Comparison of postmenopausal endogenous sex hormones among Japanese, Japanese Brazilians, and non-Japanese Brazilians

<p>Abstract</p> <p>Background</p> <p>Differences in sex hormone levels among populations might contribute to the variation in breast cancer incidence across countries. Previous studies have shown higher breast cancer incidence and mortality among Japanese Brazilians than among Japanese. To clarify the difference in hormone levels among populations, we compared postmenopausal endogenous sex hormone levels among Japanese living in Japan, Japanese Brazilians living in the state of São Paulo, and non-Japanese Brazilians living in the state of São Paulo.</p> <p>Methods</p> <p>A cross-sectional study was conducted using a control group of case-control studies in Nagano, Japan, and São Paulo, Brazil. Participants were postmenopausal women older than 55 years of age who provided blood samples. We measured estradiol, estrone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), testosterone and free testosterone by radioimmunoassay; bioavailable estradiol by the ammonium sulfate precipitation method; and sex hormone-binding globulin (SHBG) by immunoradiometric assay. A total of 363 women were included for the present analyses, comprising 185 Japanese, 44 Japanese Brazilians and 134 non-Japanese Brazilians.</p> <p>Results</p> <p>Japanese Brazilians had significantly higher levels of estradiol, bioavailable estradiol, estrone, testosterone and free testosterone levels, and lower SHBG levels, than Japanese. Japanese Brazilians also had significantly higher levels of bioavailable estradiol, estrone and DHEAS and lower levels of SHBG and androstenedione than non-Japanese Brazilians. Levels of estradiol, testosterone and free testosterone, however, did not differ between Japanese Brazilians and non-Japanese Brazilians. These differences were observed even after adjustment for known breast cancer risk factors. We also found an increase in estrogen and androgen levels with increasing body mass index, but no association for most of the other known risk factors.</p> <p>Conclusions</p> <p>We found higher levels of estrogens and androgens in Japanese Brazilians than in Japanese and levels similar to or higher than in non-Japanese Brazilians. Our findings may help explain the increase in the incidence and mortality rate of breast cancer among Japanese Brazilians.</p

protocol of a prospective, longitudinal study

Background Natural killer (NK) cells comprise the main components of lymphocyte-mediated nonspecific immunity. Through their effector function they play a crucial role combating bacterial and viral challenges. They are also thought to be key contributors to the systemic spinal cord injury-induced immune-deficiency syndrome (SCI-IDS). SCI-IDS increases susceptibility to infection and extends to the post-acute and chronic phases after SCI. Methods and design The prospective study of NK cell function after traumatic SCI was carried out in two centers in Berlin, Germany. SCI patients and control patients with neurologically silent vertebral fracture also undergoing surgical stabilization were enrolled. Furthermore healthy controls were included to provide reference data. The NK cell function was assessed at 7 (5–9) days, 14 days (11–28) days, and 10 (8–12) weeks post-trauma. Clinical documentation included the American Spinal Injury Association (ASIA) impairment scale (AIS), neurological level of injury, infection status, concomitant injury, and medications. The primary endpoint of the study is CD107a expression by NK cells (cytotoxicity marker) 8–12 weeks following SCI. Secondary endpoints are the NK cell’s TNF-α and IFN-γ production by the NK cells 8–12 weeks following SCI. Discussion The protocol of this study was developed to investigate the hypotheses whether i) SCI impairs NK cell function throughout the post-acute and sub-acute phases after SCI and ii) the degree of impairment relates to lesion height and severity. A deeper understanding of the SCI-IDS is crucial to enable strategies for prevention of infections, which are associated with poor neurological outcome and elevated mortality. Trial registration DRKS00009855

Dietary intake of folate, vitamin B6, and vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Brazilian women

