OnLine First

[Michael Scally MD]

Flavonoids (flavones, flavonols, flavanones, and isoflavones) are polyphenols present in many foods of plant origin including citrus fruits, green tea, red wine, and cocoa. Large epidemiological studies link increased consumption of flavonoid- rich foods with reduced cardiovascular morbidity and mortality. However, molecular and physiological mechanisms underlying potential cardiovascular health benefits of flavonoid consumption are poorly understood. The flavanone glycosides hesperidin and naringin are present in citrus fruits. Hesperidin (hesperetin-7-O-rutinoside) is deglycosylated by intestinal microflora in the colon to produce the active aglycone hesperetin, which is then absorbed in the gut and subsequently glucuronidated to hesperetin glucuronide that circulates in plasma. Hesperidin and naringin may have antiinflammatory, hypolipidemic, and vasoprotective properties.

Dyslipidemias contribute to endothelial dysfunction and accelerated atherosclerosis, in part, by promoting imbalances between endothelial-derived vasoconstrictors and vasodilators, growth factors, and pro- and anticoagulant factors. Endothelial dysfunction often manifests as impaired endothelium-dependent vasodilator actions secondary to decreased production and/or bioavailability of nitric oxide (NO).

In human studies, green tea polyphenol epigallocatechin gallate (EGCG; a flavan-3- ol) or polyphenol-rich cocoa intake improves endothelial dysfunction. In the present study, researchers hypothesized that hesperetin, a flavonoid related to EGCG, acutely stimulates production of NO from vascular endothelium to mediate beneficial vascular and antiinflammatory actions in humans.


Rizza S, Muniyappa R, Iantorno M, et al. Citrus Polyphenol Hesperidin Stimulates Production of Nitric Oxide in Endothelial Cells while Improving Endothelial Function and Reducing Inflammatory Markers in Patients with Metabolic Syndrome. J Clin Endocrinol Metab:jc.2010-879. Citrus Polyphenol Hesperidin Stimulates Production of Nitric Oxide in Endothelial Cells while Improving Endothelial Function and Reducing Inflammatory Markers in Patients with Metabolic Syndrome -- Rizza et al., 10.1210/jc.2010-2879 -- Journal of Cli

Context: Hesperidin, a citrus flavonoid, and its metabolite hesperetin may have vascular actions relevant to their health benefits. Molecular and physiological mechanisms of hesperetin actions are unknown.

Objective: We tested whether hesperetin stimulates production of nitric oxide (NO) from vascular endothelium and evaluated endothelial function in subjects with metabolic syndrome on oral hesperidin therapy.

Design, Setting, and Interventions: Cellular mechanisms of action of hesperetin were evaluated in bovine aortic endothelial cells (BAEC) in primary culture. A randomized, placebo-controlled, double-blind, crossover trial examined whether oral hesperidin administration (500 mg once daily for 3 wk) improves endothelial function in individuals with metabolic syndrome (n = 24).

Main Outcome Measure: We measured the difference in brachial artery flow-mediated dilation between placebo and hesperidin treatment periods.

Results: Treatment of BAEC with hesperetin acutely stimulated phosphorylation of Src, Akt, AMP kinase, and endothelial NO synthase to produce NO; this required generation of H2O2. Increased adhesion of monocytes to BAEC and expression of vascular cell adhesion molecule-1 in response to TNF- treatment was reduced by pretreatment with hesperetin. In the clinical study, when compared with placebo, hesperidin treatment increased flow-mediated dilation (10.26± 1.19 vs. 7.78 ± 0.76%; P = 0.02) and reduced concentrations of circulating inflammatory biomarkers (high-sensitivity C-reactive protein, serum amyloid A protein, soluble E-selectin).

Conclusions: Novel mechanisms for hesperetin action in endothelial cells inform effects of oral hesperidin treatment to improve endothelial dysfunction and reduce circulating markers of inflammation in our exploratory clinical trial. Hesperetin has vasculoprotective actions that may explain beneficial cardiovascular effects of citrus consumption.

 

[Michael Scally MD]

SPECIAL ISSUE: REVIEWS ON ADDICTION
Neuron

Addiction is a devastating disorder for addicted individuals and their families. Addiction has a global impact as well, in terms of both the economic costs and the manner in which addiction tears at the very fabric of society. Within this issue, Review articles provide insights into how research has shaped our understanding of the neural underpinnings of addiction and led to more informed treatment strategies, while more societal-focused NeuroViews further highlight the complexities associated with substance abuse and ways in which the field is moving toward addressing such issues. Related content is FREE through March 31st.


NeuroViews

The Doctor's Dilemma: Opiate Analgesics and Chronic Pain, by Howard L. Fields

Cognitive Enhancement: Promises and Perils, by Steven E. Hyman

Addiction: Pulling at the Neural Threads of Social Behaviors, by Nora D. Volkow, Ruben D. Baler, and Rita Z. Goldstein

Perspective

Potential Vulnerabilities of Neuronal Reward, Risk, and Decision Mechanisms to Addictive Drugs, by Wolfram Schultz

Reviews

Genetic Vulnerability and Susceptibility to Substance Dependence, by Laura Jean Bierut

How Addictive Drugs Disrupt Presynaptic Dopamine Neurotransmission, by David Sulzer

Drug-Evoked Synaptic Plasticity in Addiction: From Molecular Changes to Circuit Remodeling, by Christian Lüscher and Robert C. Malenka

Reward Mechanisms in Obesity: New Insights and Future Directions, by Paul J. Kenny

Impulsivity, Compulsivity, and Top-Down Cognitive Control, by Jeffrey W. Dalley, Barry J. Everitt, and Trevor W. Robbins

Neuroscience of Behavioral and Pharmacological Treatments for Addictions, by Marc N. Potenza, Mehmet Sofuoglu, Kathleen M. Carroll, and Bruce J. Rounsaville

 

[Michael Scally MD]

The diurnal rhythm in cortisol release has been addressed by the assessment of cortisol in saliva samples which allows measurement across the day in a relatively noninvasive manner. The general pattern is characterized by relatively high cortisol level on waking followed by a rise that reaches a peak at 30 min after waking, termed the cortisol awakening response (CAR), followed by a decline across the day reaching a nadir at midnight. Studies that fail to show an association of cortisol levels with clinical events have generally measured morning cortisol or serum cortisol that was not analyzed in relation to waking.

The few studies that have examined cortisol across the day find that flatter slopes or less steep declines in cortisol throughout the day are predictive of mortality in patient populations. In a study of elderly people, raised saliva evening levels of cortisol were predictive of mortality in women but not men, whereas high morning levels were predictive in men but not women. The interpretation of these findings is problematic because the presence of severe medical comorbidity in this population may either compound or obscure the association between diurnal cortisol patterns and mortality.

The Whitehall II study is a prospective cohort study targeting a large cohort of community-dwelling men and women. A major strength of this study is the possibility to determine diurnal cortisol pattern based on six saliva samples obtained over the course of a normal weekday: at waking, +30 mins +2.5 h, +8 h, +12 h, and bedtime. A further advantage is that the data include measurement of conventional risk factors and a follow-up of overall, cardiovascular, and noncardiovascular deaths based on comprehensive medical records. Researchers therefore sought to examine the association of diurnal patterns of cortisol with cardiovascular and noncardiovascular mortality in the Whitehall II study. More specifically, they examine two aspects of the diurnal cortisol pattern, the cortisol awakening response (CAR) and the diurnal slope in cortisol across the day.


Kumari M, Shipley M, Stafford M, Kivimaki M. Association of Diurnal Patterns in Salivary Cortisol with All-Cause and Cardiovascular Mortality: Findings from the Whitehall II Study. J Clin Endocrinol Metab:jc.2010-137. Association of Diurnal Patterns in Salivary Cortisol with All-Cause and Cardiovascular Mortality: Findings from the Whitehall II Study -- Kumari et al., 10.1210/jc.2010-2137 -- Journal of Clinical Endocrinology & Metabolism

Context: Evidence for the association of cortisol with mortality or disease events is mixed, possibly due to a failure to consider diurnal cortisol patterns.

