Adverse effects of systemic cancer therapy on skeletal muscle: myotoxicity comes out of the closet.

PURPOSE OF REVIEW: Systemic cancer therapy-associated skeletal muscle wasting is emerging as a powerful impetus to the overall loss of skeletal muscle experienced by patients with cancer. This review explores the clinical magnitude and biological mechanisms of muscle wasting during systemic cancer therapy to illuminate this adverse effect. Emerging strategies for mitigation are also discussed. RECENT FINDINGS: Clinical findings include precise, specific measures of muscle loss over the course of chemotherapy, targeted therapy and immunotherapy. All these therapeutic classes associate with quantitatively important muscle loss, independent of tumor response. Parallel experimental studies provide understanding of the specific molecular basis of wasting, which can include inhibition of protein synthesis, proliferation and differentiation, and activation of inflammation, reactive oxygen species, autophagy, mitophagy, apoptosis, protein catabolism, fibrosis and steatosis in muscle. Strategies to mitigate these muscle-specific adverse effects of cancer therapy remain in the earliest stages of development. SUMMARY: The adverse side effect of cancer therapy on skeletal muscle has been largely ignored in the development of cancer therapeutics. Given the extent to which loss of muscle mass and function can bear on patients' function and quality of life, protection/mitigation of these side effects is a research priority.

Acly Deficiency Enhances Myelopoiesis through Acetyl Coenzyme A and Metabolic-Epigenetic Cross-Talk.

Hematopoiesis integrates cytokine signaling, metabolism, and epigenetic modifications to regulate blood cell generation. These processes are linked, as metabolites provide essential substrates for epigenetic marks. In this study, we demonstrate that ATP citrate lyase (Acly), which metabolizes citrate to generate cytosolic acetyl-CoA and is of clinical interest, can regulate chromatin accessibility to limit myeloid differentiation. Acly was tested for a role in murine hematopoiesis by small-molecule inhibition or genetic deletion in lineage-depleted, c-Kit-enriched hematopoietic stem and progenitor cells from Mus musculus. Treatments increased the abundance of cell populations that expressed the myeloid integrin CD11b and other markers of myeloid differentiation. When single-cell RNA sequencing was performed, we found that Acly inhibitor-treated hematopoietic stem and progenitor cells exhibited greater gene expression signatures for macrophages and enrichment of these populations. Similarly, the single-cell assay for transposase-accessible chromatin sequencing showed increased chromatin accessibility at genes associated with myeloid differentiation, including CD11b, CD11c, and IRF8. Mechanistically, Acly deficiency altered chromatin accessibility and expression of multiple C/EBP family transcription factors known to regulate myeloid differentiation and cell metabolism, with increased Cebpe and decreased Cebpa and Cebpb. This effect of Acly deficiency was accompanied by altered mitochondrial metabolism with decreased mitochondrial polarization but increased mitochondrial content and production of reactive oxygen species. The bias to myeloid differentiation appeared due to insufficient generation of acetyl-CoA, as exogenous acetate to support alternate compensatory pathways to produce acetyl-CoA reversed this phenotype. Acly inhibition thus can promote myelopoiesis through deprivation of acetyl-CoA and altered histone acetylome to regulate C/EBP transcription factor family activity for myeloid differentiation.

Evolutionary origins of the prolonged extant squamate radiation.

Squamata is the most diverse clade of terrestrial vertebrates. Although the origin of pan-squamates lies in the Triassic, the oldest undisputed members of extant clades known from nearly complete, uncrushed material come from the Cretaceous. Here, we describe three-dimensionally preserved partial skulls of two new crown lizards from the Late Jurassic of North America. Both species are placed at the base of the skink, girdled, and night lizard clade Pan-Scincoidea, which consistently occupies a position deep inside the squamate crown in both morphological and molecular phylogenies. The new lizards show that several features uniting pan-scincoids with another major lizard clade, the pan-lacertoids, in trees using morphology were convergently acquired as predicted by molecular analyses. Further, the palate of one new lizard bears a handful of ancestral saurian characteristics lost in nearly all extant squamates, revealing an underappreciated degree of complex morphological evolution in the early squamate crown. We find strong evidence for close relationships between the two new species and Cretaceous taxa from Eurasia. Together, these results suggest that early crown squamates had a wide geographic distribution and experienced complicated morphological evolution even while the Rhynchocephalia, now solely represented by the tuatara, was the dominant clade of lepidosaurs.