<p>Abstract</p> <p>Background</p> <p>Several studies have determined that dietary intake of B vitamins may be associated with breast cancer risk as a result of interactions between <it>5,10-methylenetetrahydrofolate reductase (MTHFR) </it>and <it>methionine synthase </it>(<it>MTR</it>) in the one-carbon metabolism pathway. However, the association between B vitamin intake and breast cancer risk in Brazilian women in particular has not yet been investigated.</p> <p>Methods</p> <p>A case-control study was conducted in São Paulo, Brazil, with 458 age-matched pairs of Brazilian women. Energy-adjusted intakes of folate, vitamin B₆, and vitamin B₁₂were derived from a validated Food Frequency Questionnaire (FFQ). Genotyping was completed for <it>MTHFR </it>A1298C and C677T, and <it>MTR </it>A2756G polymorphisms. A logistical regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs).</p> <p>Results</p> <p>Neither dietary intake of folate, vitamin B₆, or vitamin B₁₂nor <it>MTHFR </it>polymorphisms were independently associated with breast cancer risk. Analysis stratified by menopausal status showed a significant association between placement in the highest tertile of folate intake and risk of breast cancer in premenopausal women (OR = 2.17, 95% CI: 1.23–3.83; <it>P</it>_{<it>trend </it>}= 0.010). The <it>MTR </it>2756GG genotype was associated with a higher risk of breast cancer than the 2756AA genotype (OR = 1.99, 95% CI = 1.01–3.92; <it>P</it>_{<it>trend </it>}= 0.801), and statistically significant interactions with regard to risk were observed between the <it>MTHFR </it>A1298C polymorphism and folate (P = 0.024) or vitamin B₆(P = 0.043), and between the <it>MTHFR </it>C677T polymorphism and folate (P = 0.043) or vitamin B₁₂(P = 0.022).</p> <p>Conclusion</p> <p><it>MTHFR </it>polymorphisms and dietary intake of folate, vitamin B₆, and vitamin B₁₂had no overall association with breast cancer risk. However, increased risk was observed in total women with the <it>MTR </it>2756GG genotype and in premenopausal women with high folate intake. These findings, as well as significant interactions between <it>MTHFR </it>polymorphisms and B vitamins, warrant further investigation.</p

Functional neurological recovery after spinal cord injury is impaired in patients with infections

Infections are a common threat to patients after spinal cord injury. Furthermore, infections might propagate neuronal death, and consequently contribute to the restriction of neurological recovery. We investigated the association of infections (i.e. pneumonia and/or postoperative wound infections) with functional neurological outcome after acute severe traumatic spinal cord injury. We screened data sets of 24 762 patients enrolled in a prospective cohort study (National Spinal Cord Injury Database, Birmingham, AL, USA). Patients were assessed according to the ASIA classification. ASIA impairment scale-classified A and B patients recruited within 24 h post-trauma (n = 1436) were selected as being a major recruitment population for interventional trials. Patients with documented pneumonia and/or postoperative wound infections (n = 581) were compared with control subjects (non-documented infections, n = 855). The functional neurological outcome parameters (i) upward ASIA impairment scale conversions; (ii) gain of ASIA motor scores; and (iii) gain of motor and sensory levels were consecutively analysed over time up to 1 year after spinal cord injury. The group with pneumonia and/or postoperative wound infections revealed less ASIA impairment scale upward conversions after 1 year than the control group (ASIA impairment scale A: 17.2 versus 23.9%, P = 0.03; ASIA impairment scale B: 57.1 versus 74.7%, P = 0.009). ASIA motor score gain [median (interquartile range)] was lower in patients with infections [ASIA impairment scale A: 8 (4-12) versus 10 (5-17), P = 0.01; ASIA impairment scale B: 19.5 (8-53.5) versus 42 (20.5-64), P = 0.03)]. Analysis of acquired motor/sensory levels supported these findings. In ASIA impairment scale A patients, the gain in motor levels (21.7 versus 33.3%, P = 0.04) and sensory levels (24.4 versus 38 of 102, 37.3%, P = 0.03) was significantly lower in the group with pneumonia and/or postoperative wound infections than in the control group. Multiple regression analysis identified pneumonia and/or postoperative wound infections as independent risk factors for impaired ASIA impairment scale upward conversion (odds ratio: 1.89, 95% confidence interval: 1.36-2.63, P < 0.0005) or lower gain in ASIA motor score (regression coefficient: -8.21, 95% confidence interval: -12.29 to -4.14, P < 0.0005). Infections associated with spinal cord injury, such as pneumonia and/or postoperative wound infections, qualify as independent risk factors for poor neurological outcome after motor complete spinal cord injury. Infections constitute a clinically relevant target for protecting the limited endogenous functional regeneration capacity. Upcoming interventional trials might gain in efficacy with improved patient stratification and might benefit from complementary protection of the intrinsic recovery potential after spinal cord injury

