with the serotonin 5-HT6 receptor. Such a combination aimed to curb neuroinflammation, remodel GABA-ergic signaling, and provide antidepressant-like activity. The most promising hybrid 3B exerted nanomolar affinity for 5-HT6 receptors and exerted agonistic properties on GABA-A receptors. Developability studies conferred that 3B exerted favorable drug-like properties and optimal brain penetration. In in vivo studies, 3B exerted robust antidepressant-like activity and proved to be highly effective in reducing levels of oxidative stress markers and the pro-inflammatory cytokine IL-6. The inetersting pharmacological profile of 3B makes it a promising candidate for further development for depression associated with neuroinflammation.


Neoadjuvant Chemotherapy for Breast Cancer: Functional Tumor Volume by MR Imaging Predicts Recurrence-free Survival-Results from the ACRIN 6657/CALGB 150007 I-SPY 1 TRIAL.
To evaluate volumetric magnetic resonance (MR) imaging for predicting recurrence-free survival (RFS) after neoadjuvant chemotherapy (NACT) of breast cancer and to consider its predictive performance relative to pathologic complete response (PCR). This HIPAA-compliant prospective multicenter study was approved by institutional review boards with written informed consent. Women with breast tumors 3 cm or larger scheduled for NACT underwent dynamic contrast-enhanced MR imaging before treatment (examination 1), after one cycle (examination 2), midtherapy (examination 3), and before surgery (examination 4). Functional tumor volume (FTV), computed from MR images by using enhancement thresholds, and change from baseline (ΔFTV) were measured after one cycle and before surgery. Association of RFS with FTV was assessed by Cox regression and compared with association of RFS with PCR and residual cancer burden (RCB), while controlling for age, race, and hormone receptor (HR)/ human epidermal growth factor receptor type 2 (HER2) status. Predictive performance of models was evaluated by C statistics. Female patients (n = 162) with FTV and RFS were included. At univariate analysis, FTV2, FTV4, and ΔFTV4 had significant association with RFS, as did HR/HER2 status and RCB class. PCR approached significance at univariate analysis and was not significant at multivariate analysis. At univariate analysis, FTV2 and RCB class had the strongest predictive performance (C statistic = 0.67; 95% confidence interval [CI]: 0.58, 0.76), greater than for FTV4 (0.64; 95% CI: 0.53, 0.74) and PCR (0.57; 95% CI: 0.39, 0.74). At multivariate analysis, a model with FTV2, ΔFTV2, RCB class, HR/HER2 status, age, and race had the highest C statistic (0.72; 95% CI: 0.60, 0.84). Breast tumor FTV measured by MR imaging is a strong predictor of RFS, even in the presence of PCR and RCB class. Models combining MR imaging, histopathology, and breast cancer subtype demonstrated the strongest predictive performance in this study.


Role of tumour necrosis factor gene polymorphisms (-308 and -238) in breast cancer susceptibility and severity.
Genetic polymorphisms in the promoter region of the tumour necrosis factor (TNF) gene can regulate gene expression and have been associated with inflammatory and malignant conditions. We have investigated two polymorphisms in the promoter of the TNF gene (-308 G>A and -238 G>A) for their role in breast cancer susceptibility and severity by means of an allelic association study. Using a case-control study design, breast cancer patients (n = 709) and appropriate age-matched and sex-matched controls obtained from the Breast Screening Unit (n = 498) were genotyped for these TNF polymorphisms, using a high-throughput allelic discrimination method. Allele frequencies for both polymorphisms were similar in both breast cancer cases and controls. However, the -308 polymorphism was found to be associated with vascular invasion in breast tumours (P = 0.024). Comparison with other standard prognostic indices did not show any association for either genotype. We demonstrated no association between the -308G>A polymorphism and the -238G>A polymorphism in the promoter region of TNF and susceptibility to breast cancer, in a large North European population. However, the -308 G>A polymorphism was found to be associated with the presence of vascular invasion in breast tumours.


STAT1 and pathogens, not a friendly relationship.
STAT1 belongs to the STAT family of transcription factors, which comprises seven factors: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6. STAT1 is a 91 kDa protein originally identified as the mediator of the cellular response to interferon (IFN) alpha, and thereafter found to be a major component of the cellular response to IFNgamma. STAT1 is, in fact, involved in the response to several cytokines and to growth factors. It is activated by cytokine receptors via kinases of the JAK family. STAT1 becomes phosphorylated and forms a dimer which enters the nucleus and triggers the transcription of its targets. Although not lethal at birth, selective gene deletion of STAT1 in mice leads to rapid death from severe infections, demonstrating its major role in the response to pathogens. Similarly, in humans who do not express STAT1, there is a lack of resistance to pathogens leading to premature death. This indicates a key, non-redundant function of STAT1 in the defence against pathogens. Thus, to successfully infect organisms, bacterial, viral or parasitic pathogens must overcome the activity of STAT1, and almost all the steps of this pathway can be blocked or inhibited by proteins produced in infected cells. Interestingly, some pathogens, like the oncogenic Epstein-Barr virus, have evolved a strategy which uses STAT1 activation.


Paravertebral muscles in disease of the cervical spine.
Cervical spine disorders are common in the older population. The paravertebral muscles are essential to the support and stabilisation of the cervical spine but have been little studied. The aim was to determine whether pathological changes develop in these muscles in patients with severe cervical spine disease, which, if present, might contribute to the pathogenesis and symptomatology of their disorder. Open biopsies of superficial and deep paravertebral muscles were obtained during the course of surgical procedures to alleviate cervical myelopathy. Most of these patients had cervical spondylosis or rheumatoid arthritis involving the cervical spine. The biopsies were compared with muscle obtained at necropsy from patients without a history of cervical spine or neuromuscular disorder. Muscle from both the study and control groups showed a similar range and severity of abnormalities. In several patients, grouped fibre atrophy suggested chronic partial denervation. Most biopsies showed type 1 fibre predominance and selective type 2 fibre atrophy. Ragged red fibres were a frequent finding and electron microscopy disclosed accumulations of mitochondria, a small proportion of which contained rounded, or longitudinally oriented, single osmiophilic inclusions. Fibres containing core-like areas were also frequent. These pathological features were seen with increasing severity and frequency with increasing age. The paravertebral cervical muscles develop pathological abnormalities with increasing age with both neurogenic and myopathic features, the pathogenesis of which is probably multifactorial. Such a muscle disorder would be expected to be accompanied by functional impairment which may contribute to the development and symptomatology of cervical spine disease with increasing age.