Inhibition of the AT1R agonistic autoantibody in a rat model of preeclampsia improves fetal growth in late gestation.

Placenta ischemia, the initiating event in preeclampsia (PE), is associated with fetal growth restriction. Inhibition of the agonistic autoantibody against the angiotensin type 1 receptor AT1-AA, using an epitope-binding inhibitory peptide ('n7AAc') attenuates increased blood pressure at gestational day (G)19 in the clinically relevant reduced uterine perfusion pressure (RUPP) model of PE. Thus we tested the hypothesis that maternal administration of 'n7AAc' does not transfer to the fetus, improves uterine blood flow and fetal growth, and attenuates elevated placental expression of miRNAs implicated in PE and FGR. Sham or RUPP surgery was performed at G14 with vehicle or 'n7AAc' (144 µg/day) administered via an osmotic pump from G14 to G20. Maternal plasma levels of the peptide on G20 were 16.28 ± 4.4 nM, and fetal plasma levels were significantly lower at 1.15 ± 1.7 nM (P = 0.0007). The uterine artery resistance index was significantly elevated in RUPP (P < 0.0001) but was not increased in 'n7AAc'-RUPP or 'n7AAc'-Sham versus Sham. A significant reduction in fetal weight at G20 in RUPP (P = 0.003) was not observed in 'n7AAc'-RUPP. Yet, percent survival was reduced in RUPP (P = 0.0007) and 'n7AAc'-RUPP (P < 0.0002). Correlation analysis indicated the reduction in percent survival during gestation was specific to the RUPP (r = 0.5342, P = 0.043) and independent of 'n7AAc'. Placental miR-155 (P = 0.0091) and miR-181a (P = 0.0384) expression was upregulated in RUPP at G20 but was not elevated in 'n7AAc'-RUPP. Collectively, our results suggest that maternal administration of 'n7AAc' does not alter fetal growth in the RUPP implicating its potential as a therapeutic for the treatment of PE.NEW & NOTEWORTHY The seven amino acid inhibitory peptide to the AT1-AA ('n7AAc') has limited transfer to the fetus at gestational day 20, improves uterine blood flow and fetal growth in the reduced uterine perfusion pressure model of preeclampsia (PE), and does not impair fetal survival during gestation in sham-operated or placental ischemic rats. Collectively, these findings suggest that maternal administration of 'n7AAc' as an effective strategy for the treatment of PE is associated with improved outcomes in the fetus.

Evaluating the effectiveness and acceptability of information and therapy guides for improving the psychosocial well-being of people with facial palsy.

OBJECTIVES: Facial palsy (FP) can have a negative impact on an individual's psychological and social well-being, irrespective of esthetic severity. There is a lack of psychological interventions tailored specifically for this population and individuals with FP report difficulties accessing specialist psychological treatment. This paper describes a pilot study evaluating the effectiveness, acceptability, and feasibility of information and therapy guides for this population. DESIGN: Quasi-experimental, repeated measures design. METHODS: Six separate information and therapy guides were designed, drawing on cognitive behavioral therapy, acceptance and commitment therapy, and social skills training approaches. These were tested by 132 participants with FP, over a 4-to-6-week period. Participants completed self-report measures assessing psychological well-being, social function, and appearance-related distress before and after the testing period, as well as provided feedback on the perceived effectiveness, acceptability, and feasibility of the intervention. RESULTS: After completing an information and therapy guide, participants reported significant improvements in psychological well-being and social function, as well as improvements in appearance-related distress. Ninety percent of participants reported having found it helpful to complete a guide, while 79.7% reported feeling more able to cope with FP and 95.3% agreed that the guide had been easy to understand and use. CONCLUSIONS: Self-guided information and therapy guides are an acceptable and effective intervention for improving the psychosocial well-being of people with FP. They provide a low-intensity, universal, and cost-effective option for supporting the psychological needs of this population. CLINICAL TRIAL REGISTRATION NUMBER: NCT03943953.

Barriers to cancer nutrition therapy: excess catabolism of muscle and adipose tissues induced by tumour products and chemotherapy.