The SCIentinel study - prospective multicenter study to define the spinal cord injury-induced immune depression syndrome (SCI-IDS) - study protocol and interim feasibility data

Abstract Background Infections are the leading cause of death in the acute phase following spinal cord injury and qualify as independent risk factor for poor neurological outcome (“disease modifying factor”). The enhanced susceptibility for infections is not stringently explained by the increased risk of aspiration in tetraplegic patients, neurogenic bladder dysfunction, or by high-dose methylprednisolone treatment. Experimental and clinical pilot data suggest that spinal cord injury disrupts the balanced interplay between the central nervous system and the immune system. The primary hypothesis is that the Spinal Cord Injury-induced Immune Depression Syndrome (SCI-IDS) is 'neurogenic’ including deactivation of adaptive and innate immunity with decreased HLA-DR expression on monocytes as a key surrogate parameter. Secondary hypotheses are that the Immune Depression Syndrome is i) injury level- and ii) severity-dependent, iii) triggers transient lymphopenia, and iv) causes qualitative functional leukocyte deficits, which may endure the post-acute phase after spinal cord injury. Methods/Design SCIentinel is a prospective, international, multicenter study aiming to recruit about 118 patients with acute spinal cord injury or control patients with acute vertebral fracture without neurological deficits scheduled for spinal surgery. The assessment points are: i) <31 hours, ii) 31–55 hours, iii) 7 days, iv) 14 days, and v) 10 weeks post-trauma. Assessment includes infections, concomitant injury, medication and neurological classification using American Spinal Injury Association impairment scale (AIS) and neurological level. Laboratory analyses comprise haematological profiling, immunophenotyping, including HLA-DR expression on monocytes, cytokines and gene expression of immune modulators. We provide an administrative interim analysis of the recruitment schedule of the trial. Discussion The objectives are to characterize the dysfunction of the innate and adaptive immune system after spinal cord injury and to explore its proposed 'neurogenic’ origin by analyzing its correlation with lesion height and severity. The trial protocol considers difficulties of enrolment in an acute setting, and loss to follow up. The administrative interim analysis confirmed the feasibility of the protocol. Better understanding of the SCI-IDS is crucial to reduce co-morbidities and thereby to attenuate the impact of disease modifying factors to protect neurological “outcome at risk”. This putatively results in improved spinal cord injury medical care. Trial registration DRKS-ID: DRKS00000122 (German Clinical Trials Registry

