Fabio Vasconcellos Comim

Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin as indicators of tubular damage in normoalbuminuric patients with type 2 diabetes.

OBJECTIVES Renal dysfunction has been reported in normoalbuminuric patients, demonstrating the necessity to improve the diagnostic and prognostic tools for diabetic kidney disease (DKD) investigation. Therefore, the aim of this study was to investigate whether the urinary levels of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) are increased in type 2 diabetes mellitus (DM) patients with normal or mildly increased albuminuria. DESIGN AND METHODS In this study, 117 type 2 DM patients classified into three groups according to urinary albumin/creatinine ratio (uACR): uACR<10mg/g creatinine, uACR 10-30mg/g creatinine and uACR>30mg/g creatinine were enrolled. Urinary concentrations of KIM-1 (uKIM-1) and NGAL (uNGAL) were measured. RESULTS uKIM-1 levels increased progressively from uACR<10mg/g creatinine (69.0±20.8pg/ml) to uACR 10-30mg/g creatinine (106.1±41.2pg/ml) and to uACR>30mg/g creatinine (166.0±31.9pg/ml) (P<0.001). In addition, uNGAL levels increased progressively from uACR<10mg/g creatinine (29.5±8.8ng/ml) to uACR 10-30mg/g creatinine (51.7±10.9ng/ml) and to uACR>30mg/g creatinine (71.0±9.6ng/ml) (P<0.001) patients. Similarly, both uKIM-1 and uNGAL adjusted by urinary creatinine were increased in patients with uACR 10-30mg/g creatinine. Significant and positive correlations were observed between uACR, uKIM-1 and uNGAL. CONCLUSIONS uKIM-1 and uNGAL were increased in type 2 DM patients with normal or mildly increased albuminuria, which indicates that tubular and glomerular injuries may be occurring even at the earliest stage of DKD.

Obesity and fractures

Until recently obesity was believed to be protective against fractures. However, a report from a Fracture Liaison Clinic in the UK (2010) reported a surprisingly high proportion of obese postmenopausal women attending the clinic with fractures, and in the GLOW study (2011), a similar prevalence and incidence of fractures in obese and non-obese postmenopausal women was observed. Subsequently, other studies have demonstrated the importance of obesity in the epidemiology of fractures. Obese women are at increased risk of fracture in ankle, leg, humerus, and vertebral column and at lower risk of wrist, hip and pelvis fracture when compared to non-obese women. In men, it has been reported that multiple rib fractures are associated with obesity. Furthermore, falls appear to play an important role in the pathogenesis of fractures in obese subjects. Regarding hip fracture and major fractures, the FRAX algorithm has proven to be a useful predictor in obese individuals. Obese people are less likely to receive bone protective treatment; they have a longer hospital stay and a lower quality of life both before and after fracture. Moreover, the efficacy of antiresorptive therapies is not well established in obese people. The latter is a field for future research.

Oxidative DNA damage is associated with inflammatory response, insulin resistance and microvascular complications in type 2 diabetes

Urinary markers of nucleic acid oxidation may be useful biomarkers in diabetes. It has been demonstrated that T2DM patients have an increased level of oxidative DNA damage; however, it is unclear whether increased DNA damage may be related to a greater degree of inflammation and insulin resistance. Thus, the aim of this present study was to investigate the relation of the impact of oxidative DNA damage, assessed by urinary 8-OHdG, on the levels of inflammatory cytokines, as well as insulin resistance. In addition, we also investigated the diagnostic ability of urinary 8-OHdG in the identification of microvascular complications in T2DM.A case-control study, enrolling 22 healthy controls and 54 subjects with T2DM, was performed to evaluate the relation between oxidative DNA damage and interleukin-6 (IL-6), IL-1,tumor necrosis factor-alpha (TNF-α), IL-10, and Homeostasis Model Assessment (HOMA-IR) index. T2DM patients presented higher urinary 8-OHdG, IL-6, IL-1, TNF-α levels and HOMA-IR, and lower IL-10 levels than control subjects. Moreover, urinary 8-OHdG levels were significantly higher in the group T2DM with microvascular complications when compared to the without complications. The areas under the curve for urinary 8-OHdG and urinary albumin were, respectively, 0.836 (P<0.001) and 0.786 (P=0.002). Thus, urinary 8-OHdG has a slightly higher ability to discriminate microvascular complications in T2DM compared with urinary albumin. It was also demonstrated that T2DM patients with higher median of urinary 8-OHdG had significantly elevated levels of IL-6, TNF-α and HOMA-IR, and decreased IL-10 levels. Our findings showed that T2DM patients with higher urinary 8-OHdG levels showed a greater inflammatory degree and higher insulin resistance. It is possible to speculate that T2DM patients present a cascade of events as increasing metabolic abnormalities such as insulin resistance and inflammatory activation, as well as increased ROS generation factors that may contribute directly to greater oxidative DNA damage.