Cancer-associated malnutrition is driven by reduced dietary intake and by underlying metabolic changes (such as inflammation, anabolic resistance, proteolysis, lipolysis and futile cycling) induced by the tumour and activated immune cells. Cytotoxic and targeted chemotherapies also elicit proteolysis and lipolysis at the tissue level. In this review, we summarise specific mediators and chemotherapy effects that provoke excess proteolysis in muscle and excess lipolysis in adipose tissue. A nutritionally relevant question is whether and to what degree these catabolic changes can be reversed by nutritional therapy. In skeletal muscle, tumour factors and chemotherapy drugs activate intracellular signals that result in the suppression of protein synthesis and activation of a transcriptional programme leading to autophagy and degradation of myofibrillar proteins. Cancer nutrition therapy is intended to ensure adequate provision of energy fuels and a complete repertoire of biosynthetic building blocks. There is some promising evidence that cancer- and chemotherapy-associated metabolic alterations may also be corrected by certain individual nutrients. The amino acids leucine and arginine provided in the diet at least partially reverse anabolic suppression in muscle, while n-3 PUFA inhibit the transcriptional activation of muscle catabolism. Optimal conditions for exploiting these anabolic and anti-catabolic effects are currently under study, with the overall aim of net improvements in muscle mass, functionality, performance status and treatment tolerance.

Neuropathic pain post spinal cord injury part 2: systematic review of dorsal root entry zone procedure.

BACKGROUND: Pharmacotherapy may not sufficiently reduce neuropathic pain in many individuals post spinal cord injury (SCI). The use of alternative therapies such as surgery may be effective in reducing neuropathic pain in these individuals. However, because of the invasive nature of surgery, it is important to examine the evidence for use of this treatment. OBJECTIVE: The purpose of this study was to conduct a systematic review of published literature on the surgical treatment of neuropathic pain after SCI. METHODS: MEDLINE, CINAHL, EMBASE, and PsycINFO databases were searched for articles in which surgical treatment of pain after SCI was examined. Articles were restricted to the English language. Article selection was conducted by 2 independent reviewers with the following inclusion criteria: the subjects participated in a surgical intervention for neuropathic pain; at least 50% of the subjects had an SCI; at least 3 subjects had an SCI; and a definable intervention involving the dorsal root entry zone (DREZ) procedure was used to reduce pain. Data extracted included study design, study type, subject demographics, inclusion and exclusion criteria, sample size, outcome measures, and study results. Randomized controlled trials (RCTs) were assessed for quality using the Physiotherapy Evidence Database (PEDro) assessment scale. Levels of evidence were assigned to each intervention using a modified Sackett scale. RESULTS: Eleven studies met the inclusion criteria. One study provided level 2 evidence, and the rest provided level 4 evidence. The DREZ procedure was shown to be more effective for segmental pain than for diffuse pain after SCI. Further, individuals with conus medullaris level injury were found to have a higher level of neuropathic pain relief than those with cervical, thoracic, or cauda equina injury. CONCLUSIONS: The studies demonstrated that the DREZ procedure may be effective in reducing segmental pain. Hence, DREZ may be important in treatment of neuropathic pain in individuals resistant to less invasive treatments. Because the studies lacked control conditions and examination of long-term effects, there is a need for larger trials with more stringent conditions.

The endoplasmic reticulum stress marker CHOP predicts survival in malignant mesothelioma.

BACKGROUND: Mesothelioma is an incurable cancer originating from the mesothelial cells that line the pleural, peritoneal and pericardial cavities. These cells synthesise large quantities of surface glycoproteins, rendering them dependent upon efficient endoplasmic reticulum (ER) function. When faced with elevated levels of secretory protein load, cells are said to experience ER stress, which has been implicated in the pathogenesis of many human diseases including cancer. METHOD: We set out to measure markers of ER stress in malignant mesothelioma and to determine whether ER stress signalling correlates with clinical parameters. RESULTS: We observed that expression of the ER stress-responsive transcription factor C/EBP homologous protein (CHOP) correlated with patient survival and remained an independent prognostic variable in pairwise comparisons with all clinical variables tested. The most parsimonious multivariate model in our study comprised only performance status and CHOP staining. In contrast, expression of the ER stress-responsive phosphatase growth arrest and DNA damage 34 (GADD34) correlated with the degree of mesothelial differentiation, being lost progressively in biphasic and sarcomatoid mesotheliomas. CONCLUSION: Our findings suggest that staining for CHOP provides prognostic information that may be useful in the stratification of patients with mesothelioma. Staining for GADD34 may prove useful in classification of mesothelioma histopathology.