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BACKGROUND: Infections are the leading cause of death in the acute phase following spinal cord injury and qualify as independent risk factor for poor neurological outcome ("disease modifying factor"). The enhanced susceptibility for infections is not stringently explained by the increased risk of aspiration in tetraplegic patients, neurogenic bladder dysfunction, or by high-dose methylprednisolone treatment. Experimental and clinical pilot data suggest that spinal cord injury disrupts the balanced interplay between the central nervous system and the immune system. The primary hypothesis is that the Spinal Cord Injury-induced Immune Depression Syndrome (SCI-IDS) is 'neurogenic' including deactivation of adaptive and innate immunity with decreased HLA-DR expression on monocytes as a key surrogate parameter. Secondary hypotheses are that the Immune Depression Syndrome is i) injury level- and ii) severity-dependent, iii) triggers transient lymphopenia, and iv) causes qualitative functional leukocyte deficits, which may endure the post-acute phase after spinal cord injury.Methods/design: SCIentinel is a prospective, international, multicenter study aiming to recruit about 118 patients with acute spinal cord injury or control patients with acute vertebral fracture without neurological deficits scheduled for spinal surgery. The assessment points are: i) <31 hours, ii) 31--55 hours, iii) 7 days, iv) 14 days, and v) 10 weeks post-trauma. Assessment includes infections, concomitant injury, medication and neurological classification using American Spinal Injury Association impairment scale (AIS) and neurological level. Laboratory analyses comprise haematological profiling, immunophenotyping, including HLA-DR expression on monocytes, cytokines and gene expression of immune modulators. We provide an administrative interim analysis of the recruitment schedule of the trial. DISCUSSION: The objectives are to characterize the dysfunction of the innate and adaptive immune system after spinal cord injury and to explore its proposed 'neurogenic' origin by analyzing its correlation with lesion height and severity. The trial protocol considers difficulties of enrolment in an acute setting, and loss to follow up. The administrative interim analysis confirmed the feasibility of the protocol. Better understanding of the SCI-IDS is crucial to reduce co-morbidities and thereby to attenuate the impact of disease modifying factors to protect neurological "outcome at risk". This putatively results in improved spinal cord injury medical care.Trial registration: DRKS-ID: DRKS00000122 (German Clinical Trials Registry)

The spinal cord injury-induced immune deficiency syndrome: results of the SCIentinel study

Infections are prevalent after spinal cord injury (SCI), constitute the main cause of death and are a rehabilitation confounder associated with impaired recovery. We hypothesize that SCI causes an acquired lesion-dependent (neurogenic) immune suppression as an underlying mechanism to facilitate infections. The international prospective multicentre cohort study (SCIentinel; protocol registration DRKS00000122; n = 111 patients) was designed to distinguish neurogenic from general trauma-related effects on the immune system. Therefore, SCI patient groups differing by neurological level, i.e. high SCI [thoracic (Th)4 or higher]; low SCI (Th5 or lower) and severity (complete SCI; incomplete SCI), were compared with a reference group of vertebral fracture (VF) patients without SCI. The primary outcome was quantitative monocytic Human Leukocyte Antigen-DR expression (mHLA-DR, synonym MHC II), a validated marker for immune suppression in critically ill patients associated with infection susceptibility. mHLA-DR was assessed from Day 1 to 10 weeks after injury by applying standardized flow cytometry procedures. Secondary outcomes were leucocyte subpopulation counts, serum immunoglobulin levels and clinically defined infections. Linear mixed models with multiple imputation were applied to evaluate group differences of logarithmic-transformed parameters. Mean quantitative mHLA-DR [ln (antibodies/cell)] levels at the primary end point 84 h after injury indicated an immune suppressive state below the normative values of 9.62 in all groups, which further differed in its dimension by neurological level: high SCI [8.95 (98.3% confidence interval, CI: 8.63; 9.26), n = 41], low SCI [9.05 (98.3% CI: 8.73; 9.36), n = 29], and VF without SCI [9.25 (98.3% CI: 8.97; 9.53), n = 41, P = 0.003]. Post hoc analysis accounting for SCI severity revealed the strongest mHLA-DR decrease [8.79 (95% CI: 8.50; 9.08)] in the complete, high SCI group, further demonstrating delayed mHLA-DR recovery [9.08 (95% CI: 8.82; 9.38)] and showing a difference from the VF controls of −0.43 (95% CI: −0.66; −0.20) at 14 days. Complete, high SCI patients also revealed constantly lower serum immunoglobulin G [−0.27 (95% CI: −0.45; −0.10)] and immunoglobulin A [−0.25 (95% CI: −0.49; −0.01)] levels [ln (g/l × 1000)] up to 10 weeks after injury. Low mHLA-DR levels in the range of borderline immunoparalysis (below 9.21) were positively associated with the occurrence and earlier onset of infections, which is consistent with results from studies on stroke or major surgery. Spinal cord injured patients can acquire a secondary, neurogenic immune deficiency syndrome characterized by reduced mHLA-DR expression and relative hypogammaglobulinaemia (combined cellular and humoral immune deficiency). mHLA-DR expression provides a basis to stratify infection-risk in patients with SCI