Objective: Our objective was to examine the association of diurnal cortisol patterns throughout the day with cardiovascular and noncardiovascular mortality in a community-dwelling population.

Design: This was a prospective cohort study among 4047 civil servants, the Whitehall II study, United Kingdom. We measured diurnal cortisol patterns in 2002–2004 from six saliva samplesobtained over the course of a normal weekday: at waking, +30 min, +2.5 h, +8 h, +12 h, and bedtime. Participants were subsequently followed for all-cause and cause-specific mortality until January 2010.

Participants: Participants included 4047 men and women aged 61 yr on average at baseline.

Outcomes: We assessed all-cause, cardiovascular, and noncardiovascular death.

Results: There were 139 deaths, 32 of which were deaths due to cardiovascular disease, during a mean follow-up period of 6.1 yr. Flatter slopes in cortisol decline across the day were associated with increased risk of all-cause mortality (hazard ratio for 1 sd reduction in slope steepness 1.30; 95% confidence interval (CI) = 1.09–1.55). This excess mortality risk was mainly driven by an increased risk of cardiovascular deaths (hazard ratio = 1.87; 95% confidence interval = 1.32–2.64). The association with cardiovascular deaths was independent of a wide range of covariates measured at the time of cortisol assessment. There was no association between morning cortisol, the cortisol awakening response, and mortality outcomes.

Conclusions: These findings demonstrate, for the first time, the relationship between a flatter slope in cortisol levels across the day and an increased risk of cardiovascular disease mortality in a nonclinical population.

 

[Michael Scally MD]

The aim of this study was to investigate exclusively patients with endogenous subclinical hyperthyroidism who had not had previous thyroid disease and to exclude patients who developed subsequent overt hyperthyroidism. The aim was to see whether they had an increased risk of nonfatal cardiovascular disease, osteoporotic fracture, dysrhythmia, dementia, or cancer and whether there is a difference between patients with differing levels of serum TSH concentrations. A question to ask or ponder is what, if any, do these results mean to those that take thyroid replacement.


Vadiveloo T, Donnan PT, Cochrane L, Leese GP. The Thyroid Epidemiology, Audit, and Research Study (TEARS): Morbidity in Patients with Endogenous Subclinical Hyperthyroidism. J Clin Endocrinol Metab:jc.2010-693. The Thyroid Epidemiology, Audit, and Research Study (TEARS): Morbidity in Patients with Endogenous Subclinical Hyperthyroidism -- Vadiveloo et al., 10.1210/jc.2010-2693 -- Journal of Clinical Endocrinology & Metabolism

Objective: Our objective was to investigate the long-term outcomes for patients with endogenous subclinical hyperthyroidism (SH).

Design: Population record-linkage technology was used retrospectively to identify patients with SH and hospital admissions from January 1, 1993, to December 31, 2009.

Patients: All Tayside residents over 18 yr old with at least two serum TSH measurements below the reference range for at least 4 months apart and normal free T4/total T4 and normal total T3 concentrations at baseline were included as potential cases. Using a unique patient identifier, data linkage enabled a cohort of SH cases to be identified from biochemistry, prescription, admission, and radioactive iodine treatment records matched to five comparators from the general population.

Outcome Measures: The association between endogenous SH and cardiovascular disease, fracture, dysrhythmia, dementia, and cancer was assessed.

Results: Compared with the reference population, SH was associated with an increased risk of nonfatal cardiovascular morbidity, osteoporotic fracture, dysrhythmia, and dementia, with adjusted hazard ratios (HR) of 1.39 (1.22–1.58), 1.25 (1.04–1.50), 1.65 (1.26–2.17), and 1.64 (1.20–2.25), respectively. When SH patients who developed overt hyperthyroidism during follow-up were excluded, SH patients were associated with an increased risk of cardiovascular morbidity [HR = 1.36 (1.19–1.57)], dysrhythmia [HR = 1.39 (1.02–1.90)], and dementia [HR = 1.79 (1.28–2.51)] but not fracture and cancer.

Conclusion: Patients with endogenous SH have an increased risk of cardiovascular disease and dysrhythmia. There is an association with fracture and dementia that is not related to TSH concentration and therefore is less likely to be causally related. No association was found between SH and cancer.

 

[Michael Scally MD]

With the increased incidence of obesity worldwide, nonalcoholic fatty liver disease (NAFLD) has become a growing problem. NAFLD is a common and emergent condition now recognized as the most frequent cause of abnormal liver tests, especially in obese individuals. It is characterized by a wide spectrum of liver damage, ranging from simple macro vesicular steatosis to steatohepatitis (NASH), cirrhosis or liver carcinoma. In the general population, the estimated prevalence ranges from 3% to 24%, with most estimates in the 6% to 14% range. NAFLD is extremely common among patients undergoing bariatric surgery, ranging from 84% to 96%, these patients, 25% to 55% have NASH, 34% to 47% have fibrosis, and 2% to 12% have bridging fibrosis or cirrhosis.

Since the majority of NAFLD patients are asymptomatic, investigation usually begins after detection of abnormal liver enzymes on routine evaluation. Serum aspartate aminotransferase (AST) and, more commonly, alanine aminotransferase (ALT) show mild to moderate elevation. The correlation with gammaglutaril-transferase (GGT) remains uncertain. Therefore, there is no overall correlation between the degree of liver enzyme elevation and the level of damage observed on histopathological analysis, beyond most of the patients with NAFLD show normal liver chemistries.

NAFLD appears to be most strongly associated with obesity and insulin resistance. There is some correlation between the severity of NAFLD and other features of metabolic syndrome, such as high triglycerides and low HDL, suggesting that NAFLD is an hepatic manifestation of metabolic syndrome. Nonalcoholic steatohepatitis (NASH), which is the most severe histological form of NAFLD, is emerging as the most common clinically important form of liver disease in diabetes, obese patients and metabolic syndrome. NASH has been associated with slight elevation of liver enzymes (mostly ALT and GGT).

The “gold standard” for the diagnosis of NASH is liver biopsy, which allows one to differentiate simple bland steatosis from NASH. However, liver biopsy is an expensive and invasive method associated with a low, but important procedure risk. Ultrasound (US), computerized tomography (CT), Magnetic resonance imaging (MRI), and H magnetic resonance spectroscopy (H MRS) are noninvasive methods and should be preferred. One limitation being that US does not provide reliable quantitative information. Both the CT and MRI techniques are nonspecific and can be affected by processes such as excessive glycogen storage, edema and inflammation.

The aim of this study was to create a clinical laboratory score capable of identify individual with most risk for NASH in severely obese patients submitted to bariatric surgery. Using this score, the severity of fatty liver infiltration would be predicted without the risks associated with hepatic biopsy.


Pulzi FB, Cisternas R, Melo MR, Ribeiro CM, Malheiros CA, Salles JE. New clinical score to diagnose nonalcoholic steatohepatitis in obese patients. Diabetology & Metabolic Syndrome 2011, 3:3 (23 February 2011). http://www.dmsjournal.com/content/pdf/1758-5996-3-3.pdf

Background - Nonalcoholic fatty liver disease (NAFLD) is the most frequent disease associated with abnormal liver tests, that is characterized by a wide spectrum of liver damage, ranging from simple macro vesicular steatosis to steatohepatitis (NASH), cirrhosis or liver carcinoma. Liver biopsy is the most precise test to differentiate NASH from other stages of NAFLD, but it is an invasive and expensive method. This study aimed to create a clinical laboratory score capable of identify individual with NASH in severely obese patients submitted to bariatric surgery.

Methods - The medical records from 66 patients submitted to gastroplasty were reviewed. Their chemistry profile, abdominal ultrasound (US) and liver biopsy done during the surgical procedure were analyzed. Patients were classified into 2 groups according to liver biopsy: Non-NASH group - those patients without NAFLD or with grade I, II or III steatosis; and NASH group - those with steatohepatitis or fibrosis. The t-test was used to compare each variable with normal distribution between NASH and Non-NASH groups. When comparing proportions of categorical variables, we used chi-square or z-test, where appropriate. A p-value <0.05 was considered statistically significant.

