The 11th edition of Harrison's Principles of Internal Medicine welcomes Anthony Fauci to its editorial staff, in addition to more than 85 new contributors. While the organization of the book is similar to previous editions, major emphasis has been placed on disorders that affect multiple organ systems. Important advances in genetics, immunology, and oncology are emphasized. Many chapters of the book have been rewritten and describe major advances in internal medicine. Subjects that received only a paragraph or two of attention in previous editions are now covered in entire chapters. Among the chapters that have been extensively revised are the chapters on infections in the compromised host, on skin rashes in infections, on many of the viral infections, including cytomegalovirus and Epstein-Barr virus, on sexually transmitted diseases, on diabetes mellitus, on disorders of bone and mineral metabolism, and on lymphadenopathy and splenomegaly. The major revisions in these chapters and many

Harrison's Principles of Internal Medicine

Background Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrho­ sis. Currently, there is no established treatment for this disease. Methods We randomly assigned 247 adults with nonalcoholic steatohepatitis and without dia­ betes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 weeks. The pri­ mary outcome was an improvement in histologic features of nonalcoholic steato­ hepatitis, as assessed with the use of a composite of standardized scores for steato­ sis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indi­ cate statistical significance. Results Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P = 0. 001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; P = 0. 04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pio­ glitazone, as compared with placebo (P<0.001 for both comparisons), and both agents were associated with reductions in hepatic steatosis (P = 0. 005 for vitamin E and P<0.001 for pioglitazone) and lobular inflammation (P = 0. 02 for vitamin E and P = 0. 004 for pioglitazone) but not with improvement in fibrosis scores (P = 0. 24 for vitamin E and P = 0. 12 for pioglitazone). Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups. Conclusions Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes. (ClinicalTrials.gov number, NCT000 63622.)

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Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis

This article represents the update of the European Stroke Initiative Recommendations for Stroke Management. These guidelines cover both ischaemic stroke and transient ischaemic attacks, which are now considered to be a single entity. The article covers referral and emergency management, Stroke Unit service, diagnostics, primary and secondary prevention, general stroke treatment, specific treatment including acute management, management of complications, and rehabilitation.

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Guidelines for management of ischaemic stroke and transient ischaemic attack 2008

ContextDietary patterns and lifestyle factors are associated with mortality
from all causes, coronary heart disease, cardiovascular diseases, and cancer,
but few studies have investigated these factors in combination.ObjectiveTo investigate the single and combined effect of Mediterranean diet,
being physically active, moderate alcohol use, and nonsmoking on all-cause
and cause-specific mortality in European elderly individuals.Design, Setting, and ParticipantsThe Healthy Ageing: a Longitudinal study in Europe (HALE) population,
comprising individuals enrolled in the Survey in Europe on Nutrition and the
Elderly: a Concerned Action (SENECA) and the Finland, Italy, the Netherlands,
Elderly (FINE) studies, includes 1507 apparently healthy men and 832 women,
aged 70 to 90 years in 11 European countries. This cohort study was conducted
between 1988 and 2000.Main Outcome MeasuresTen-year mortality from all causes, coronary heart disease, cardiovascular
diseases, and cancer.ResultsDuring follow-up, 935 participants died: 371 from cardiovascular diseases,
233 from cancer, and 145 from other causes; for 186, the cause of death was
unknown. Adhering to a Mediterranean diet (hazard ratio [HR], 0.77; 95% confidence
interval [CI], 0.68-0.88), moderate alcohol use (HR, 0.78; 95% CI, 0.67-0.91),
physical activity (HR, 0.63; 95% CI, 0.55-0.72), and nonsmoking (HR, 0.65;
95% CI, 0.57-0.75) were associated with a lower risk of all-cause mortality
(HRs controlled for age, sex, years of education, body mass index, study,
and other factors). Similar results were observed for mortality from coronary
heart disease, cardiovascular diseases, and cancer. The combination of 4 low
risk factors lowered the all-cause mortality rate to 0.35 (95% CI, 0.28-0.44).
In total, lack of adherence to this low-risk pattern was associated with a
population attributable risk of 60% of all deaths, 64% of deaths from coronary
heart disease, 61% from cardiovascular diseases, and 60% from cancer.ConclusionAmong individuals aged 70 to 90 years, adherence to a Mediterranean
diet and healthful lifestyle is associated with a more than 50% lower rate
of all-causes and cause-specific mortality.