Changes in traditional chronic disease risk factors over time and their relationship with leisure-time physical activity in people living with spinal cord injury.

This study examined whether levels of chronic disease risk factors change over time, and whether leisure-time physical activity (LTPA) can explain any of the variation in those risk factors that change, in a sample of community-dwelling people living with spinal cord injury (SCI) in or near Hamilton, Ontario, Canada. LTPA was measured using the Physical Activity Recall Assessment for People with SCI at baseline (n = 76 adults with chronic (≥1 year) paraplegia or tetraplegia), at 6 months (n = 71) and at 18 months (n = 63). Body mass index, waist circumference at the lowest rib (WC(lowest rib)) and iliac crest (WC(iliac crest)), fat mass, blood pressure, and biochemical data were collected at all 3 time points. Women's BMI was higher at baseline (least square means (LSM) = 26.2 ± SE = 1.56 kg·m(-2), p = 0.0004) and 6 months (25.9 ± 1.6, p = 0.0024) than at 18 months (22.1 ± 1.72). Men's WC(lowest rib) increased from baseline (92.1 ± 1.87 cm) to 18 months (93.6 ± 1.87, p = 0.0253). Women who were active vs. inactive at baseline had a lower BMI at 6 months (23.1 ± 2.91 vs. 29.7 ± 2.52, p = 0.0957) and WC(iliac crest) at 6 months (82.8 ± 6.59 vs. 97.7 ± 5.10, p = 0.0818). Women who were active vs. inactive at 6 months had a lower WC(iliac crest) at 18 months (73.4 ± 14.3 vs. 102.5 ± 6.41, p = 0.0723). There was little change in traditional risk factors over 18 months. Future studies should extend beyond 18 months in a larger sample, and explore traditional vs. novel risk factors and onset of cardiovascular disease and diabetes in the SCI population.

A novel STAT1 mutation associated with disseminated mycobacterial disease.

STAT1 is a key component of Interferon (IFN)-γ and IFN-α signaling and mediates protection against mycobacteria, fungal, viral infections, and cancer. Dominant negative inhibitory as well as gain of function heterozygous STAT1 mutations demonstrate that IFN-γ driven cellular responses need to be tightly regulated to control infections. We describe an autosomal dominant mutation in the SH2 domain of STAT1 that disrupts protein phosphorylation, c.1961T>A (M654K). The mutant allele does not permit STAT1 phosphorylation, and impairs STAT1 phosphorylation of the wild type allele. Protein dimerization is preserved but DNA binding activity, IFN-γ driven GAS-luciferase activity, and expression of IFN-γ target genes are reduced. IFN-α driven ISRE response, but not IFN-α driven GAS response, are preserved when cells are co-transfected with wild type and the mutant STAT1 constructs. M654K exerts a dominant negative effect on IFN-γ related immunity and is recessive for IFN-α induced immune function.

Synthesis, antiproliferative activity in cancer cells and theoretical studies of novel 6α,7ß-dihydroxyvouacapan-17ß-oic acid Mannich base derivatives.

Natural products are great prototypes for the design of new anticancer agents. The plant-derived natural product 6α,7ß-dihydroxyvouacapan-17ß-oic acid (1) is promising for the development of more potent antiproliferative agents against human cancer cells. Indeed, its lactone derivative 6α-hydroxyvouacapan-7ß,17ß-lactone (2), a non-natural furanoditerpene, exhibited higher anticancer activity than compound 1. Herein, we describe the synthesis and antiproliferative activity of six new Mannich derivatives of compound 2 against nine cancer cell lines. Overall, our results revealed that Mannich derivatives 3-8 were more potent than compound 2 in inhibiting the proliferation of cancer cells. Theoretical studies also supported our findings, revealing the nucleophilic character of furan ring as an important feature for antiproliferative activity of the studied Mannich derivatives.

Greater daily leisure time physical activity is associated with lower chronic disease risk in adults with spinal cord injury.

