Simon Chang

Mice Lacking MSK1 and MSK2 Show Reduced Skin Tumor Development in a Two-Stage Chemical Carcinogenesis Model

Mitogen- and stress-activated protein kinase (MSK)1/2 are two kinases involved in inflammation as well as in cell transformation. Purpose: To examine the role of MSK1/2 in skin tumor development. Results: MSK1/2 knockout mice developed significantly fewer skin tumors compared with wild-type mice. The myeloperoxidase activity in TPA-treated skin from MSK1/2 knockout mice was significantly elevated compared with wild-type mice. Furthermore, the mRNA and protein levels of IL-1β as well as the mRNA expression of TNF-α were significantly increased in MSK1/2 knockout mice. Conclusion: These data provide in vivo evidence that MSK1/2 signaling represents a novel tumor-promoting axis in skin carcinogenesis.

Anthropometry in Klinefelter syndrome - multifactorial influences due to CAG length, testosterone treatment and possibly intrauterine hypogonadism

CONTEXT Klinefelter syndrome, 47, XXY (KS), is underdiagnosed partly due to few clinical signs complicating identification of affected individuals. Certain phenotypic traits are common in KS. However, not all aspects of the KS phenotype are well described. OBJECTIVE To describe anthropometry and body composition in KS and relate findings to biochemistry and X-chromosome related genetic markers. DESIGN, SETTING AND PARTICIPANTS Seventy three KS males referred to our clinic and 73 age-matched controls underwent comprehensive measurements of anthropometry and body composition in a cross-sectional, case-controlled study. Furthermore, genetic analysis for parental origin of the supernumerary X-chromosome, skewed X-chromosome inactivation and androgen receptor (AR) CAG repeat length was done. MAIN OUTCOME MEASURE Anthropometry and body composition in KS and the effect of genotype hereon. RESULTS KS males were taller (absolute difference: 5.1 cm, P < .001) with longer legs (5.7 cm, P < .001) compared with controls. Furthermore, 2D:4D was increased in KS males (relative effect size: Cohens d = 0.40), reflecting reduced fetal testosterone exposure. Also, bi-iliac width (0.41), waist (0.52), and hip circumference (0.47) (P < .02 for all), as well as total fat mass (0.74), abdominal fat mass (0.67), and total body fat percentage (0.84) was increased in KS males (P < .001 for all), while bitesticular volume was reduced (4.6). AR CAG repeat length was comparable in KS and controls, and among KS CAG correlated to arm length (P = .04), arm span (P = .01), and leg length (P = .04). Effects of parental origin of the supernumerary X-chromosome and skewed X-chromosome inactivation were negligible. CONCLUSIONS Anthropometry and body composition in KS is specific and dysmorphic and affected by AR CAG repeat length and decreased exposure to testosterone already during fetal life.

Klinefelter syndrome and medical treatment: hypogonadism and beyond

Klinefelter syndrome (KS), though described more than 70 years ago, still imposes significant diagnostic challenges. Based on data from epidemiological studies, KS is associated with increased morbidity and mortality. Although the pathophysiology and etiology behind these observations are as yet not well understood, a significant contribution of hypogonadism, central to the syndrome, is traditionally suspected. However, other unknown effects inherent to the syndrome also seem to modify the disease pattern. Herein we show that KS is under-diagnosed since only roughly 25% of patients are diagnosed and the mean age of diagnosis is during adult life. KS is associated with increased morbidity resulting in loss of 2–5 years in lifespan with increased mortality from different diseases and a poor socioeconomic profile. Small testes, hypergonadothrophic hypogonadism and cognitive impairment are usually found. The accompanying hypogonadism can lead to altered body composition and a risk of developing metabolic syndrome, type 2 diabetes and cardiovascular disease. Cancer risk is generally not different from that observed in the background population, although specific cancers like breast cancer and extragonadal germ cell tumors are seen more frequently in KS. The mainstay of medical treatment is testosterone replacement therapy to both attenuate acute and long-term consequences of hypogonadism and possibly prevent the frequent comorbidity. We believe that the diagnostic challenges should be tackled more efficiently, while there is also a pressing need to generate better evidence for timing and the proper dose of testosterone replacement. We advocate for a multidisciplinary setup with the inclusion of pediatricians, speech therapists, general practitioners, psychologists, infertility specialists, urologists and endocrinologists.