Nutritional and functional importance of intestinal sulfur amino acid metabolism.
The metabolism of sulfur amino acids, methionine and cysteine, has been linked to several key aspects of human health and cellular function. In addition, the metabolism of dietary amino acids by the gastrointestinal tract is nutritionally important for normal function. In the case of sulfur amino acids (SAAs), in vivo, stable isotope studies in adults suggest that the splanchnic tissues utilize as much as 30-44% of the dietary methionine and cysteine. Similarly, the dietary methionine requirement is 30% lower in total parenteral nutrition (TPN)-fed piglets, a condition in which dietary nutrients largely bypass intestinal metabolism. These data suggest that intestinal metabolism of methionine is substantial, yet the intestinal metabolic fate of dietary methionine is largely unknown. Dietary cysteine likely plays a key role in intestinal epithelial antioxidant function as a precursor for glutathione. Moreover, cysteine and glutathione may also regulate epithelial cell proliferation via modulation of redox status. Recent evidence indicates that transformed colonic epithelial cells are capable of methionine transmethylation and transsulfuration. This review discusses the evidence of intestinal SAA metabolism and how this affects nutrient requirements and epithelial function.


Interactions of the antitumor agents mitoxantrone and bisantrene with deoxyribonucleic acids studied by electron microscopy.
The interactions of the low cardiotoxic antitumor agents 1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9, 10-anthracenedione (mitoxantrone) and 9,10-anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazoyl-2-yl)hydrazone] (bisantrene) with pBR322 and PM2 DNA have been examined by electron microscopy. Direct evidence was obtained for intercalative binding of both drugs, with mitoxantrone causing a 13% average length increase in pBR322 corresponding to approximately 580 drug molecules per circle at saturation and bisantrene causing an 11% increase in length corresponding to approximately 480 drug molecules bound per circle. Considerations of the known GC preference for non-nearest neighbor binding of the drugs and inspection of the known sequence of pBR322 suggest that the available intercalation sites are occupied and that additional external electrostatic binding of the cationic drugs also occurs. An apparent difference in behavior of mitoxantrone as compared with that of bisantrene in causing no net increase in length of supercoiled pBR322 was shown to be attributable to an offsetting compaction due to extensive supercoiling by mitoxantrone molecules. This conclusion was confirmed by independent experiments with PM2 covalently closed-circular DNA--both native, negatively supercoiled and relaxed--with calf thymus topoisomerase, using ethidium for comparison. Ethidium caused a 21.3 +/- 3.6% length increase in nicked, open-circular PM2-DNA, or 2100 molecules bound per 10,300 base pairs. Mitoxantrone caused a 16.6% length increase in nicked PM2-DNA equivalent to approximately 1700 drug molecules per circle. Electron microscopic measurements on relaxed PM2-DNA with progressively increasing proportions of mitoxantrone (from 1.4:1 to 14:1 drug molecules per base pair) revealed the onset of formation of lacelike networks of DNA circles linked together. This phenomenon, which is not produced by bisantrene, is attributed to inter-DNA links by the charged side arms of mitoxantrone and is in accord with previous reports that mitoxantrone causes severe compaction and distortion of chromatin. Electron microscopic examination of the interaction of six additional mitoxantrone derivatives, two of which produced lacelike DNA networks, revealed strict structural requirements for this phenomenon.


Using Survival Analysis to Understand Patterns of Sustainment within a System-Driven Implementation of Multiple Evidence-Based Practices for Children's Mental Health Services.
Evidence-based practice (EBP) implementation requires substantial resources in workforce training; yet, failure to achieve long-term sustainment can result in poor return on investment. There is limited research on EBP sustainment in mental health services long after implementation. This study examined therapists' continued vs. discontinued practice delivery based on administrative claims for reimbursement for six EBPs [Cognitive Behavioral Interventions for Trauma in Schools (CBITS), Child-Parent Psychotherapy, Managing and Adapting Practices (MAP), Seeking Safety (SS), Trauma-Focused Cognitive Behavior Therapy (TF-CBT), and Positive Parenting Program] adopted in a system-driven implementation effort in public mental health services for children. Our goal was to identify agency and therapist factors associated with a sustained EBP delivery. Survival analysis (i.e., Kaplan-Meier survival functions, log-rank tests, and Cox regressions) was used to analyze 19 fiscal quarters (i.e., approximately 57 months) of claims data from the Prevention and Early Intervention Transformation within the Los Angeles County Department of Mental Health. These data comprised 2,322,389 claims made by 6,873 therapists across 88 agencies. Survival time was represented by the time elapsed from therapists' first to final claims for each practice and for any of the six EBPs. Results indicate that therapists continued to deliver at least one EBP for a mean survival time of 21.73 months (median = 18.70). When compared to a survival curve of the five other EBPs, CBITS, SS, and TP demonstrated a higher risk of delivery discontinuation, whereas MAP and TF-CBT demonstrated a lower risk of delivery discontinuation. A multivariate Cox regression model revealed that agency (centralization and service setting) and therapist (demographics, discipline, and case-mix characteristics) characteristics were significantly associated with risk of delivery discontinuation for any of the six EBPs. This study illustrates a novel application of survival analysis to administrative claims data in system-driven implementation of multiple EBPs. Findings reveal variability in the long-term continuation of therapist-level delivery of EBPs and highlight the importance of both agency and workforce characteristics in the sustained delivery of EBPs. Findings direct the field to potential targets of sustainment interventions (e.g., strategic assignment of therapists to EBP training and strategic selection of EBPs by agencies).


Position-Specific Metabolic Probing and Metagenomics of Microbial Communities Reveal Conserved Central Carbon Metabolic Network Activities at High Temperatures.
Temperature is a primary driver of microbial community composition and taxonomic diversity; however, it is unclear to what extent temperature affects characteristics of central carbon metabolic pathways (CCMPs) at the community level. In this study, 16S rRNA gene amplicon and metagenome sequencing were combined with 13C-labeled metabolite probing of the CCMPs to assess community carbon metabolism along a temperature gradient (60-95°C) in Great Boiling Spring, NV. 16S rRNA gene amplicon diversity was inversely proportional to temperature, and Archaea were dominant at higher temperatures. KO richness and diversity were also inversely proportional to temperature, yet CCMP genes were similarly represented across the temperature gradient and many individual metagenome-assembled genomes had complete pathways. In contrast, genes encoding cellulosomes and many genes involved in plant matter degradation and photosynthesis were absent at higher temperatures. In situ 13C-CO2 production from labeled isotopomer pairs of glucose, pyruvate, and acetate suggested lower relative oxidative pentose phosphate pathway activity and/or fermentation at 60°C, and a stable or decreased maintenance energy demand at higher temperatures. Catabolism of 13C-labeled citrate, succinate, L-alanine, L-serine, and L-cysteine was observed at 85°C, demonstrating broad heterotrophic activity and confirming functioning of the TCA cycle. Together, these results suggest that temperature-driven losses in biodiversity and gene content in geothermal systems may not alter CCMP function or maintenance energy demands at a community level.