Results - 83% of patients with obesity grades II or III showed NAFLD, and the majority was asymptomatic. Total Cholesterol (TC)[greater than or equal to]200mg/dL, alanine aminotransferase (ALT) [greater than or equal to]30U/L, AST/ALT ratio (AAR)[less than or equal to] 1, gammaglutaril-transferase (gammaGT)[greater than or equal to]30U/L and abdominal US, compatible with steatosis, showed association with NASH group. We proposed 2 scores: Complete score (TC, ALT, AAR, gammaGT and US) and the simplified score, where US was not included. The combination of biochemical and imaging results improved accuracy to 84.4% the recognition of NASH (sensitivity 70%, specificity 88.6%, NPV 91.2%, PPV 63. 6%).

Conclusion - Alterations in TC, ALT, AAR, gammaGT and US are related to the most risk for NASH. The combination of biochemical and imaging results improved accuracy to 84.4% the recognition of NASH. Additionally, negative final scores exclude the presence of an advanced illness. Using this score, the severity of fatty liver infiltration would be predicted without the risks associated with hepatic biopsy.

 

[Michael Scally MD]

Epilepsy, antiepileptic drugs, and the reproductive system have complex interactions and reproductive disorders are more common among men with epilepsy than in the general population. These effects seem to have an heterogeneous origin. Brain regulates hormonal secretion and it is sensitive to hormonal feedback; the neuroendocrine feedback system includes hypothalamus, pituitary, gonads, but also the amygdala that is linked to the hypothalamic-pituitary axis (HPA) involved in the regulation, production and secretion of sex hormones. Reproductive endocrine disorders associated with epilepsy can be expected, in view of the complex interconnections between the HPA and the limbic system: for example the involvement of medial temporal lobe regions in epilepsy may confer a predisposition for altered reproductive endocrine secretion and, consequently, reproductive function. It has been demonstrated that steroid receptor-mediated events may be indirectly associated with seizure phenomena in the central nervous system and can modulate the protective activity of some conventional antiepileptic drugs (AEDs). Moreover, AEDs may also alter sex hormones levels and interfere with reproductive function. The main hormonal and reproductive disturbances of epileptic patients can be summarized in the following groups:

- Functional clinical symptoms (erectile dysfunction-impotency, hyposexuality, premature ejaculation, diminished libido, potency, fertility and secondary sexual characteristics);

- Organic clinical symptoms (gynecomastia, testicular atrophy, loss of male escutcheon, reduced genital blood flow, reduced spermatogenesis);

- Laboratory examination of semen (number, morphology or motility of spermatozoa);

- Laboratory examination of hormones (estrogens, estradiol, progesterone, androgens, gonadotrophic releasing hormone, prolactin, gonadotropins);

- Secondary or concomitant psychological symptoms/diseases (depression, anxiety, psychological distress, diminished energy, mood, competitive drive, bone and muscle mass).

This review focuses on the reproductive endocrine effects of epilepsy and its treatment.


Verrotti A, Loiacono G, Laus M, Coppola G, Chiarelli F, Tiboni GM. Hormonal and reproductive disturbances in epileptic male patients: emerging issues. Reprod Toxicol. Hormonal and reproductive disturbances in epilepti... [Reprod Toxicol. 2011] - PubMed result

OBJECTIVE: To review the relationship between epilepsy, antiepileptic drugs and reproductive function.

METHODS: Pertinent articles were identified through a computer PubMed search. References of selected articles were hand searched for additional citations.

CONCLUSIONS: Disturbances of reproductive endocrine hormones occur more frequently in men with epilepsy than in the general population; they manifest as loss of libido, impotence and infertility. These disturbances can be caused by epilepsy itself, by chronic use of antiepileptic drugs (AEDs) or both. AEDs can induce various hormonal abnormalities; in particular, the use of the liver enzyme inducing AEDs, such as phenobarbital, phenytoin and carbamazepine, which increases serum sex hormone binding globulin (SHBG) concentrations. This increase leads to diminished bioactivity of testosterone, which may result in diminished potency and thus reduced fertility. Men taking valproic acid have significantly higher dehydroepiandrosterone levels and lower gonadotropin concentration. Better understanding of molecular properties of AEDs and their effect on reproduction function will be the basis for on management of men suffering from epilepsy.

 

[Michael Scally MD]

Acne vulgaris, the most common dermatological disease, has evolved to an epidemic in western countries, affecting more than 85% of adolescents and often persisting into adulthood. Adults in the US within the age range of 20–29 years, exhibit acne prevalence rates of 50.9% in women and 42.5% in men, respectively. In contrast, acne is absent in non-westernized populations such as the Inuit, Okinawa islanders, Ache hunter-gatherers and Kitavan islanders which do not consume milk and dairy products and ingest less carbohydrates with high glycemic index (GI). Thus, epidemiological observations clearly point to nutritional factors in the etiology of acne.

Until 2005, cross-sectional, case-control, cohort, and clinical intervention studies designed to address the relationship between diet and acne failed to incorporate adequate controls, objective measures, and appropriate statistical analyses. However, well-designed prospective studies published since 2005 provided evidence that components of western diets, particularly milk and dairy products and diets enriched in carbohydrates with high GI and glycemic load (GL) are associated with acne. It has been recognized that acne pathogenesis is closely related to the consumption of insulinemic foods providing increased growth factor signaling of insulin and insulin-like growth factor-I (IGF-I). Insulinotropic food, especially refined sugars and grains, potatoes, milk and dairy products are ubiquitous elements in western diet and comprise nearly 50% of the per capita energy intake.


Melnik BC. Evidence for acne-promoting effects of milk and other insulinotropic dairy products. Nestle Nutr Workshop Ser Pediatr Program 25011;67:131-45. Evidence for acne-promoting effects of milk and ot... [Nestle Nutr Workshop Ser Pediatr Program. 2011] - PubMed result

Acne vulgaris, the most common skin disease of western civilization, has evolved to an epidemic affecting more than 85% of adolescents. Acne can be regarded as an indicator disease of exaggerated insulinotropic western nutrition. Especially milk and whey protein-based products contribute to elevations of postprandial insulin and basal insulin-like growth factor-I (IGF-I) plasma levels. It is the evolutional principle of mammalian milk to promote growth and support anabolic conditions for the neonate during the nursing period. Whey proteins are most potent inducers of glucose-dependent insulinotropic polypeptide secreted by enteroendocrine K cells which in concert with hydrolyzed whey protein-derived essential amino acids stimulate insulin secretion of pancreatic beta-cells. Increased insulin/IGF-I signaling activates the phosphoinositide-3 kinase/Akt pathway, thereby reducing the nuclear content of the transcription factor FoxO1, the key nutrigenomic regulator of acne target genes. Nuclear FoxO1 deficiency has been linked to all major factors of acne pathogenesis, i.e. androgen receptor transactivation, comedogenesis, increased sebaceous lipogenesis, and follicular inflammation. The elimination of the whey protein-based insulinotropic mechanisms of milk will be the most important future challenge for nutrition research. Both, restriction of milk consumption or generation of less insulinotropic milk will have an enormous impact on the prevention of epidemic western diseases like obesity, diabetes mellitus, cancer, neurodegenerative diseases and acne.

 

[Michael Scally MD]

Nonalcoholic Steatohepatitis

With the increased incidence of obesity worldwide, nonalcoholic fatty liver disease (NAFLD) has become a growing problem. NAFLD is a common and emergent condition now recognized as the most frequent cause of abnormal liver tests, especially in obese individuals. It is characterized by a wide spectrum of liver damage, ranging from simple macro vesicular steatosis to steatohepatitis (NASH), cirrhosis or liver carcinoma. In the general population, the estimated prevalence ranges from 3% to 24%, with most estimates in the 6% to 14% range. NAFLD is extremely common among patients undergoing bariatric surgery, ranging from 84% to 96%, these patients, 25% to 55% have NASH, 34% to 47% have fibrosis, and 2% to 12% have bridging fibrosis or cirrhosis.