Increased risk of humerus and lower leg fractures in postmenopausal women with self-reported premenopausal hirsutism and/or oligomenorrhea

OBJECTIVE The aim of this study was to investigate the prevalence of fracture in women aged >55 years with self-reported premenopausal hirsutism and/or oligomenorrhea. STUDY DESIGN A cross-sectional study including 1057 post-menopausal women aged >55 years who were treated in a primary care facility in Santa Maria, South Brazil, from March 2013 through August 2013. Data were collected using a standardized questionnaire for characteristics including fracture history, medication use, and reproductive history (oligomenorrhea, hirsutism, miscarriage, the diagnosis or treatment of hypothyroidism, hyperprolactinemia, or infertility). RESULTS A non-significant trend towards an increased prevalence of all fragility fractures was observed in women with premenopausal hirsutism and/or oligomenorrhea when compared to those without (20.4% vs. 15.7%). After correction for age, falls, and comorbidities, fracture prevalence was significantly higher in the lower leg (OR 3.1 [CI 1.1-8.6]; P=0.029), and humerus (OR 2.6 [CI 1.2-5.4]; P=0.015) in the women with hirsutism and/or oligomenorrhea. CONCLUSION This is a hypothesis-generating study which evaluated the association between hirsutism and/or oligomenorrhea and fractures in postmenopausal women. Our results suggest that premenopausal hirsutism and/or oligomenorrhea may be associated with an increased risk of fracture postmenopause, particularly in the humerus and lower leg.

Urinary inflammatory cytokines as indicators of kidney damage in type 2 diabetic patients

BACKGROUND The aim of this study was to investigate whether urinary levels of interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) are altered in normoalbuminuric patients with type 2 diabetes mellitus (T2DM), and whether these cytokines are able to identify diabetic kidney disease (DKD) among these patients. METHODS This study included 125 T2DM patients classified into 3 groups according to urinary albumin/creatinine ratio (uACR): uACR <10mg/g creatinine, uACR 10-30mg/g creatinine and uACR >30mg/g creatinine. Urinary inflammatory cytokines were measured. RESULTS The urinary IL-6 concentrations increased from uACR <10 (97.2±26.4pg/ml) to uACR 10-30 (113.6±28.0pg/ml) and to uACR >30mg/g creatinine (163.5±25.6pg/ml) (P<0.05 and P<0.001, respectively) patients. The urinary IL-10 concentrations decreased in these uACR ranges [100.0 (58.0-141.0) pg/ml vs. 62.0 (54.5-71.5) pg/ml vs. 42.0 (32.0-48.0) pg/ml] (P<0.05 and P<0.001, respectively). All urinary cytokines demonstrated good ability to identify DKD (areas under curves >0.9). CONCLUSIONS Urinary inflammatory cytokines, especially IL-6 and IL-10, may assist in the identification of DKD in T2DM patients, even in the absence of micro- and macroalbuminuria.

Low health related quality of life associated with fractures in obese postmenopausal women in Santa Maria, Brazil

Although health-related quality of life is well studied in subjects with obesity or fractures, there are few studies approaching both diseases together. The aim of this study was to evaluate the health-related quality of life (HRQL) in obese postmenopausal women with fractures. A cross-sectional study was carried out at Santa Maria, Brazil. Postmenopausal women aged 55 years or older were recruited from March 1st to August 31st, 2013. Women with cognitive impairment were excluded. The Short-Form Health Survey (SF-36) were applied (QM0 16,471). Height and weight were measured according to the World Health Organization protocol. Bone fractures (excluding hand, feet, and head) that occur after age 45 years were considered as the outcome. Of the 1057 women allocated to study, 975 had their weight and height measured. Obese women with fractures had significantly lower SF-36 physical component scores when compared with non-obese subjects with fracture, obese subjects without fractures, and non-obese non-fracture subjects. Both obesity and fractures were independently associated with a lower SF-36 physical component score in the regression model. In conclusion, fractures appear to have an adverse effect on quality of life which is more pronounced in obese postmenopausal women.