Flood risk and adaptation strategies under climate change and urban expansion: A probabilistic analysis using global data.
An accurate understanding of flood risk and its drivers is crucial for effective risk management. Detailed risk projections, including uncertainties, are however rarely available, particularly in developing countries. This paper presents a method that integrates recent advances in global-scale modeling of flood hazard and land change, which enables the probabilistic analysis of future trends in national-scale flood risk. We demonstrate its application to Indonesia. We develop 1000 spatially-explicit projections of urban expansion from 2000 to 2030 that account for uncertainty associated with population and economic growth projections, as well as uncertainty in where urban land change may occur. The projections show that the urban extent increases by 215%-357% (5th and 95th percentiles). Urban expansion is particularly rapid on Java, which accounts for 79% of the national increase. From 2000 to 2030, increases in exposure will elevate flood risk by, on average, 76% and 120% for river and coastal floods. While sea level rise will further increase the exposure-induced trend by 19%-37%, the response of river floods to climate change is highly uncertain. However, as urban expansion is the main driver of future risk, the implementation of adaptation measures is increasingly urgent, regardless of the wide uncertainty in climate projections. Using probabilistic urban projections, we show that spatial planning can be a very effective adaptation strategy. Our study emphasizes that global data can be used successfully for probabilistic risk assessment in data-scarce countries.


Advanced hip osteoarthritis: magnetic resonance imaging aspects and histopathology correlations.
To correlate magnetic resonance imaging (MRI) aspects of the femoral head with histological findings in advanced hip osteoarthritis (OA), with special emphasis on bone marrow edema (BME). MRI was performed in patients with advanced hip OA scheduled for hip arthroplasty. Coronal T1-, fat-suppressed T2-, T1 with gadolinium intravenous injection sequences were obtained on a 1.5 T MR-scanner within 1 month before surgery. Coronal MR images corresponding to the ligamentum teres plane were analyzed by two independent readers blinded to histological data. Normal bone marrow, subchondral cyst, subchondral fracture, edema-like, necrosis-like, and necrosis MR patterns were reported on a synthesis scheme. After surgery, the femoral heads specimens were cut through the ligamentum teres plane and histologically analyzed for correlations. Twenty-three femoral heads were analyzed (female 56.5%, mean age 64.5 years). Edema-like MR pattern was correlated with histological (H) edema (Kappa (K): 0.77). Necrosis-like MR pattern was correlated with H fibrosis (K: 0.49) and with H necrosis (K: 0.24). Cyst MR pattern was correlated with H bone cysts (K: 0.58). Necrosis MR pattern corresponded to a mixture of histological lesions. Sensitivity and specificity of MRI varied from 26% to 80% and from 86% to 95% respectively. In advanced hip OA, the so-called "BME" MR lesion corresponds to a combination of edema, fibrosis, and necrosis at histopathology. When the classical "BME" is more specifically separated into edema-like and necrosis-like MR patterns, MR Imaging and histological findings show substantial agreement, with edema-like MR pattern mainly corresponding to histological edema.


Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus.
Systemic lupus erythematosus (SLE) is an autoimmune disease, characterised by increased expression of type I interferon (IFN)-regulated genes and a striking sex imbalance towards females. Through combined genetic, in silico, in vitro, and ex vivo approaches, we define CXorf21, a gene of hitherto unknown function, which escapes X-chromosome inactivation, as a candidate underlying the Xp21.2 SLE association. We demonstrate that CXorf21 is an IFN-response gene and that the sexual dimorphism in expression is magnified by immunological challenge. Fine-mapping reveals a single haplotype as a potential causal cis-eQTL for CXorf21. We propose that expression is amplified through modification of promoter and 3'-UTR chromatin interactions. Finally, we show that the CXORF21 protein colocalises with TLR7, a pathway implicated in SLE pathogenesis. Our study reveals modulation in gene expression affected by the combination of two hallmarks of SLE: CXorf21 expression increases in a both an IFN-inducible and sex-specific manner.


Use of drinking protective behavioral strategies in association to sex-related alcohol negative consequences: the mediating role of alcohol consumption.
Alcohol use has been implicated as a risk factor for sexual negative consequences, such as unprotected sexual intercourse. The present research was conducted to examine the relationship between drinking protective behavioral strategies and consensual sex-related alcohol negative consequences, and whether this relationship varied by gender. Additionally, typical number of drinks during sexual behavior was evaluated as a potential mediator of this association. Heavy drinking, sexually active college students (N = 297, 50.2% women) completed self-report measures of drinking protective behavioral strategies, alcohol consumption, and sex-related alcohol negative consequences. Findings indicated that women who used drinking protective behavioral strategies more frequently were less likely to experience sex-related alcohol negative consequences whereas this relationship was not significant for men. For women, this relationship was mediated by the typical number of drinks consumed during sexual behavior. The current research demonstrates that use of drinking protective behavioral strategies is related to a reduction in women's sex-related risks when drinking. Findings are discussed in terms of alcohol myopia theory. Implications for interventions aimed to reduce higher risk sexual behavior among college students are discussed.


Flexible depth-of-field imaging system using a spatial light modulator.
A major problem of optical microscopes is their small depth-of-field (DOF), which hinders automation of micro object manipulation using visual feedback. Wavefront coding, a well-known method for extending DOF, is not suitable for direct application to micro object manipulation systems based on visual feedback owing to its expensive computational cost and due to a trade-off between the DOF and the image resolution properties. To solve such inherent problems, a flexible DOF imaging system using a spatial light modulator in the pupil plane is proposed. Especially, the trade-off relationship is quantitatively analyzed by experiments. Experimental results show that, for low criterion resolution, the DOF increases as the strength of the mask increases, while such a trend was not found for high criterion resolution. With high criterion resolution, the DOF decreases as the mask strength increases when high-resolution images are required. The results obtained can be used effectively to find the optimum mask strength given the desired image resolution.


Standardized Assessment of Biodiversity Trends in Tropical Forest Protected Areas: The End Is Not in Sight.
Extinction rates in the Anthropocene are three orders of magnitude higher than background and disproportionately occur in the tropics, home of half the world's species. Despite global efforts to combat tropical species extinctions, lack of high-quality, objective information on tropical biodiversity has hampered quantitative evaluation of conservation strategies. In particular, the scarcity of population-level monitoring in tropical forests has stymied assessment of biodiversity outcomes, such as the status and trends of animal populations in protected areas. Here, we evaluate occupancy trends for 511 populations of terrestrial mammals and birds, representing 244 species from 15 tropical forest protected areas on three continents. For the first time to our knowledge, we use annual surveys from tropical forests worldwide that employ a standardized camera trapping protocol, and we compute data analytics that correct for imperfect detection. We found that occupancy declined in 22%, increased in 17%, and exhibited no change in 22% of populations during the last 3-8 years, while 39% of populations were detected too infrequently to assess occupancy changes. Despite extensive variability in occupancy trends, these 15 tropical protected areas have not exhibited systematic declines in biodiversity (i.e., occupancy, richness, or evenness) at the community level. Our results differ from reports of widespread biodiversity declines based on aggregated secondary data and expert opinion and suggest less extreme deterioration in tropical forest protected areas. We simultaneously fill an important conservation data gap and demonstrate the value of large-scale monitoring infrastructure and powerful analytics, which can be scaled to incorporate additional sites, ecosystems, and monitoring methods. In an era of catastrophic biodiversity loss, robust indicators produced from standardized monitoring infrastructure are critical to accurately assess population outcomes and identify conservation strategies that can avert biodiversity collapse.