Since the majority of NAFLD patients are asymptomatic, investigation usually begins after detection of abnormal liver enzymes on routine evaluation. Serum aspartate aminotransferase (AST) and, more commonly, alanine aminotransferase (ALT) show mild to moderate elevation. The correlation with gammaglutaril-transferase (GGT) remains uncertain. Therefore, there is no overall correlation between the degree of liver enzyme elevation and the level of damage observed on histopathological analysis, beyond most of the patients with NAFLD show normal liver chemistries. NAFLD appears to be most strongly associated with obesity and insulin resistance. There is some correlation between the severity of NAFLD and other features of metabolic syndrome, such as high triglycerides and low HDL, suggesting that NAFLD is an hepatic manifestation of metabolic syndrome.

Nonalcoholic steatohepatitis (NASH), which is the most severe histological form of NAFLD, is emerging as the most common clinically important form of liver disease in diabetes, obese patients and metabolic syndrome. NASH has been associated with slight elevation of liver enzymes (mostly ALT and GGT).

The “gold standard” for the diagnosis of NASH is liver biopsy, which allows one to differentiate simple bland steatosis from NASH. However, liver biopsy is an expensive and invasive method associated with a low, but important procedure risk. Ultrasound (US), computerized tomography (CT), Magnetic resonance imaging (MRI), and H magnetic resonance spectroscopy (H MRS) are noninvasive methods and should be preferred. One limitation being that US does not provide reliable quantitative information. Both the CT and MRI techniques are nonspecific and can be affected by processes such as excessive glycogen storage, edema and inflammation.

The aim of this study was to create a clinical laboratory score capable of identify individual with most risk for NASH in severely obese patients submitted to bariatric surgery. Using this score, the severity of fatty liver infiltration would be predicted without the risks associated with hepatic biopsy.


Pulzi FB, Cisternas R, Melo MR, Ribeiro CM, Malheiros CA, Salles JE. New clinical score to diagnose nonalcoholic steatohepatitis in obese patients. Diabetology & Metabolic Syndrome 2011, 3:3 (23 February 2011). http://www.dmsjournal.com/content/pdf/1758-5996-3-3.pdf

Background - Nonalcoholic fatty liver disease (NAFLD) is the most frequent disease associated with abnormal liver tests, that is characterized by a wide spectrum of liver damage, ranging from simple macro vesicular steatosis to steatohepatitis (NASH), cirrhosis or liver carcinoma. Liver biopsy is the most precise test to differentiate NASH from other stages of NAFLD, but it is an invasive and expensive method. This study aimed to create a clinical laboratory score capable of identify individual with NASH in severely obese patients submitted to bariatric surgery.

Methods - The medical records from 66 patients submitted to gastroplasty were reviewed. Their chemistry profile, abdominal ultrasound (US) and liver biopsy done during the surgical procedure were analyzed. Patients were classified into 2 groups according to liver biopsy: Non-NASH group - those patients without NAFLD or with grade I, II or III steatosis; and NASH group - those with steatohepatitis or fibrosis. The t-test was used to compare each variable with normal distribution between NASH and Non-NASH groups. When comparing proportions of categorical variables, we used chi-square or z-test, where appropriate. A p-value <0.05 was considered statistically significant.

Results - 83% of patients with obesity grades II or III showed NAFLD, and the majority was asymptomatic. Total Cholesterol (TC)[greater than or equal to]200mg/dL, alanine aminotransferase (ALT) [greater than or equal to]30U/L, AST/ALT ratio (AAR)[less than or equal to] 1, gammaglutaril-transferase (gammaGT)[greater than or equal to]30U/L and abdominal US, compatible with steatosis, showed association with NASH group. We proposed 2 scores: Complete score (TC, ALT, AAR, gammaGT and US) and the simplified score, where US was not included. The combination of biochemical and imaging results improved accuracy to 84.4% the recognition of NASH (sensitivity 70%, specificity 88.6%, NPV 91.2%, PPV 63. 6%).

Conclusion - Alterations in TC, ALT, AAR, gammaGT and US are related to the most risk for NASH. The combination of biochemical and imaging results improved accuracy to 84.4% the recognition of NASH. Additionally, negative final scores exclude the presence of an advanced illness. Using this score, the severity of fatty liver infiltration would be predicted without the risks associated with hepatic biopsy.

 

[Michael Scally MD]

2010 Census Count

The 2010 Census represented the most massive participation movement ever witnessed in our country. Approximately 74 percent of the households returned their census forms by mail; the remaining households were counted by census workers walking neighborhoods throughout the United States. National and state population totals from the 2010 Census were released on December 21, 2010. Redistricting data, which include additional state, county and local counts, will be released starting in February 2011. 2010 Census

 

[Michael Scally MD]

In this study, researchers determined the PK profiles of oral T alone and combined with the 5alpha-reductase inhibitor D in hypogonadal men during 28 days of dosing to assess the feasibility of this approach for treating male hypogonadism.


Amory JK, Bush MA, Zhi H, et al. Oral testosterone with and without concomitant inhibition of 5alpha-reductase by dutasteride in hypogonadal men for 28 days. J Urol 2011;185(2):626-32. Oral testosterone with and without concomitant inh... [J Urol. 2011] - PubMed result

PURPOSE: Co-administration of the 5alpha-reductase inhibitor dutasteride increases the oral testosterone bioavailability in men with experimentally induced hypogonadism. We examined oral testosterone with and without dutasteride administration in hypogonadal men for 28 days.

MATERIALS AND METHODS: We randomly assigned 43 hypogonadal men to twice daily oral doses of 150, 250 or 400 mg testosterone with 0.25 mg dutasteride, 400 mg testosterone alone or 0.25 mg dutasteride alone for 28 days in a multicenter study. Subjects underwent pharmacokinetic profiling of serum hormones on days 1 and 28. A total of 32 men completed all study procedures.

RESULTS: Serum testosterone increased in all groups on testosterone compared with that in the dutasteride only group. At the 400 mg dose the combination of testosterone and dutasteride resulted in average testosterone concentrations that were 2.7 and 4.6 times higher than in the testosterone only group on days 1 and 28, respectively (p <0.01). On day 28 average testosterone was 20% to 30% lower in all groups on testosterone and dutasteride, and 50% lower in the testosterone only group compared with day 1. Serum dihydrotestosterone was suppressed in all groups on dutasteride and increased in the testosterone only group.

CONCLUSIONS: Oral testosterone administration resulted in a therapeutic serum testosterone concentration in hypogonadal men. Dutasteride improved the oral bioavailability of testosterone while suppressing dihydrotestosterone. Compared with day 1, testosterone was decreased after 28 days of administration. Additional study is warranted of oral testosterone with dutasteride for testosterone deficiency.

 

[Michael Scally MD]

This investigation to estimate the prospective effect of serum testosterone on health care utilization and costs using data obtained from the cohort Study of Health in Pomerania (SHIP) conducted from 1997 to 2006 among the general population of West Pomerania, Germany.