Procoagulant State in Current and Former Anabolic Androgenic Steroid Abusers

BACKGROUND Anabolic androgenic steroid (AAS) abusers are considered at increased risk of cardiovascular morbidity and mortality. We hypothesized that current and former AAS abuse would induce a procoagulant shift in the haemostatic balance. METHODS Men 18 to 50 years of age were included as current AAS abusers, former AAS abusers or controls. Morning blood samples were collected after overnight fasting. Thrombin generation (lag time, time to peak, peak height, and endogenous thrombin potential [ETP]) and coagulation factor II (prothrombin), VII and X, antithrombin, protein C, free protein S and tissue factor pathway inhibitor (TFPI) were assessed. Groups were compared by ANOVA or Kruskal-Wallis test and probabilities were corrected for multiple comparisons. Associations were evaluated using linear regression models. RESULTS ETP was increased around 15% in current (n = 37) and former (n = 33) AAS abusers compared with controls (n = 30; p < 0.001). Prothrombin and factor X were increased ≥10% in AAS abusers and prothrombin was a predictor of ETP (p < 0.0005). Lag time and time to peak were increased 10 to 30% in current AAS abusers (p < 0.001) and associated with higher concentrations of TFPI, antithrombin, protein C and protein S (p < 0.0005; = 0.005). Multivariate linear regression, with all coagulation inhibitors as covariates, identified TFPI to be independently associated with lag time and time to peak (p < 0.0005). CONCLUSION Thrombin generation is augmented in current and former AAS abusers, reflecting a procoagulant state, with altered concentrations of coagulation proteins. Prospective studies are needed to clarify whether these findings translate into an increased thrombotic risk in AAS abusers potentially even after cessation.

Quality of life in men with Klinefelter syndrome: the impact of genotype, health, socioeconomics, and sexual function

PurposeKlinefelter syndrome (KS) is associated with lower socioeconomic status and greater morbidity. However, relatively little is known about the quality of life for men with KS, or how KS and other factors combine to determine it.MethodsA total of 132 men with KS were recruited in clinics, and 313 matched controls were identified by Statistics Denmark. Demographics, socioeconomic status, health problems and behaviors, sexual function, medical follow-up, and mental and physical quality of life (MQoL and PQoL, respectively) were assessed for all participants through surveys.ResultsMen with KS reported significantly lower education attainment levels, income, physical activity, and both PQoL and MQoL, as well as more illness, medication, and sexual dysfunction. KS status was associated directly with lower PQoL, as well as indirectly through reduced income, physical activity, and sexual function, and increased body mass index. KS status and younger age were associated directly with lower MQoL, as well as indirectly through reduced income, physical activity, and partner status (for KS status), or through partner status (for age).ConclusionKS status is associated with lower PQoL and MQoL through both direct and indirect paths. These results suggest the need for more comprehensive research and clinical approaches to addressing quality of life for men with KS.

Klinefelter Syndrome: Integrating Genetics, Neuropsychology, and Endocrinology

Although first identified over 70 years ago, Klinefelter syndrome (KS) continues to pose substantial diagnostic challenges, as many patients are still misdiagnosed, or remain undiagnosed. In fact, as few as 25% of patients with KS are accurately diagnosed and most of these diagnoses are not made until adulthood. Classic characteristics of KS include small testes, infertility, hypergonadothropic hypogonadism, and cognitive impairment. However, the pathophysiology behind KS is not well understood, although genetic effects are also thought to play a role. For example, recent developments in genetics and genomics point to a fundamental change in our understanding of KS, with global epigenetic and RNA expression changes playing a central role for the phenotype. KS is also associated with more general health markers, including higher morbidity and mortality rates and lower socioeconomic status (which likely affect both morbidity and mortality). In addition, hypogonadism is associated with greater risk of metabolic syndrome, type 2 diabetes, cardiovascular disease, breast cancer, and extragonadal germ cell tumors. Medical treatment typically focuses on testosterone replacement therapy (TRT), although the effects of this therapy have not been studied rigorously, and future studies need to evaluate the effects of TRT on metabolic risk and neurocognitive outcomes. This review presents a comprehensive interdisciplinary examination of recent developments in genetic, endocrine, and neurocognitive science, including the study of animal models. It provides a number of recommendations for improving the effectiveness of research and clinical practice, including neonatal KS screening programs, and a multidisciplinary approach to KS treatment from childhood until senescence.

Anabolic Androgenic Steroid Abuse: The Effects on Thrombosis Risk, Coagulation, and Fibrinolysis

Abstract Anabolic androgenic steroid (AAS) abuse surged during the 1980s and is seen in approximately 1 in 20 of all males today. A wide spectrum of AAS compounds and abuse regimens are applied and AAS abuse has been associated with an unfavorable cardiovascular profile. The aim of this review is to critique the collected data concerning effects of AAS abuse on thrombosis risk through presentation of condensed evidence from studies investigating AAS‐induced changes in coagulation, fibrinolysis, and cardiovascular risk markers. AAS abuse inflicts a procoagulant distribution of cardiovascular risk markers including dyslipidemia and atherosclerosis proneness. AAS abuse overall stimulates synthesis of coagulation factors, inhibitors, and fibrinolytic proteins resulting in both increased global coagulation and stimulation of fibrinolysis. Overall, supported by many case reports and some epidemiological studies, AAS abuse is associated with an increased risk of thrombosis. However, to provide clear evidence for a causal relationship between AAS abuse and thrombosis risk, future studies need to address a range of potential biases, insufficient methodology, and other shortcomings of the current literature as highlighted in this review.