Retrievable vena cava filters: a clinical review.
Vena cava filters were developed as a method of preventing pulmonary embolism (PE) in patients with venous thromboembolism (VTE) at risk for bleeding from therapeutic anticoagulation. However, the long-term complications of filter placement, such as caval thrombosis, have mitigated some of the benefits, particularly in those patients with only a temporary contraindication to anticoagulation. Retrievable filters were designed to avoid the long-term risks of a permanent filter while still providing short-term protection against PE. As a result, their use has expanded from patients with known thrombosis to those without VTE who are at high risk for developing PE. In this review, we discuss the different types of retrievable filters, indications for their placement, complications that can occur during and after placement, and their use as prophylaxis in surgical patients. Although the use of retrievable filters in patients with known VTE is clear, further studies are needed to establish their prophylactic efficacy in the surgical patient. Until this evidence is available, we recommend that retrievable filters should be used only in patients with acute VTE who are at risk for recurrent thromboembolism and have a transient risk for bleeding.


Pathophysiology of ST-segment elevation myocardial infarction: novel mechanisms and treatments.
Despite major advances in mechanical and pharmacological reperfusion strategies to improve acute myocardial infarction (MI) injury, substantial mortality, morbidity, and socioeconomic burden still exists. To further reduce infarct size and thus ameliorate clinical outcome, the focus has also shifted towards early detection of MI with high-sensitive troponin assays, imaging, cardioprotection against pathophysiological targets of myocardial reperfusion injury with mechanical (ischaemic post-conditioning, remote ischaemic pre-conditioning, therapeutic hypothermia, and hypoxemia) and newer pharmacological interventions (atrial natriuretic peptide, cyclosporine A, and exenatide). Evidence from animal models of myocardial ischaemia and reperfusion also demonstrated promising results on more selective anti-inflammatory compounds that require additional validation in humans. Cardiac stem cell treatment also hold promise to reduce infarct size and negative remodelling of the left ventricle that may further improves symptoms and prognosis in these patients. This review focuses on the pathophysiology, detection, and reperfusion strategies of ST-segment elevation MI as well as current and future challenges to reduce ischaemia/reperfusion injury and infarct size that may result in a further improved outcome in these patients.


Genotypic identification of some lactic acid bacteria by amplified fragment length polymorphism analysis and investigation of their potential usage as starter culture combinations in Beyaz cheese manufacture.
In this study, 2 different starter culture combinations were prepared for cheesemaking. Starter culture combinations were formed from 8 strains of lactic acid bacteria. They were identified as Lactococcus lactis ssp. lactis (2 strains), Lactobacillus plantarum (5 strains), and Lactobacillus paraplantarum (1 strain) by amplified fragment length polymorphism analysis. The effects of these combinations on the physicochemical and microbiological properties of Beyaz cheeses were investigated. These cheeses were compared with Beyaz cheeses that were produced with a commercial starter culture containing Lc. lactis ssp. lactis and Lc. lactis ssp. cremoris as control. All cheeses were ripened in brine at 4 degrees C for 90 d. Dry matter, fat in dry matter, titratable acidity, pH, salt in dry matter, total N, water-soluble N, and ripening index were determined. Sodium dodecyl sulfate-PAGE patterns of cheeses showed that alpha(S)-casein and beta-casein degraded slightly during the ripening period. Lactic acid bacteria, total mesophilic aerobic bacteria, yeast, molds, and coliforms were also counted. All analyses were repeated twice during d 7, 30, 60, and 90. The starter culture combinations were found to be significantly different from the control group in pH, salt content, and lactobacilli, lactococci, and total mesophilic aerobic bacteria counts, whereas the cheeses were similar in fat, dry matter content, and coliform, yeast, and mold counts. The sensory analysis of cheeses indicated that textural properties of control cheeses presented somewhat lower scores than those of the test groups. The panelists preferred the tastes of treatment cheeses, whereas cheeses with starter culture combinations and control cheeses had similar scores for appearance and flavor. These results indicated that both starter culture combinations are suitable for Beyaz cheese production.


Mantle cell lymphoma diagnosed by conjunctival salmon-pink lesion biopsy.
Conjunctival lesions are rarely seen in mantle cell lymphoma. Here, we report a patient who developed bilateral conjunctival lesions in the course of chronic lymphocytic leukemia as an initial diagnosis, resulting in the final diagnosis of mantle cell lymphoma by conjunctival biopsy. A 66-year-old man developed conjunctival salmon-pink lesions on both sides in the 1.5-year course of chronic lymphocytic leukemia. He also had irregularly shaped masses with low tissue density in the orbital apex on both sides. Bilateral conjunctival biopsy showed subepithelial infiltration with lymphoid cells, positive for CD20, CD5, and cyclin D1, but negative for CD3, CD10, and CD23. Immunohistochemical restaining of the previous bone marrow biopsy specimen demonstrated lymphoid cells positive for cyclin D1, confirming the diagnosis of mantle cell lymphoma with leukemic presentation. As the case presenting stage IV lymphoma with systemic lymphadenopathy, he underwent 3 courses of combination chemotherapy with fludarabine and cyclophosphamide, and then 6 courses of bendamustine with rituximab, leading to complete remission for the following 3 years. In conclusion, mantle cell lymphoma should be included in the differential diagnosis of conjunctival salmon-pink lesions.


Ternary alloyed AgCl(x)Br(1-x) nanocrystals: facile modulation of electronic structures toward advanced photocatalytic performance.
Manipulating the electronic structure of semiconductor photocatalysts represents an ideal approach for the exploration and development of photocatalysis. However, it still remains a challenge in terms of silver halide photocatalysts. Herein, we report ternary alloyed AgClxBr1-x nanocrystals (NCs) synthesized by controlling the crystal growth process within a facile microemulsion system. The alloyed NCs crystallize in a homogeneous rock-salt crystal structure and possess tunable bandgaps from 2.5 to 3.0 eV obtained by varying the halogen mole ratios (Cl/Br). Their photocatalytic activities for dye degradation and CO2 reduction are found to depend strongly on the chemical compositions, and among them, the AgCl0.75Br0.25 sample exhibits the highest activity (about 2-4 times higher than AgCl and AgBr). Further theoretical calculations demonstrate that a decrease of the ratios of Cl/Br lowers the levels of the conduction band minimum and thereby narrows the bandgaps. Combining the theoretical and experimental results, the highest activity can be rationally ascribed to the optimum conduction band levels, which balances the overall effect of bandgap, electronic coupling and redox potential. This methodological exploration of engineering the bandgap of silver halide materials is a step forward toward the development of advanced photocatalysts and will shed light on devising various semiconductor photocatalytic systems.