The objective of this study was to examine the relationship between leisure time physical activity (LTPA) and common risk factors for cardiovascular disease (CVD) and type 2 diabetes in community-dwelling adults with chronic spinal cord injury (SCI). LTPA was measured using the Physical Activity Recall Assessment for People with SCI in 76 men and women with chronic (> or =1 year) paraplegia or tetraplegia, living in or near Hamilton, Ontario. Body mass index (BMI), waist circumference, body composition (fat mass (FM) and fat-free mass (FFM)), blood pressure, and biochemical data were collected. Thirty-seven percent (n = 28 participants) were inactive, reporting no LTPA whatsoever, and were compared with an equal-sized group consisting of the most active study participants (> or =25 min of LTPA per day). After adjusting for significant covariates, BMI (18.7%), %FM (19.4%), and C-reactive protein (143%) were all lower, and %FFM was higher (7.2%), in active participants (all p < or = 0.05). Ten percent of active participants vs. 33% of inactive participants were insulin resistant (p = 0.03). Waist circumference (17.6%) and systolic blood pressure (15.3%) were lower in active vs. inactive participants with paraplegia (both p < or = 0.05), but not tetraplegia. In conclusion, greater daily LTPA is associated with lower levels of selected CVD and type 2 diabetes risk factors in individuals living with SCI. Whether this relationship translates into a lower incidence of these chronic diseases has yet to be determined.

Seasonality, estrous cycle characterization, estrus synchronization, semen cryopreservation, and artificial insemination in the Pacific white-sided dolphin (Lagenorhynchus obliquidens).

The reproductive physiology of the Pacific white-sided dolphin, Lagenorhynchus obliquidens, was characterized to facilitate the development of artificial insemination (AI) using cryopreserved spermatozoa. Specific objectives were to: 1) describe reproductive seasonality of the Pacific white sided dolphins; 2) describe urinary LH and ovarian steroid metabolites during the estrous cycle; 3) correlate LH and ovarian steroidal metabolite patterns to ultrasound-monitored follicular growth and ovulation; and 4) assess the efficacy of synchronizing estrus, sperm collection/cryopreservation, and intrauterine insemination. Ovulations (64%, n=37) and conceptions (83%, n=18) occurred from August to October. Peak mean serum testosterone (24 ng/ml), cross-sectional testicular area (41.6 cm(2)), and sperm concentration (144.3 x 10(7) sperm/ml) occurred in July, August, and September respectively. Spermatozoa were only found in ejaculates from July to October. Estrous cycles (n=22) were 31 d long and were comprised of a 10 d follicular and 21 d luteal phase. Ovulation occurred 31.2 h after the onset of the LH surge and 19.3 h after the LH peak. Follicular diameter and circumference within 12 h of ovulation were 1.52 and 4.66 cm respectively. Estrus synchronization attempts with altrenogest resulted in 17 (22%) ovulatory cycles with ovulation occurring 21 d post-altrenogest. Ten AI attempts using cryopreserved semen resulted in five pregnancies (50%). The mean gestation length was 356 days (range 348-367). These data provide new information on the Pacific white-sided dolphin's reproductive physiology and collectively enabled the first application of AI in this species.

Effect of 6 alpha,7 beta-dihydroxyvouacapan-17 beta-oic acid and its lactone derivatives on the growth of human cancer cells.

The furanditerpene 6 alpha,7 beta-dihydroxyvouacapan-17 beta-oic acid (1) is a natural product biosynthesized by some species from the genus Pterodon (Leguminosae). This secondary metabolite has multiple biological activities that include anti-inflammatory, analgesic, plant growth regulatory, anti-edematogenic, photosystem II inhibitory and photosynthesis uncoupler, and antifungal properties. However, few studies on the antiproliferative profile of compound 1 and/or its derivatives have been reported up to date. Here, we describe the isolation of compound 1 from hexane extract of P. polygalaeflorus fruits as well as the semisynthesis of three lactone derivatives: 6 alpha-hydroxyvouacapan-7 beta,17 beta-lactone (2), 6 alpha-acetoxyvouacapan-7 beta,17 beta-lactone (3), and 6-oxovouacapan-7 beta,17 beta-lactone (4). Additionally, antiproliferative activity of these compounds against nine human cancer cell lines was investigated. Our results revealed that 6 alpha-hydroxyvouacapan-7 beta,17 beta-lactone (2) was the most potent furanditerpene against all cancer cell lines studied. The presence of non-substituted hydroxyl group at C-6 and the presence of 7 beta,17 beta-lactone ring are important for the antiproliferative activity of these compounds.