Haring R, Baumeister SE, Volzke H, et al. Prospective association of low serum total testosterone levels with health care utilization and costs in a population-based cohort of men. Int J Androl 2010;33(6):800-9. Prospective association of low serum total testost... [Int J Androl. 2010] - PubMed result

Despite the burgeoning interest in the field of andrology, no studies have specifically addressed the impact of serum testosterone levels on healthcare utilization and costs. We analysed data from the population-based cohort Study of Health in Pomerania (SHIP), Germany, to assess the association of serum testosterone levels with self-reported health care utilization and costs at baseline and at 5 years follow up. Study sample comprised 2023 men at baseline, of whom 1530 men were repeatedly examined. Low and high serum testosterone levels, defined according to the age-specific 10th and 90th percentile, were compared with reference subjects with serum testosterone levels >/=10th -</=90th percentile. Two-part econometric models were applied adjusting for socio-economic and medical confounders. Cross-sectional models revealed higher numbers of outpatient visits and higher costs for both, men with low (+19.1 and +19.9%, respectively) and high serum testosterone levels (+25.3 and +30.2%, respectively), whereas number of inpatient days and costs were not associated with serum testosterone levels. Adjustment for age, educational level, income, waist circumference, smoking status, physical activity and alcohol consumption did not considerably alter the results. Longitudinal models revealed a significant association of low serum testosterone levels with increased number of follow-up outpatient visits (age-adjusted: +28.6%) and costs (+38.0%) only. Low and high serum testosterone levels were associated with increased short-term outpatient health care costs, whereas low serum testosterone levels appear to be predictive of long-term outpatient health care costs. Cost-effectiveness studies of available treatments are necessary to identify benefits for physicians, patients and health care system as a whole.

 

[Michael Scally MD]

What is 5b?

Nagata N, Miyakawa M, Amano S, Furuya K, Yamamoto N, Inoguchi K. Design and synthesis of tricyclic tetrahydroquinolines as a new series of nonsteroidal selective androgen receptor modulators (SARMs). Bioorg Med Chem Lett. Design and synthesis of tricyclic tetrahydroquinol... [Bioorg Med Chem Lett. 2011] - PubMed result

Some tricyclic tetrahydroquinolines (THQs) were found to have the potential of a new series of nonsteroidal selective androgen receptor modulators (SARMs). Compound 5b was first designed and synthesized under our hypothesis based on a four-point pharmacophoric requirement of the 3-carbonyl, 18-methyl, 17-hydroxyl, and 13-quaternary carbon groups of dihydrotestosterone (DHT). It was revealed that this compound exhibits not only a strong androgen receptor (AR) agonistic activity (EC(50)=9.2nM) but also the highest selectivity in binding affinity to AR among the steroid hormone receptors. Furthermore, this compound showed a weak virilizing effect with retention of the desired anabolic effect as compared with DHT in vivo.

 

[Michael Scally MD]

Prostate Guideline Causes Many Needless Biopsies, Study Says
http://www.nytimes.com/2011/03/01/health/research/01prostate.html

By NICHOLAS BAKALAR
Published: February 27, 2011

Current guidelines for the early detection of prostate cancer recommend a biopsy for men whose P.S.A. rises rapidly, no matter what the initial level. But a new study says that the practice does not help patients find aggressive cancers and results in many unnecessary biopsies.

P.S.A., or prostate-specific antigen, rises with age, and what is considered normal varies. In general, a level under 4 nanograms per milliliter is considered safe. But even with a normal reading, an increase of 0.35 nanograms per year is widely believed to be high enough to require a biopsy.

Researchers examined the records of 5,519 men with a base-line P.S.A. under 3. They followed them for seven years with yearly tests and a biopsy if the level rose above 4.

They also analyzed P.S.A. velocity — the rate of change in readings from year to year. But after adjusting for age, base-line P.S.A. and other factors, they found little evidence that ordering a biopsy for men whose velocity was greater than 0.35 helped find prostate cancer. And it was particularly useless in uncovering the most aggressive types of cancer, the ones most important to treat.

The researchers, writing in the March 16 issue of The Journal of the National Cancer Institute, concluded that using P.S.A. velocity for prostate cancer detection is ineffective, that it leads to unnecessary biopsies and that references to it should be removed from professional guidelines and policy statements.

Andrew J. Vickers, the lead author, drew an analogy: A basketball player’s height, he said, is important to his ability to play, and it correlates very closely with his shoe size. But once you know his height, his shoe size is irrelevant to judging his value as a player.

Similarly, it is easy to demonstrate a statistical relationship between sharp rises in P.S.A. and cancer, but the correlation reveals no more information than is already available with a P.S.A. reading, a digital examination and a family history. It is irrelevant in deciding whether a biopsy is needed.

Not all experts agree. Dr. Anthony V. D’Amico, a professor of radiation oncology at Harvard, said that the methodology of Dr. Vickers’s study was sound, but that the data gathered was almost certainly flawed.

The problem, Dr. D’Amico said, is that many factors that have nothing to do with prostate cancer can cause a rapid increase in prostate-specific antigen. Sexual activity, riding on a bicycle or on horseback, a recent colonoscopy, a bladder or prostate infection, even variations in the ways laboratories perform the test can radically affect the readings.

“It may well be that the high velocity in your case is not important,” he said. “But before you reach that conclusion, I would get a repeat P.S.A.” If there is still a spike after eliminating those other possible causes, he continued, a biopsy should be the next step.

Dr. Vickers, a researcher at Memorial Sloan-Kettering Cancer Center in New York, agreed that prostate cancer was only one of many reasons for a high P.S.A. “A doctor sees a high P.S.A. and says, ‘Could this be cancer or some other reason?’ ” he said. “Well, the thought was that P.S.A. velocity could help you think this through” — that measuring the rate of change would be decisive.

But in practice, Dr. Vickers said, it does not work. If he had strictly applied the guidelines to the men in his study, he said, one in every seven would have required a biopsy. This would mean millions of American men would need biopsies, he said, with almost none revealing a cancer.

Dr. Vickers and his colleagues acknowledged that there might be better methods of calculating P.S.A. velocity that could lead to more accurate predictions, and that some effect might have been found if the patients had been followed for more than seven years.

But at this point, he is firmly against biopsies on the basis of velocity alone. “If your P.S.A. is in the normal range, you shouldn’t get a biopsy,” he said. “Changes or spikes in P.S.A. are not something to worry about if your P.S.A. is still normal.”


Vickers AJ, Till C, Tangen CM, Lilja H, Thompson IM. An Empirical Evaluation of Guidelines on Prostate-specific Antigen Velocity in Prostate Cancer Detection. Journal of the National Cancer Institute. An Empirical Evaluation of Guidelines on Prostate-specific Antigen Velocity in Prostate Cancer Detection — J. Natl. Cancer Inst.

Background The National Comprehensive Cancer Network and American Urological Association guidelines on early detection of prostate cancer recommend biopsy on the basis of high prostate-specific antigen (PSA) velocity, even in the absence of other indications such as an elevated PSA or a positive digital rectal exam (DRE).

Methods To evaluate the current guideline, we compared the area under the curve of a multivariable model for prostate cancer including age, PSA, DRE, family history, and prior biopsy, with and without PSA velocity, in 5519 men undergoing biopsy, regardless of clinical indication, in the control arm of the Prostate Cancer Prevention Trial. We also evaluated the clinical implications of using PSA velocity cut points to determine biopsy in men with low PSA and negative DRE in terms of additional cancers found and unnecessary biopsies conducted. All statistical tests were two-sided.

Results Incorporation of PSA velocity led to a very small increase in area under the curve from 0.702 to 0.709. Improvements in predictive accuracy were smaller for the endpoints of high-grade cancer (Gleason score of 7 or greater) and clinically significant cancer (Epstein criteria). Biopsying men with high PSA velocity but no other indication would lead to a large number of additional biopsies, with close to one in seven men being biopsied. PSA cut points with a comparable specificity to PSA velocity cut points had a higher sensitivity (23% vs 19%), particularly for high-grade (41% vs 25%) and clinically significant (32% vs 22%) disease. These findings were robust to the method of calculating PSA velocity.

Conclusions We found no evidence to support the recommendation that men with high PSA velocity should be biopsied in the absence of other indications; this measure should not be included in practice guidelines.

 

[Michael Scally MD]

Doctors who get their news from free journals funded by advertisers should be wary -- they may just be reading biased recommendations for advertised drugs, researchers found.

A cross-sectional study of 2007 issues of 11 German journals published found free journals were more likely to recommend specific drugs advertised in the same issue than were those with revenue derived from a mix of subscriptions and advertising or from subscriptions alone, Annette Becker, MD, MPH, of the University of Marburg, and colleagues reported inCMAJ.