Responses of young girls to two modes of aerobic training.
To investigate the physiological effects of two different three times a week, eight week training programmes on the aerobic fitness of nine to ten year old girls. Treadmill determined peak VO2, submaximal heart rates, and submaximal blood lactate were the criterion measures. Seventeen girls completed a programme of "aerobics" training where sessions lasted 20-25 minutes. Eighteen girls followed a cycle ergometer training programme which involved pedalling continuously for 20 minutes with the heart rate maintained between 160 and 170 beats/minute. A control group of 16 girls completed the criterion tests but did not train. In the cycle ergometer group and eight control subjects plasma total cholesterol and high density lipoprotein cholesterol were determined before and after training. Peak VO2 did not change significantly with training in either training group, neither were there any significant changes in submaximal heart rates. Blood lactate declined significantly at the two lowest submaximal exercise intensities in the cycle ergometer training group (from 2.3 (1.1) to 1.4 (0.06) mmol/l at stage 1 and from 2.1 (1.2) to 1.6 (0.06) mmol/l at stage 2; means (SD); P < 0.01). Total cholesterol and high density lipoprotein cholesterol remained unchanged with training. These findings suggest that an eight week structured exercise programme produces minimal changes in either the aerobic fitness or blood lipids of young girls. It may be more beneficial for long term health to promote enjoyment in activity and positive attitudes to exercise rather than attempting to enhance aerobic fitness through strenuous exercise programmes.


Chemoprevention of colon carcinogenesis by phenylethyl-3-methylcaffeate.
Previous studies from this laboratory have established that caffeic acid esters present in propolis, a natural resin produced by honey bees, are potent inhibitors of human colon adenocarcinoma cell growth, carcinogen-induced biochemical changes, and preneoplastic lesions in the rat colon. The present study was designed to investigate the chemopreventive action of dietary phenylethyl-3-methylcaffeate (PEMC) on azoxymethane-induced colon carcinogenesis and to examine the modulating effect of PEMC on phosphatidylinositol-specific phospholipase C (PI-PLC), phospholipase A2, lipoxygenase (LOX), and cyclooxygenase activities in the colonic mucosa and tumor tissues in male F344 rats. At 5 weeks of age, groups of rats were fed the control (modified AIN-76A) diet, or a diet containing 750 ppm of PEMC. At 7 weeks of age, all animals except those in the vehicle (normal saline)-treated groups were given 2 weekly s.c. injections of azoxymethane at a dose rate of 15 mg/kg body weight/week. All groups were maintained on their respective dietary regimen until the termination of the experiment 52 weeks after the carcinogen treatment. Colonic tumors were evaluated histopathologically. Both colonic mucosa and tumors were analyzed for PI-PLC, phospholipase A2, cyclooxygenase, and LOX activities. The results indicate that dietary administration of PEMC significantly inhibited the incidence and multiplicity of invasive, noninvasive, and total (invasive plus noninvasive) adenocarcinomas of the colon (P < 0.05-0.004). Dietary PEMC also suppressed the colon tumor volume by 43% compared to the control diet. Animals fed the PEMC diet showed significantly decreased activities of colonic mucosal and tumor PI-PLC (about 50%), but PEMC diet had no effect on phospholipase A2. The production of 5(S)-, 8(S)-, 12(S)-, and 15(S)-hydroxyeicosatetraenoic acids via the LOX pathway from arachidonic acid was reduced in colonic mucosa and tumors (30-60%) of animals fed the PEMC diet as compared to control diet. PEMC had no effect on the formation of colonic mucosal cyclooxygenase metabolites but inhibited the formation in colonic tumors by 15-30%. The precise mechanism by which PEMC inhibits colon tumorigenesis remains to be elucidated. It is likely that the chemopreventive action may be related, at least in part, to the modulation of PI-PLC-dependent signal transduction and LOX-mediated arachidonic acid metabolism.


Uropathogenic Escherichia coli AL511 requires flagellum to enter renal collecting duct cells.
Escherichia coli is the leading cause of urinary tract infections, but the mechanisms governing renal colonization by this bacterium remain poorly understood. We investigated the ability of 13 E. coli strains isolated from the urine of patients with pyelonephritis and cystitis and normal stools to invade collecting duct cells, which constitute the first epithelium encountered by bacteria ascending from the bladder. The AL511 clinical isolate adhered to mouse collecting duct mpkCCD(cl4) cells, used as a model of renal cell invasion, and was able to enter and persist within these cells. Previous studies have shown that bacterial flagella play an important role in host urinary tract colonization, but the role of flagella in the interaction of E. coli with renal epithelial cells remains unclear. An analysis of the ability of E. coli AL511 mutants to invade renal cells showed that flagellin played a key role in bacterial entry. Both flagellum filament assembly and the motor proteins MotA and MotB appeared to be required for E. coli AL511 uptake into collecting duct cells. These findings indicate that pyelonephritis-associated E. coli strains may invade renal collecting duct cells and that flagellin may act as an invasin in this process.


Identification and assessment of COPD exacerbations.
Chronic Obstructive Pulmonary Disease (COPD) exacerbations play a central role in the disease natural history of the disease, affecting its overall severity, decreasing pulmonary function, worsening underlying co-morbidities, impairing quality of life (QoL) and leading to severe morbidity and mortality. Therefore, identification and correct assessment of COPD exacerbations is paramount, given it will strongly influence therapy success. For the identification of exacerbations, several questionnaires exist, with varying degrees of complexity. However, most questionnaires remain of limited clinical utility, and symptom scales seem to be more useful in clinical practice. In the assessment of exacerbations, the type and degree of severity should be ascertained in order to define the management setting and optimize treatment options. Still, a consensual and universal classification system to assess the severity and type of an exacerbation is lacking, and there are no established criteria for less severely ill patients not requiring hospital assessment. This might lead to under-reporting of minor to moderate exacerbations, which has an impact on patients' health status. There is a clear unmet need to develop clinically useful questionnaires and a comprehensive system to evaluate the severity of exacerbations that can be used in all settings, from primary health care to general hospitals.