HIV and Vertebral Fractures: a Systematic Review and Metanalysis

The survival of HIV-infected patients has increased with the advent of antiretroviral therapy with the emergence of new comorbidities. Vertebral fracture is a manifestation of reduced bone strength and osteoporosis. This study aims to assess the frequency of spine fractures in HIV-positive men and women aged over 18 years. We performed a systematic review of randomized controlled trials, cohort studies, cross-sectional studies, and case-control studies. Studies that evaluated morphometric and/or clinical vertebral fracture were included. In total 488 studies were found, of which 53 had their full texts evaluated. A total of 85,411 HIV positive individuals were identified in 26 studies. The meta-analysis of the prevalence of vertebral fractures included 12 studies with 10,593 subjects. The prevalence was 11.1% [95% confidence interval (95% CI) 4.5%, 25.0%, I2 98.2% p < 0.00001]. When we evaluated independently studies of clinical vertebral fracture and morphometric vertebral fracture, the prevalence was 3.9% (95% CI 0.9, 15.8, I2 96.4% p < 0.00001) and 20.2% (95% CI 15.7%, 25.6%, I2 69.9% p = 0.003) respectively. HIV-infected individuals had an odds ratio of vertebral fractures of 2.3 (95% CI 1.37, 3.85, I2 98.2% p < 0.00001) when compared with HIV-uninfected patients (n = 9 studies). In conclusion, HIV-positive subjects had a higher risk of vertebral fractures when compared with HIV-negative subjects.

The yerba mate intake has a neutral effect on bone: A case-control study in postmenopausal women

Nutritional factors have been associated with osteoporosis and fractures. The intake of coffee may increase the risk of fracture whereas the intake of black and green tea is associated with its reduction. Recently, consumption of yerba mate was associated with increased bone mineral density in postmenopausal women. Nonetheless, its influence on fracture is not known. The aim of this study was to evaluate the effect of yerba mate tea intake on fractures, bone markers, calcium homeostasis, and oxidative stress in postmenopausal women. A case–control study was carried out in South Brazil, 46 women with fractures and 49 controls completed the study. There was no significant difference between the frequency of fractures in women who drank mate tea and women who did not (48.3% vs. 48.5%, p = .99). Moreover, there was no significant difference concerning the serum levels of total calcium, phosphorus, PTH, vitamin D, P1NP, and CTX in the subjects with the history of yerba mate use when compared to controls. Higher serum levels of NOx were found in women who drank the yerba mate infusion. In conclusion, the yerba mate intake is not associated with fracture, and it appears to have a neutral effect on the bone metabolism.

Gonadotoxic effects of busulfan in two strains of mice.

Busulfan is a chemotherapy drug that has side effects on spermatogonial stem cells (SSC). The effects of bulsufan treatment on male germ cells and fertility vary significantly between individuals. In this study, we have used molecular, cellular and histopathology approaches to investigate the effects of a single intraperitoneal dose of busulfan (40mgkg(-1)) in two mice strains, Balb/C and Swiss, at two different periods after treatment, 30 and 90 days. Testicular degeneration was observed in both Balb/C and Swiss mice after busulfan injection. Interestingly, testicular functions and fertility recovered spontaneously post busulfan treatment in Swiss mice, but not in Balb/C mice. Abnormal fertility induced by busulfan in Balb/C mice was associated with altered seminiferous tubules, sperm morphology and transcript levels of Nanos2, Nanos3, Gdnf and Plzf genes. These findings revealed that SSC of Balb/C mice are more sensitive to the toxic effects of busulfan then those of Swiss mice.

Effects of Adiponectin Including Reduction of Androstenedione Secretion and Ovarian Oxidative Stress Parameters In Vivo.

Adiponectin is the most abundantly produced human adipokine with anti-inflammatory, anti-oxidative, and insulin-sensitizing properties. Evidence from in vitro studies has indicated that adiponectin has a potential role in reproduction because it reduces the production of androstenedione in bovine theca cells in vitro. However, this effect on androgen production has not yet been observed in vivo. The current study evaluated the effect of adiponectin on androstenedione secretion and oxidative stress parameters in a rodent model. Seven-week-old female Balb/c mice (n = 33), previously treated with equine gonadotropin chorionic, were assigned to one of four different treatments: Group 1, control (phosphate-buffered saline); Group 2, adiponectin 0.1 μg/mL; Group 3, adiponectin 1.0 μg/mL; Group 4, adiponectin 5.0 μg/mL. After 24 h, all animals were euthanized and androstenedione levels were measured in the serum while oxidative stress markers were quantified in whole ovary tissue. Female mice treated with adiponectin exhibited a significant reduction (about 60%) in serum androstenedione levels in comparison to controls. Androstenedione levels decreased from 0.78 ± 0.4 ng/mL (mean ± SD) in controls to 0.28 ± 0.06 ng/mL after adiponectin (5 μg/mL) treatment (P = 0.01). This change in androgen secretion after 24 hours of treatment was associated with a significant reduction in the expression of CYP11A1 and STAR (but not CYP17A1). In addition, ovarian AOPP product levels, a direct product of protein oxidation, decreased significantly in adiponectin-treated mice (5 μg/mL); AOPP (mean ± SD) decreased to 4.3 ± 2.1 μmol/L in comparison with that of the controls (11.5 ± 1.7 μmol/L; P = 0.0003). Our results demonstrated for the first time that acute treatment with adiponectin reduced the levels of a direct oxidative stress marker in the ovary as well as decreased androstenedione serum levels in vivo after 24 h.