A systematic review of therapeutic interventions for pressure ulcers after spinal cord injury.

OBJECTIVE: To systematically review evidence on the prevention and treatment of pressure ulcers in those with a spinal cord injury (SCI). DATA SOURCES: For this evidence-based review, the following data sources were used: MEDLINE/PubMed, CINAHL, EMBASE, and PsycINFO. STUDY SELECTION: To be selected for inclusion in the current review, there had to have been an intervention, studies had to have 3 or more subjects, and 50% or more of the participating group had to have an SCI. DATA EXTRACTION: Data extracted included study design, subject demographics, inclusion and exclusion criteria, study type, sample size, outcome measures used, and study results. DATA SYNTHESIS: Articles selected for this review were organized into 1 of 2 categories: prevention or treatment. Within each broad category, several smaller ones were created, and articles were grouped according to the prevention (direct or indirect) or treatment intervention discussed. CONCLUSIONS: Of the 26 articles selected for inclusion in the systematic review, 7 were randomized controlled trials (RCTs) that dealt with treatment for pressure ulcers, and there was 1 RCT on prevention. Despite the cost-effectiveness of prevention, little research exists on preventative interventions, and what does exist is mostly level 4 evidence. More research is needed for both prevention and treatment, but especially the former.

Inhibition and uncoupling of photosynthetic electron transport by diterpene lactone amide derivatives.

Nine diterpene lactone amide derivatives 1-9 were synthesized from 6-oxovouacapan-7beta,17beta-lactone, which was obtained from 6alpha,7beta-dihydroxyvouacapan-17beta-oic acid isolated from Pterodon polygalaeflorus Benth., and tested for their activity on photosynthetic electron transport. Amide derivatives 3-5 behaved as electron transport chain inhibitors; they inhibited the photophosphorylation and uncoupled non-cyclic electron transport from water to methylviologen (MV). Furthermore, 4 and 5 enhanced the basal electron rate acting as uncouplers. Compound 6 behaved as an uncoupler; it enhanced the light-activated Mg2+-ATPase and basal electron flow, without affecting the uncoupled non-cyclic electron transport. Compounds 1-2 and 7-9 were less active or inactive. Compounds 3-5 did not affect photosystem I (PSI); they inhibited photosystem II (PSII) from water to 2,6-dichlorophenol indophenol (DCPIP). Compound 4 inhibited PSII from water to silicomolybdate (SiMo), but it had no effect on the reaction from diphenylcarbazide (DPC) to DCPIP indicating that its inhibition site was at the water splitting enzyme complex (OEC). Compounds 3 and 5 inhibited PSII from water to DCPIP without any effect from water to SiMo, therefore they inhibited the acceptor site of PSII. Chlorophyll a fluorescence kinetics confirmed the behaviour of 3-5.

O Ensino da bioética nos cursos de graduação em odontologia do estado de São Paulo / Bioethics teaching in dentistry undergraduate courses at São Paulo state, Brazil

O ensino da disciplina de Bioética nos cursos de graduação é um tema emergente cuja discussão é imperativa,especialmente na área de ciências da saúde. Em se tratando dos cursos de Odontologia, a maioria das faculdades reconhece a necessidade da formação de um profissional sensível às reflexões éticas na relação com o paciente. Assim, foi realizada uma verificação quantitativa do oferecimento da disciplina de Bioética nos cursos de graduação em Odontologia do Estado de São Paulo, por meio da observação de suas respectivas estruturas curriculares. Os resultados evidenciaram graves lacunas quanto ao ensino da Bioética nas Faculdades de Odontologia paulistas, uma vez que dos 47 cursos pesquisados, apenas quatro a possuem em sua grade curricular. Nestas, a disciplina é ministrada por docentes com inserção na área de Bioética. Em três delas o oferecimento da disciplina se dá a partir da metade do curso e em uma no primeiro ano. Assim, há a necessidade de se incrementar a carga horária ou, na maioria dos casos, de se criar a disciplina de Bioética nos cursos de graduação em Odontologia investigados, de modo que o aluno possa autonomamente refletir e tomar decisões pautado em princípios éticos.