EIN2, a bifunctional transducer of ethylene and stress responses in Arabidopsis.
Ethylene regulates plant growth, development, and responsiveness to a variety of stresses. Cloning of the Arabidopsis EIN2 gene identifies a central component of the ethylene signaling pathway. The amino-terminal integral membrane domain of EIN2 shows similarity to the disease-related Nramp family of metal-ion transporters. Expression of the EIN2 CEND is sufficient to constitutively activate ethylene responses and restores responsiveness to jasmonic acid and paraquat-induced oxygen radicals to mutant plants. EIN2 is thus recognized as a molecular link between previously distinct hormone response pathways. Plants may use a combinatorial mechanism for assessing various stresses by enlisting a common set of signaling molecules.


Significance of specificity of Tinetti B-POMA test and fall risk factor in third age of life.
As for the third age, psychophysical abilities of humans gradually decrease, while the ability of adaptation to endogenous and exogenous burdens is going down. In 1987, "Harada" et al. (1) have found out that 9.5 million persons in USA have difficulties running daily activities, while 59% of them (which is 5.6 million) are older than 65 years in age. The study has encompassed 77 questioned persons of both sexes with their average age 71.73 +/- 5.63 (scope of 65-90 years in age), chosen by random sampling. Each patient has been questioned in his/her own home and familiar to great extent with the methodology and aims of the questionnaire. Percentage of questioned women was 64.94% (50 patients) while the percentage for men was 35.06% (27 patients). As for the value of risk factor score achieved conducting the questionnaire and B-POMA test, there are statistically significant differences between men and women, as well as between patients who fell and those who never did. As for the way of life (alone or in the community), there are no significant statistical differences. Average results gained through B-POMA test in this study are statistically significantly higher in men and patients who did not provide data about falling, while there was no statistically significant difference in the way of life. In relation to the percentage of maximum number of positive answers to particular questions, regarding gender, way of life and the data about falling, there were no statistically significant differences between the value of B-POMA test and the risk factor score (the questionnaire).


Nanoscale thermal-mechanical probe determination of 'softening transitions' in thin polymer films.
We report a quantitative study of the softening behavior of glassy polystyrene (PS) films at length scales on the order of 100 nm using nano-thermomechanometry (nano-TM), an emerging scanning probe technique in which a highly doped silicon atomic force microscopy (AFM) tip is resistively heated on the surface of a polymer film. The apparent 'softening temperature' T(s) of the film is found to depend on the logarithm of the square root of the thermal ramping rate R. This relation allows us to estimate a quasi-equilibrium (or zero rate) softening transition temperature T(s0) by extrapolation. We observe marked shifts of T(s0) with decreasing film thickness, but the nature of these shifts, and even their sign, depend strongly on both the thermal and mechanical properties of the supporting substrate. Finite element simulations suggest that thin PS films on rigid substrates with large thermal conductivities lead to increasing T(s0) with decreasing film thickness, whereas softer, less thermally conductive substrates promote reductions in T(s0). Experimental observations on a range of substrates confirm this behavior and indicate a complicated interplay between the thermal and mechanical properties of the thin PS film and the substrate. This study directly points to relevant factors for quantitative measurements of thermophysical properties of materials at the nanoscale using this nano-TM based method.


Risk of upper gastrointestinal bleeding from different drug combinations.
Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin increases the risk of upper gastrointestinal bleeding (UGIB). Guidelines suggest avoiding certain drug combinations, yet little is known about the magnitude of their interactions. We estimated the risk of UGIB during concomitant use of nonselective (ns)NSAIDs, cyclooxygenase -2 selective inhibitors (COX-2 inhibitors), and low-dose aspirin with other drugs. We performed a case series analysis of data from 114,835 patients with UGIB (930,888 person-years of follow-up) identified from 7 population-based health care databases (approximately 20 million subjects). Each patient served as his or her own control. Drug exposure was determined based on prescriptions of nsNSAIDs, COX-2 inhibitors, or low-dose aspirin, alone and in combination with other drugs that affect the risk of UGIB. We measured relative risk (incidence rate ratio [IRR] during drug exposure vs nonexposure) and excess risk due to concomitant drug exposure (relative excess risk due to interaction [RERI]). Monotherapy with nsNSAIDs increased the risk of diagnosis of UGIB (IRR, 4.3) to a greater extent than monotherapy with COX-2 inhibitors (IRR, 2.9) or low-dose aspirin (IRR, 3.1). Combination therapy generally increased the risk of UGIB; concomitant nsNSAID and corticosteroid therapies increased the IRR to the greatest extent (12.8) and also produced the greatest excess risk (RERI, 5.5). Concomitant use of nsNSAIDs and aldosterone antagonists produced an IRR for UGIB of 11.0 (RERI, 4.5). Excess risk from concomitant use of nsNSAIDs with selective serotonin reuptake inhibitors (SSRIs) was 1.6, whereas that from use of COX-2 inhibitors with SSRIs was 1.9 and that for use of low-dose aspirin with SSRIs was 0.5. Excess risk of concomitant use of nsNSAIDs with anticoagulants was 2.4, of COX-2 inhibitors with anticoagulants was 0.1, and of low-dose aspirin with anticoagulants was 1.9. Based on a case series analysis, concomitant use of nsNSAIDs, COX-2 inhibitors, or low-dose aspirin with SSRIs significantly increases the risk of UGIB. Concomitant use of nsNSAIDs or low-dose aspirin, but not COX-2 inhibitors, with corticosteroids, aldosterone antagonists, or anticoagulants produces significant excess risk of UGIB.


Electroencephalography in Normotensive and Hypertensive Pregnancies and Subsequent Quality of Life.
To compare electroencephalography (EEG) findings during pregnancy and postpartum in women with normotensive pregnancies and pregnancies complicated by hypertensive disorders. Also the health related quality of life postpartum was related to these EEG findings. An observational case-control study in a university hospital in the Netherlands. Twenty-nine normotensive and 58 hypertensive pregnant women were included. EEG's were recorded on several occasions during pregnancy and 6-8 weeks postpartum. Postpartum, the women filled out health related quality of life questionnaires. Main outcome measures were qualitative and quantitative assessments on EEG, multidimensional fatigue inventory, Short Form (36) Health Survey and EuroQoL visual analogue scale. In women with severe preeclampsia significantly lower alpha peak frequency, more delta and theta activity bilaterally and a higher EEG Sum Score were seen. Postpartum, these women showed impaired mental health, mental fatigue and social functioning, which could not be related to the EEG findings. Severe preeclamptic patients show more EEG abnormalities and have impaired mental wellbeing postpartum, but these findings are not correlated.