The researchers reviewed 465 issues of 11 journals for writings on nine drugs or drug classes. The drugs chosen had patents in effect, so they were likely to be more expensive, and there was some controversy over their effectiveness or indications for use.

There were 592 advertisements for those drugs in 312 of the issues reviewed. The free journals recommended for or against the chosen drug in 256 articles in 250 issues, after accounting for repeat ads and recommendations.

The number of ads in each issue ranged from 14 to 161, while the number of recommendations per issue ranged from 2 to 105.

This was compared against 46 advertisements for and 7 articles recommending a drug in journals with multiple sources of income, and 34 articles with drug recommendations from journals sustained through subscription.

Independent journal reviewers (dental students) rated the strength of the recommendations on a five-point scale from -2 (recommending against) to +2 (recommending for).

The free journals averaged a recommendation strength score of 1.9, while the mixed-revenue journals averaged 0.86 and the subscription-only journals averaged -1.03.

A logistic regression model of the free journals showed that the frequency of recommendations depended on the journal, and that recommendations for the drug increased when the drug was advertised in a particular issue.

For example, against the reference drug clopidogrel, glitazones were recommended nearly three-to-one at an odds ratio of 2.61 (95% CI 1.59 to 4.2).

Recommendations for incretin mimetics against the clopidogrel reference had an odds ratio of 3.15 (95% CI 1.93 to 5.14), while angiotensin-receptior blockers had an odds ratio of 5.18 (95% CI 3.20 to 8.40). The model also found that in two of the free journals, the odds of a drug receiving a positive review more than doubled if that same drug was advertised in that issue.

The authors noted a seperate survey of Canadian general practitioners that found most healthcare professionals considered journals that did not have a peer review process -- which predominantly included free journals -- as unreliable information sources, but more than half of those surveyed said they used free journals as a source of information in the past month.

"Physicians need to realize that the alternatives are to either pay for journals with objective information or rely on potentially biased information published in free journals," the authors wrote in their conclusion.

The authors noted their study was limited by a number of factors, including that the researchers only included a single mixed-revenue journal in the study and that advertisements were not reviewed for adverse events or other similar boxed warnings and safety information. In addition, over time, independent raters became more apt at recognizing how the journal they were reading was funded.

Finally, the study was limited to German journals. However, the authors noted that free journals in the U.S. are similar to those in Germany and that results could be generalized between countries.

Medical News: Recommendations in Free Journals May Be Biased - in Public Health & Policy, General Professional Issues from MedPage Today



Becker A, Dorter F, Eckhardt K, et al. The association between a journal's source of revenue and the drug recommendations made in the articles it publishes. CMAJ:cmaj.100951. http://www.cmaj.ca/cgi/rapidpdf/cmaj.100951v1.pdf

Background: There is evidence to suggest that pharmaceutical companies influence the publication and content of research papers. Most German physicians rely on journals for their continuing medical education. We studied the influence of pharmaceutical advertising on the drug recommendations made in articles published in 11 German journals that focus on continuing medical education.

Methods: We conducted a cross-sectional study of all of the issues of 11 journals published in 2007. Only journals frequently read by general practitioners were chosen. Issues were screened for pharmaceutical advertisements and recommendations made in the editorial content for a specified selection of drugs. Each journal was rated on a five-point scale according to the strength with which it either recommended or discouraged the use of these drugs. We looked for differences in these ratings between free journals (i.e., those financed entirely by pharmaceutical advertising), journals with mixed sources of revenue and journals financed solely by subscription fees. The journals were also screened for the simultaneous appearance of advertisements and recommendations for the same drug within a certain period, which was adjusted for both journal and class of drug.

Results: We identified 313 issues containing at least one advertisement for the selected drugs and 412 articles in which drug recommendations were made. Free journals were more likely to recommend the specified drugs than journals with sources of revenue that were mixed or based solely on subscriptions. The simultaneous appearance of advertisements and recommendations for the same drug in the same issue of a journal showed an inconsistent association.

Interpretation: Free journals almost exclusively recommended the use of the specified drugs, whereas journals financed entirely with subscription fees tended to recommend against the use of the same drugs. Doctors should be aware of this bias in their use of material published in medical journals that focus on continuing medical education.

 

[Michael Scally MD]

Male depression ‘set to increase’
BBC News - Male depression 'set to increase'

1 March 2011

Psychiatrists have warned that the number of men with depression could rise because of changes in Western society.

An article in the British Journal of Psychiatry suggests economic and social changes will erode traditional sources of male self-esteem.

The authors say men will struggle with the shift away from traditional male and female roles.

The Men's Health Forum said male identity was bound up in employment.

One of the authors, Dr Boadie Dunlop from Emory University School of Medicine, said: "Women are almost twice as likely to develop major depressive disorder in their lifetime as men, but we believe this difference may well change in the coming decades."

He argues that traditional males jobs such as manufacturing or physical labour are being lost, either through improved technology or jobs moving to other countries.

On the other hand the article states that as women are now more likely to go to university than men so the number of households where the main breadwinner is female will increase.

Male identity

"Men's failure to fulfil the role of breadwinner is associated with greater depression and martial conflict," the article states.

Dr Dunlop said: "Western men will face a difficult road in the 21st century, particularly those with low levels of education. We believe economic and societal changes will have significant implications for men's mental health."

Peter Baker, chief executive of the Men's Health Forum, said: "This really confirms what we already know about unemployment and that it has a much bigger impact on men, mainly because male identity is bound up as a worker.

"Male social networks are based around work so losing a job can lead to isolation and depression."

Dr Cosmo Hallstrom, a consultant psychiatrist, said: "If you've spent 20 years pouring steel and the mill closes you can't just go and do something else.

"It seems self evident in a recession with joblessness that it will be bad for physical and mental health and some people will get depression.

"Having to send your wife out and feel like a parasite surely would put up the rate of depression, but overall is it unique to men? I don't know."

Mr Baker said men do not seek help when they have depression and were "more likely to self medicate in the pub" than seek professional care.

He said: "As we see more men affected we need to think about how to support and get them back to work."


Dunlop BW, Mletzko T. Will current socioeconomic trends produce a depressing future for men? The British Journal of Psychiatry 2011;198(3):167-8. Will current socioeconomic trends produce a depressing future for men? -- Dunlop and Mletzko 198 (3): 167 -- The British Journal of Psychiatry

The changing economic and social environment of Western nations is having a profound impact on men's lives. Men who assume a greater share of roles traditionally filled by women will experience challenges to traditional sources of male self-esteem, potentially heightening the risk for depressive disorders among men.

 

[Michael Scally MD]

Texas HB 1290

A curious event happened in Texas last year that went almost unnoticed. With little fanfare, the governor signed into law a new bill on June 19, 2009, that took effect September 1, mandating insurance coverage for imaging tests used for cardiovascular disease (CVD) screening. [Texas House Bill 1290 (HB 1290). ]Texas Legislature Online Texas HB 1290 quietly made its way into law but its ramifications will ring loudly. Despite the quiet birth of this bill, its impact and the debate surrounding its merits will reverberate for some time. In the early period, a few considerations are worthy of discussion: How did this bill come about? What are the potential implications of this legislation? Where does this bill fit in the broader construct of legislative advocacy for heart disease and other illnesses?

While atherosclerosis imaging tests may someday play a valuable role in broader screening for CVD risk, the current data supporting population-level implementation of these tests are far from sufficient to warrant legislative action. Only time will tell whether HB 1290 will be viewed as bold legislation that improved public health or an example of the unintended consequences of putting the cart before the horse.