The teaching of Bioethics in undergraduate courses is an issue that needs to be discussed, especially inHealth Sciences. Particularly, in relation to Dentistry, it was verified that the majority of the college programsrecognizes the need to prepare a professional sensible to the ethical reflections about his/her patient. Theaim of this research was to verify the disciplines offered in the Dentistry undergraduate courses at São PauloState, Brazil, through the analysis of their respective curricular structures. The results have highlightedsignificant gaps about Bioethics teaching in Dentistry courses. From the 47 educational courses searchedonly four had this subject in their curricular grade. In these courses these disciplines were ministered byteachers with degree in Bioethics. In three of them, the discipline offered was ministered from the secondgrade onward, and only in one, it was ministered in the first grade. So it is necessary to increase the educationload or, in the majority of the cases, to create the discipline of Bioethics in the Dentistry undergraduatecourses investigated, so that the academics would have autonomy to reflect upon and take decisions basedon ethical principles.

Spinal Cord Injury Rehabilitation Evidence: Methods of the SCIRE Systematic Review.

The Spinal Cord Injury Rehabilitation Evidence (SCIRE) is a synthesis of the research evidence underlying rehabilitation interventions to improve the health of people living with SCI. SCIRE covers a comprehensive set of topics and in this issue we present six papers relevant to SCI rehabilitation clinicians (SCI inpatient rehabilitation practices, gait strategies, upper extremity reconstructive surgery, spasticity treatments, cardiovascular health and bone health). The SCIRE used a systematic and well-defined protocol to assess and synthesize the evidence. Each article was scored for its methodological quality using either the Physiotherapy Evidence Database (PEDro) Score for randomized controlled trials or the Downs and Black Tool for other types of studies. Following the individual study assessment, conclusions were drawn about the accumulated studies for each topic of interest based on the levels of evidence, quality of studies and concurring evidence. The SCIRE project was designed for health professionals to inform them of best practices.

Revisäo: efeitos imunomoduladores da vitamina D / Revision: immunomodulator effect of vitamin D

A forma ativa da vitamina D apresenta efeitos imunomoduladores observados sobre a populaçäo de linfócitos,macrófagos e células citotóxicas naturais (natural Liller) e sobre a produ135132o e a açäo de citocinas tanto in vivo quanto in vitro. Esses efeitos säo observados em modelos experimentais de doençäas autoimunes através da melhora clínica e histológica das lesöes, em neoplasias, nas quais verifica-se a reduçäo do volume de tumores sólidos, e em transplantes, com o aumento da sobrevida dos enxertos, o que torna a vitamina D um possível imunossupressor para futura utilizaçäo clínica

Histologic grading of breast cancer: linkage of patient outcome with level of pathologist agreement.

In the histologic grading of invasive breast cancer with the Nottingham modification of the Scarff-Bloom-Richardson grading scheme (NSBR), it has been found that when pathologists disagree, they tend not to disagree by much. However, if tumor grade is to be used as an important parameter in making treatment decisions, then even this generally small degree of pathologist variability in assessing grade needs to be correlated with patient outcome. Findings from the Nottingham/Tenovus Primary Breast Cancer Study were used for patient outcome data. Kaplan-Meier survival curves were constructed for NSBR scores grouped according to the level at which pathologists tend to agree in assessing grade, from a reproducibility perspective. For example, if a given tumor were assessed by several pathologists as having either an NSBR score of 5 or 6, then what is the correct score--the intermediate-grade Score 6 assessments or the low-grade Score 5 assessments? By "regrouping" the Nottingham outcome data such that data from patients with Score 5 tumors are grouped with patients having Score 6 tumors (a 5-6 group), then the level in which the pathologists agreed with each other (that the tumor was either score 5 or 6) is better matched with patient outcome. In response to the above example, it was not surprising to find that patients with Score 5-6 tumors had a probability of survival between the established low and intermediate NSBR final combined grades. However, it is the discussion of this approach that highlights that optimal use of grading requires awareness of the level of pathologist agreement and understanding the value of pathologists' reaching consensus in assessments. Also, knowledge of possible clinical decision thresholds can help in providing relevant interpretations of grading results.