Mineral deposition in the extracellular matrices of vertebrate tissues: identification of possible apatite nucleation sites on type I collagen.
The possible means by which type I collagen may mediate mineralization in normal vertebrate bone, tendon, dentin and cementum as well as in pathological mineral formation are not fully understood. One consideration in this regard is that the structure of the protein is somehow important in binding calcium and phosphate ions in a stereochemical configuration conducive to nucleation of apatite crystals. In the present study, type I collagen, packed in a quarter-staggered arrangement in two dimensions and a quasi-hexagonal model of microfibrillar assembly in three dimensions, has been examined in terms of several of its charged amino acid residues. These included glutamic and aspartic acid, lysine, arginine, hydroxylysine and histidine, whose positions along the three alpha-chain axes of the collagen molecule were determined with respect to each other. It was found that the locations of these residues specified sites uniquely suited as potential apatite nucleation centers following binding of calcium and phosphate ions. From this analysis, it would appear that type I collagen provides a template of charged amino acid residues that dictates ion binding critical to subsequent nucleation events for mineral formation in vertebrate tissues.


Use of paracetamol during pregnancy and child neurological development.
Paracetamol (acetaminophen) remains the first line for the treatment of pain and fever in pregnancy. Recently published epidemiological studies suggested a possible association between paracetamol exposure in utero and attention-deficit-hyperactivity disorder/hyperkinetic disorder (ADHD/HKD) or adverse development issues in children. However, the effects observed are in the weak to moderate range, and limitations in the studies' design prevent inference on a causal association with ADHD/HKD or child neurological development. In parallel, recent animal data showed that cognition and behaviour may be altered following exposure to therapeutic doses of paracetamol during early development. These effects may be mediated by interference of paracetamol with brain-derived neurotrophic factor, neurotransmitter systems (including serotonergic, dopaminergic, adrenergic, as well as the endogenous endocannabinoid systems), or cyclooxygenase-2. However, no firm conclusion can be made on the relevance of these observations to humans. We conclude that additional well-designed cohort studies are necessary to confirm or disprove the association. In the context of current knowledge, paracetamol is still to be considered safe in pregnancy and should remain the first-line treatment for pain and fever.


Global glomerulosclerosis with nephrotic syndrome; the clinical importance of age adjustment.
Globally sclerotic glomeruli (GSG) occur with both normal aging and kidney disease. However, it is unknown whether any GSG or only GSG exceeding that expected for age is clinically important. To evaluate this, we identified patients with a glomerulopathy that often presents with nephrotic syndrome (focal segmental glomerulosclerosis, membranous nephropathy, or minimal change disease) in the setting of the Nephrotic Syndrome Study Network (NEPTUNE), China-Digital Kidney Pathology (DiKiP), and the Southeast Minnesota cohorts. Age-based thresholds (95th percentile) for GSG based on normotensive living kidney donors were used to classify each patient into one of three groups; no GSG, GSG normal for age, or GSG abnormal for age. The risk of end-stage renal disease or a 40% decline in glomerular filtration rate during follow-up was then compared between groups. Among the 425 patients studied, 170 had no GSG, 107 had GSG normal for age, and 148 had GSG abnormal for age. Compared to those with no GSG, the risk of kidney disease progression with GSG normal for age was similar but was significantly higher with GSG abnormal for age. This increased risk with GSG abnormal for age remained significant after adjustment for interstitial fibrosis, arteriosclerosis, age, hypertension, diabetes, body mass index, glomerulopathy type, glomerular filtration rate, and proteinuria. Thus, in patients with glomerulopathy that often presents with nephrotic syndrome, global glomerulosclerosis is clinically important only if it exceeds that expected for age.


Bones and Joints: The Effects of Cannabinoids on the Skeleton.
The endocannabinoid system uses tissue-specific lipid ligands and G protein‒coupled transmembrane receptors to regulate neurologic, metabolic, and immune responses. Recent studies demonstrate that the endocannabinoid system influences bone metabolism. With the increasing use of endocannabinoid mimetics (e.g., tetrahydrocannabinol and cannabidiol), the involvement of endocannabinoids in bone growth and remodeling has become clinically relevant. This literature review is based on a search of PubMed and Google Scholar databases as of June 2019 for all English-language publications relating to cannabinoids and bone. We evaluated retrieved articles for relevance, experimental design, data acquisition, statistical analysis, and conclusions. Preclinical studies establish a role for endocannabinoids in bone metabolism. These studies yield complex and often contradictory results attributed to differences in the specific experimental model examined. Studies using human cells or subjects are limited. In vitro and animal models document that endocannabinoids are involved in bone biology. The relevance of these observations to humans is not clear. The increasing long-term use of medical and recreational cannabis underscores the need to better understand the role of endocannabinoids in human bone metabolism. Moreover, it is important to evaluate the role of endocannabinoids as a therapeutic target to prevent and treat disorders associated with bone loss.


Motivational counselling and SMS-reminders for reduction of daily sitting time in patients with rheumatoid arthritis: a descriptive randomised controlled feasibility study.
Patients with rheumatoid arthritis (RA) spend a high proportion of their waking time in sedentary behaviour (SB) and have an increased risk of cardiovascular disease. Reduction of SB and increase in light intensity physical activity has been suggested as a means of improvement of health in patients with mobility problems. Short-term intervention studies have demonstrated that SB can be reduced by behavioural interventions in sedentary populations. To evaluate descriptively the feasibility of recruitment, randomisation, outcome assessments, retention and the acceptability of an individually tailored, theory-based behavioural intervention targeting reduction in daily sitting time in patients with RA. A randomised, controlled trial with two parallel groups. RA patients >18 years of age and Health Assessment Questionnaire (HAQ) score < 2.5 were consecutively invited and screened for daily leisure time sitting > 4 h. The 16-week intervention included 1) three individual motivational counselling sessions and 2) individual text message reminders aimed at reducing daily sitting time. The control group was encouraged to maintain their usual lifestyles. Outcomes were assessed at baseline and after the 16 week intervention. Daily sitting time was measured using an ActivPAL3TM activity monitor. The study was not powered to show superiority; rather the objective was to focus on acceptability among patients and clinical health professionals. In total, 107 patients were invited and screened before 20 met eligibility criteria and consented; reasons for declining study participation were mostly flares, lack of time and co-morbidities. One patient from the control group dropped out before end of intervention (due to a RA flare). Intervention participants completed all counselling sessions. All procedures regarding implementation of the trial protocol were feasible. The daily sitting time was reduced on average by 0.30 h in the intervention group unlike the control group that tended to increase it by 0.15 h after 16 weeks. This study shows that an individually tailored behavioural intervention targeting reduction of SB was feasible and acceptable to patients with RA. The Danish Data Protection Agency (ref.nb. 711-1-08 - 20 March 2011), the Ethics Committee of the Capital Region of Denmark (ref.nb. H-2-2012-112- 17 October 2012), clinicaltrials.gov ( NCT01969604 - October 17 2013, retrospectively registered).