Khera A. Texas Atherosclerosis Imaging Bill: Quiet Origins, Broad Implications. Arch Intern Med 2011;171(4):281-3. Arch Intern Med -- Sign In Page

 

[Michael Scally MD]

Overweight and obese individuals are at a greater risk for developing coronary heart disease and type 2 diabetes, compared to their normal-weight counterparts. Weight loss has been shown to lower the risk of these diseases in obese individuals by modulating several key biomarkers. More specifically, losing 5–15% of initial body weight is associated with improved plasma lipid profile, decreased systolic and diastolic blood pressure, and increased insulin sensitivity. Although the mechanisms that link weight loss to disease risk reduction remain unclear, evidence suggests fat-cell-derived hormones (i.e., adipokines) may play a role. Adiponectin is a fat-cell-derived hormone shown to be inversely related to body weight and visceral fat mass, though the data are not consistent. This hormone is also currently thought to exert cardioprotective effects. Leptin, resistin, interleukin 6 (IL-6), interleukin 8 (IL-8), monocyte chemotactic protein 1 (MCP-1), and retinol-binding protein 4 (RBP-4), in contrast, are adipokines that are augmented in overweight and obese individuals and exhibit proinflammatory properties. Thus, diet therapies that are able to increase adiponectin concentrations while decreasing leptin, resistin, IL-6, IL-8,MCP-1, and RBP-4 concentrations may confer protection against chronic disease in obese patients.

Calorie restriction (CR) regimens are the most commonly prescribed diet strategies to help overweight and obese individuals lose weight. CR regimens typically involve restricting energy intake from 15% to 40% of needs daily. More extreme CR regimens that require an individual to restrict energy intake by up to 75% of daily requirements (i.e., very-low-calorie diets) have also been implemented to induce rapid weight loss. Previous reports indicate that CR-induced weight loss beneficially affects plasma levels and expression of key adipokines. What has yet to be determined, however, is the minimal degree of weight loss required to improve the expression and levels of each of these adipokines. Moreover, the dose-response effect of body weight loss and visceral fat mass loss on adipokine concentrations also remains unclear.

This review examines how varying degrees of Calorie restriction (CR) -induced weight loss (i.e., >10% from baseline, 5–10% from baseline, and <5% from baseline) impacts adiponectin, leptin, resistin, IL-6, IL-8, MCP-1, and RBP-4 plasma levels and expression. The dose response relationship between visceral fat mass loss and adipokine profile improvement will also be explored. Only randomized clinical trials of CR (conducted from 1999 until present) performed in adults were included in the review. Trials that included diabetic individuals were excluded from the analysis.


Klempel MC, Varady KA. Reliability of leptin, but not adiponectin, as a biomarker for diet-induced weight loss in humans. Nutr Rev 2011;69(3):145-54. Reliability of leptin, but not adiponectin, as a b... [Nutr Rev. 2011] - PubMed result

Calorie restriction (CR)-induced weight loss has been shown to lower the risk of chronic disease in obese individuals. Although the mechanisms that link weight loss to disease risk reduction remain unclear, evidence suggests adipokines may play a role. What has yet to be determined, however, is the dose-response effect of body weight loss and visceral fat mass loss on adipokines. Accordingly, this review examines how varying degrees of CR-induced weight loss (i.e., >10%, 5-10%, and <5% from baseline) impact plasma levels and expression of adiponectin, leptin, resistin, interleukin 6 (IL-6), interleukin 8 (IL-8), monocyte chemotactic protein 1 (MCP-1), and retinol-binding protein 4 (RBP-4). The dose-response relationship between visceral fat mass loss and adipokine profile improvement will also be explored. Results from this review demonstrate that even mild weight loss induced by CR may have beneficial effects on leptin levels, but it has no clear impact on adiponectin, resistin, IL-6, IL-8, MCP-1, or RBP-4 concentrations.

 

[Michael Scally MD]

Most risk factors are not useful as screening tests for the diseases with which they are associated because the association is too small, even if they are large enough to have important causal implications. A risk factor (which may be causal or noncausal) has to be very strongly associated with a disease to be seriously considered as a possible screening test. For example, the odds ratio between the highest and lowest 20% of the population needs to be about 50 or more. Despite this, it is often suggested that a particular risk factor may be a useful screening test or disease predictor, even though it can be deduced from published relative risk estimates that this cannot be the case. For example (considered further in the subsection titled "Example 1: CRP as Possible Test for CHD" in the "Four Examples" section), C-reactive protein (CRP) is not useful as a screening test, even though it has been suggested as a possible predictor of ischemic heart disease.

There are few risk factors with odds ratios that are high enough to qualify as disease predictors or screening tests. DNA polymorphisms, sometimes promoted as being predictive of common diseases, are, for practical purposes, useless when used in this way—most polymorphisms associated with particular diseases have relative risks of less than 2. Their utility lies in elucidating the pathogenesis of disease rather than predicting disease. Even etiologically important risk factors, such as blood pressure and serum cholesterol (or apolioprotein B), that are important causes of cardiovascular disease (CVD), have odds ratios too low to be of much value in predicting disease. Herein, they limit their consideration of risk factors to their use as predictors of disease.


Wald NJ, Morris JK. Assessing Risk Factors as Potential Screening Tests: A Simple Assessment Tool. Arch Intern Med. Arch Intern Med -- Sign In Page

Many risk factors for disease are suggested as screening tests when there is little prospect that they could be useful in predicting disease. To avoid this, it is useful to know the relationship between the relative risk of a disease or disorder in people with high and low values of a risk factor, and the equivalent screening performance in terms of the detection rate (sensitivity) for a specified false-positive rate. We describe an interactive Risk-Screening Converter, accessible from the Internet (http://www.wolfson.qmul.ac.uk/rsc/), that transforms an odds ratio into the equivalent estimates of detection and false-positive rates. The converter is intended for general clinicians, for people engaged in research into risk factors and disease, and for those who give advice on applying such research findings into medical practice. It should help to distinguish effective screening methods from ineffective ones, and so improve clinical guidelines relating to screening and the prediction and prevention of disease.

 

[Michael Scally MD]

Functional Variants of the HMGA1 Gene and Type 2 Diabetes Mellitus

"Scientists have identified a gene variant present in some people of white European descent who have type 2 diabetes" that could potentially be a future target for treatment, according to a study in the Journal of the American Medical Association. Investigators looked at people with and without diabetes in "about 6,500 Italian patients; close to 2,000 US residents; and about 400 French people." They found that about 7 to 8 percent of the study participants with type 2 diabetes had one of four HMGA1 gene variants. Notably, in the "Italian group, this represented a 16-fold higher risk in people with type 2 diabetes." The study found only 0.6% percent of the control group "carried HMGA1 defects." The HMGA1 findings "mark the first time an important protein has been identified as a genetic culprit in type 2 diabetes," said study co-author Ira D. Goldfine, MD, of the University of California San Francisco.

In an accompanying editorial, Abhimanyu Garg, MD, of the University of Texas Southwestern Medical Center wrote that the findings "strongly support the theory that insulin resistance is a key factor along the path to diabetes" but they will have to be confirmed by further research. Dr. Garg added, "it is anticipated that the discoveries of [new gene variants] such as HMGA1 will soon be translated into therapeutic decision-making."


Chiefari E, Tanyolac S, Paonessa F, et al. Functional Variants of the HMGA1 Gene and Type 2 Diabetes Mellitus. JAMA: The Journal of the American Medical Association;305(9):903-12. http://jama.ama-assn.org/content/305/9/903.abstract

Context High-mobility group A1 (HMGA1) protein is a key regulator of insulin receptor (INSR) gene expression. We previously identified a functional HMGA1gene variant in 2 insulin-resistant patients with decreased INSR expression and type 2 diabetes mellitus (DM).

Objective To examine the association of HMGA1 gene variants with type 2 DM.

Design, Settings, and Participants Case-control study that analyzed theHMGA1 gene in patients with type 2 DM and controls from 3 populations of white European ancestry. Italian patients with type 2 DM (n = 3278) and 2 groups of controls (n = 3328) were attending the University of Catanzaro outpatient clinics and other health care sites in Calabria, Italy, during 2003-2009; US patients with type 2 DM (n = 970) were recruited in Northern California clinics between 1994 and 2005 and controls (n = 958) were senior athletes without DM collected in 2004 and 2009; and French patients with type 2 DM (n = 354) and healthy controls (n = 50) were enrolled at the University of Reims in 1992. Genomic DNA was either directly sequenced or analyzed for specific HMGA1 mutations. Messenger RNA and protein expression for HMGA1 and INSR were measured in both peripheral lymphomonocytes and cultured Epstein-Barr virus–transformed lymphoblasts from patients with type 2 DM and controls.