Restricted ketogenic diet enhances the therapeutic action of N-butyldeoxynojirimycin towards brain GM2 accumulation in adult Sandhoff disease mice.
Sandhoff disease is an autosomal recessive, neurodegenerative disease involving the storage of brain ganglioside GM2 and asialo-GM2. Previous studies showed that caloric restriction, which augments longevity, and N-butyldeoxynojirimycin (NB-DNJ, Miglustat), an imino sugar that hinders the glucosyltransferase catalyzing the first step in glycosphingolipid biosynthesis, both increase longevity and improve motor behavior in the beta-hexosaminidase (Hexb) knockout (-/-) murine model of Sandhoff disease. In this study, we used a restricted ketogenic diet (KD-R) and NB-DNJ to combat ganglioside accumulation. Adult Hexb-/- mice were placed into one of the following groups: (i) a standard diet (SD), (ii) a SD with NB-DNJ (SD + NB-DNJ), (iii) a KD-R, and (iv) a KD-R with NB-DNJ (KD-R + NB-DNJ). Forebrain GM2 content (mug sialic acid/100 mg dry wt) in the four groups was 375 +/- 15, 312 +/- 8, 340 +/- 28, and 279 +/- 26, respectively, indicating an additive interaction between NB-DNJ and the KD-R. Most interestingly, brain NB-DNJ content was 3.5-fold greater in the KD-R + NB-DNJ mice than in the SD + NB-DNJ mice. These data suggest that the KD-R and NB-DNJ may be a potential combinatorial therapy for Sandhoff disease by enhancing NB-DNJ delivery to the brain and may allow lower dosing to achieve the same degree of efficacy as high dose monotherapy.


Analgesic Effect of Indian Gooseberry (Emblica officinalis Fruit) Extracts on Postoperative and Neuropathic Pain in Rats.
Indian gooseberry (Emblica officinalis fruit), also known as "Amla" is one of the oldest edible fruits known in India. It has also traditionally been used to treat inflammation, and as an analgesic to treat wounds. However, experimental evidence for the analgesic effects of E. officinalis has been lacking. The present study investigated whether E. officinalis extracts exhibit analgesic effects in the plantar incision (PI) and spared nerve injury (SNI) pain-model rats. We evaluated the mechanical withdrawal threshold (MWT) using von Frey filaments, and pain-related behavior was determined after surgery based on ultrasonic vocalization (USV). The group treated with E. officinalis extracts at 300 mg/kg had significantly increased MWT values at 6 h and 24 h after the PI, and had a significantly reduced number of 22-27-kHz USVs at 6 h and 24 h after PI. Moreover, after 15 days of continuous treatment with E. officinalis extracts, the treated group showed significantly alleviated SNI-induced hypersensitivity and reduced pro-inflammatory cytokine levels. Thus, E. officinalis extracts have potential analgesic effects in both postoperative and neuropathic pain models in vivo.


Pharmacologic management of neuropathic pain: evidence-based recommendations.
Patients with neuropathic pain (NP) are challenging to manage and evidence-based clinical recommendations for pharmacologic management are needed. Systematic literature reviews, randomized clinical trials, and existing guidelines were evaluated at a consensus meeting. Medications were considered for recommendation if their efficacy was supported by at least one methodologically-sound, randomized clinical trial (RCT) demonstrating superiority to placebo or a relevant comparison treatment. Recommendations were based on the amount and consistency of evidence, degree of efficacy, safety, and clinical experience of the authors. Available RCTs typically evaluated chronic NP of moderate to severe intensity. Recommended first-line treatments include certain antidepressants (i.e., tricyclic antidepressants and dual reuptake inhibitors of both serotonin and norepinephrine), calcium channel alpha2-delta ligands (i.e., gabapentin and pregabalin), and topical lidocaine. Opioid analgesics and tramadol are recommended as generally second-line treatments that can be considered for first-line use in select clinical circumstances. Other medications that would generally be used as third-line treatments but that could also be used as second-line treatments in some circumstances include certain antiepileptic and antidepressant medications, mexiletine, N-methyl-D-aspartate receptor antagonists, and topical capsaicin. Medication selection should be individualized, considering side effects, potential beneficial or deleterious effects on comorbidities, and whether prompt onset of pain relief is necessary. To date, no medications have demonstrated efficacy in lumbosacral radiculopathy, which is probably the most common type of NP. Long-term studies, head-to-head comparisons between medications, studies involving combinations of medications, and RCTs examining treatment of central NP are lacking and should be a priority for future research.


How Often Do Patients with Localized Melanoma Attend Follow-Up at a Specialist Center?
Post-treatment follow-up for patients with American Joint Committee on Cancer (AJCC) stage I/II melanoma is believed to be important for early detection of disease recurrence and new primary melanomas, but comes with costs to both patients and healthcare providers. We aimed to determine how frequently a cohort of patients attended follow-up after surgical treatment at one Specialist Center. We used prospectively collected data from the Melanoma Institute Australia (MIA) for patients with AJCC stage I/II melanoma diagnosed between January 2008 and December 2011. The distribution of the number of recorded follow-up visits per patient was analyzed and compared with the number of follow-up visits recommended in the 2008 Australian and New Zealand Melanoma Management Guidelines. A total of 3813 patients with stage I/II melanoma were identified. During the first year of follow-up post-surgery, 34 % of stage I patients and 14 % of stage II patients had the number of follow-up visits recommended in the guidelines. A large proportion of melanoma patients did not appear to be routinely followed up at MIA, with 43.2 % of stage I patients and 28.7 % of stage II patients having either no visit or only one visit post-surgery. During all years of follow-up, 13.2 % of stage I patients and 4.1 % of stage II patients had the number of follow-up visits at the specialist center as recommended in the guidelines. The large proportion of patients who had fewer follow-up visits than expected suggests (i) many patients are followed up in clinics elsewhere, and/or (ii) post-surgical surveillance is less frequent in practice.


Unilateral medial frontal cortex lesions cause a cognitive decision-making deficit in rats.
The medial frontal cortex (MFC) is critical for cost-benefit decision-making. Generally, cognitive and reward-based behaviour in rodents is not thought to be lateralised within the brain. In this study, however, we demonstrate that rats with unilateral MFC lesions show a profound change in decision-making on an effort-based decision-making task. Furthermore, unilateral MFC lesions have a greater effect when the rat has to choose to put in more effort for a higher reward when it is on the contralateral side of space to the lesion. Importantly, this could not be explained by motor impairments as these animals did not show a turning bias in separate experiments. In contrast, rats with unilateral dopaminergic midbrain lesions did exhibit a motoric turning bias, but were unimpaired on the effort-based decision-making task. This rare example of a cognitive deficit caused by a unilateral cortical lesion in the rat brain indicates that the MFC may have a specialised and lateralised role in evaluating the costs and benefits of actions directed to specific spatial locations.