Main Outcome Measures The frequency of HMGA1 gene variants among cases and controls. Odds ratios (ORs) for type 2 DM were estimated by logistic regression analysis.

Results The most frequent functional HMGA1 variant, IVS5-13insC, was present in 7% to 8% of patients with type 2 DM in all 3 populations. The prevalence of IVS5-13insC variant was higher among patients with type 2 DM than among controls in the Italian population (7.23% vs 0.43% in one control group; OR, 15.77 [95% confidence interval {CI}, 8.57-29.03]; P < .001 and 7.23% vs 3.32% in the other control group; OR, 2.03 [95% CI, 1.51-3.43]; P < .001). In the US population, the prevalence of IVS5-13insC variant was 7.7% among patients with type 2 DM vs 4.7% among controls (OR, 1.64 [95% CI, 1.05-2.57]; P = .03). In the French population, the prevalence of IVS5-13insC variant was 7.6% among patients with type 2 DM and 0% among controls (P = .046). In the Italian population, 3 other functional variants were observed. When all 4 variants were analyzed, HMGA1 defects were present in 9.8% of Italian patients with type 2 DM and 0.6% of controls. In addition to the IVS5 C-insertion, the c.310G>T (p.E104X) variant was found in 14 patients and no controls (Bonferroni-adjusted P = .01); the c.*82G>A variant (rs2780219) was found in 46 patients and 5 controls (Bonferroni-adjustedP < .001); the c.*369del variant was found in 24 patients and no controls (Bonferroni-adjusted P < .001). In circulating monocytes and Epstein-Barr virus–transformed lymphoblasts from patients with type 2 DM and the IVS5-13insC variant, the messenger RNA levels and protein content of both HMGA1 and the INSR were decreased by 40% to 50%, and these defects were corrected by transfection with HMGA1 complementary DNA.

Conclusions Compared with healthy controls, the presence of functional HMGA1gene variants in individuals of white European ancestry was associated with type 2 DM.


Garg A. HMGA1, A Novel Locus for Type 2 Diabetes Mellitus. JAMA: The Journal of the American Medical Association 2011;305(9):938-9. HMGA1, A Novel Locus for Type 2 Diabetes Mellitus, March 2, 2011, Garg 305 (9): 938 — JAMA

 

[Michael Scally MD]

Marijuana Use Precedes Psychosis
Medical News: Marijuana Use Precedes Psychosis - in Psychiatry, General Psychiatry from MedPage Today

Teens and young adults who started using cannabis had an increased risk of having psychotic experiences in subsequent years, a longitudinal German study showed.

Among young people who had never smoked pot and did not have any psychotic symptoms at baseline, those who started using the drug were nearly twice as likely to develop subclinical symptoms of psychosis (OR 1.9, 95% CI 1.1 to 3.1), Jim van Os, PhD, of Maastricht University Medical Center in the Netherlands, and colleagues reported online in BMJ.

In a separate analysis, those who used cannabis consistently were more likely to report persistent psychotic experiences at more than one follow-up visit (OR 2.2, 95% CI 1.2 to 4.2)

The findings were independent of age, sex, socioeconomic status, use of other drugs, childhood trauma, and urban/rural environment, and remained significant after further adjustment for other psychiatric diagnoses.

There was no evidence that psychotic symptoms precipitated cannabis use, which would have suggested a self-medication explanation for the association.

According to the researchers, the results help clarify the temporal association between cannabis use and psychotic experiences, which are common and generally transitory phenomena that could potentially progress to a clinical psychotic disorder in the presence of certain environmental risks.

"Our study confirmed cannabis as an environmental risk factor, impacting on risk of psychosis by increasing the risk of incident psychotic experiences, and, if use continues over time, increasing the risk of persistent psychotic experiences," van Os and his colleagues wrote.

Although cannabis has been consistently associated with psychosis in prior studies, there is an ongoing debate about whether the relationship is causal, whether it can be explained by residual confounding, or whether it can be explained by the use of the drug to self-medicate for existing psychotic symptoms.

In an accompanying editorial, Wayne Hall, PhD, of the University of Queensland in Herston, Australia, and Louisa Degenhardt, PhD, of the Burnet Institute in Melbourne, Australia, argued that the study findings discounted the latter two possibilities, leaving only a causal explanation.

"Sensible reasoning supports the policy of providing young people with information about the risks of using cannabis," they wrote. "The case for communication is strengthened by evidence that regular cannabis use in adolescence predicts poorer educational outcomes, increased risk of using other illicit drugs, increased risk of depression, and poorer social relationships in early adulthood."

Van Os and his colleagues examined data from the longitudinal, population-based EDSP (early developmental stages of psychopathology) study, which was conducted in the greater Munich area.

The current analysis included 1,923 individuals ages 14 to 24 at baseline in 1995. All completed follow-up visits at an average of 3.5 years and 8.4 years.

The presence of psychotic symptoms was measured using the Munich version of the composite international diagnostic interview (M-CIDI). Items addressing delusions, hallucinations, and passivity indicated the presence of subclinical psychotic experiences.

At baseline, 13% of the participants reported using cannabis at least five times at some point during their lives. That figure rose to 20% by the 3.5-year assessment.

The proportion of individuals overall who reported subclinical psychotic experiences was 23% at the 3.5-year visit and 12% at the 8.4-year visit. Rates were higher among those who reported using cannabis.

After adjusting for potential confounders, cannabis use was associated with both incident and persistent psychotic experiences.

Psychotic symptoms did not, however, precede cannabis use, which ruled out self-medication as an explanation for the association.

The researchers proposed that sensitization, in which repeated exposure to a stressor results in progressively greater responses over time, may explain the findings, "as our study showed that the risk of persistent psychotic experiences increases with longer periods of cannabis exposure."

They acknowledged some limitations, including the use of self-reported data, the lack of adjustment for a family history of psychosis, and possible bias from selected recall.


Kuepper R, van Os J, Lieb R, Wittchen H-U, Hofler M, Henquet Cc. Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study. BMJ 2011;342. http://www.bmj.com/content/342/bmj.d738.full.pdf / http://www.bmj.com/content/342/bmj.d738.full

Objective To determine whether use of cannabis in adolescence increases the risk for psychotic outcomes by affecting the incidence and persistence of subclinical expression of psychosis in the general population (that is, expression of psychosis below the level required for a clinical diagnosis).

Design Analysis of data from a prospective population based cohort study in Germany (early developmental stages of psychopathology study).

Setting Population based cohort study in Germany.

Participants 1923 individuals from the general population, aged 14-24 at baseline.

Main outcome measure Incidence and persistence of subthreshold psychotic symptoms after use of cannabis in adolescence. Cannabis use and psychotic symptoms were assessed at three time points (baseline, T2 (3.5 years), T3 (8.4 years)) over a 10 year follow-up period with the Munich version of the composite international diagnostic interview (M-CIDI).

Results In individuals who had no reported lifetime psychotic symptoms and no reported lifetime cannabis use at baseline, incident cannabis use over the period from baseline to T2 increased the risk of later incident psychotic symptoms over the period from T2 to T3 (adjusted odds ratio 1.9, 95% confidence interval 1.1 to 3.1; P=0.021). Furthermore, continued use of cannabis increased the risk of persistent psychotic symptoms over the period from T2 to T3 (2.2, 1.2 to 4.2; P=0.016). The incidence rate of psychotic symptoms over the period from baseline to T2 was 31% (152) in exposed individuals versus 20% (284) in non-exposed individuals; over the period from T2 to T3 these rates were 14% (108) and 8% (49), respectively.

Conclusion Cannabis use is a risk factor for the development of incident psychotic symptoms. Continued cannabis use might increase the risk for psychotic disorder by impacting on the persistence of symptoms.