https://jamanetwork.com/journals/jama/articlepdf/199485/JOC32767.pdf

Mediterranean Diet, Lifestyle Factors, and 10-Year Mortality in Elderly European Men and Women: The HALE Project

Objective To conduct a comprehensive systematic review and meta-analysis of studies assessing the effect of alcohol consumption on multiple cardiovascular outcomes. Design Systematic review and meta-analysis. Data sources A search of Medline (1950 through September 2009) and Embase (1980 through September 2009) supplemented by manual searches of bibliographies and conference proceedings. Inclusion criteria Prospective cohort studies on the association between alcohol consumption and overall mortality from cardiovascular disease, incidence of and mortality from coronary heart disease, and incidence of and mortality from stroke. Studies reviewed Of 4235 studies reviewed for eligibility, quality, and data extraction, 84 were included in the final analysis. Results The pooled adjusted relative risks for alcohol drinkers relative to non-drinkers in random effects models for the outcomes of interest were 0.75 (95% confidence interval 0.70 to 0.80) for cardiovascular disease mortality (21 studies), 0.71 (0.66 to 0.77) for incident coronary heart disease (29 studies), 0.75 (0.68 to 0.81) for coronary heart disease mortality (31 studies), 0.98 (0.91 to 1.06) for incident stroke (17 studies), and 1.06 (0.91 to 1.23) for stroke mortality (10 studies). Dose-response analysis revealed that the lowest risk of coronary heart disease mortality occurred with 1–2 drinks a day, but for stroke mortality it occurred with ≤1 drink per day. Secondary analysis of mortality from all causes showed lower risk for drinkers compared with non-drinkers (relative risk 0.87 (0.83 to 0.92)). Conclusions Light to moderate alcohol consumption is associated with a reduced risk of multiple cardiovascular outcomes.

https://www.bmj.com/content/bmj/342/bmj.d671.full.pdf

Association of alcohol consumption with selected cardiovascular disease outcomes: a systematic review and meta-analysis

background Although moderate drinking confers a decreased risk of myocardial infarction, the roles of the drinking pattern and type of beverage remain unclear. methods We studied the association of alcohol consumption with the risk of myocardial infarction among 38,077 male health professionals who were free of cardiovascular disease and cancer at base line. We assessed the consumption of beer, red wine, white wine, and liquor individually every four years using validated food-frequency questionnaires. We documented cases of nonfatal myocardial infarction and fatal coronary heart disease from 1986 to 1998. results During 12 years of follow-up, there were 1418 cases of myocardial infarction. As compared with men who consumed alcohol less than once per week, men who consumed alcohol three to four or five to seven days per week had decreased risks of myocardial infarction (multivariate relative risk, 0.68 [95 percent confidence interval, 0.55 to 0.84] and 0.63 [95 percent confidence interval, 0.54 to 0.74], respectively). The risk was similar among men who consumed less than 10 g of alcohol per drinking day and those who consumed 30 g or more. No single type of beverage conferred additional benefit, nor did consumption with meals. A 12.5-g increase in daily alcohol consumption over a four-year follow-up period was associated with a relative risk of myocardial infarction of 0.78 (95 percent confidence interval, 0.62 to 0.99). conclusions Among men, consumption of alcohol at least three to four days per week was inversely associated with the risk of myocardial infarction. Neither the type of beverage nor the proportion consumed with meals substantially altered this association. Men who increased their alcohol consumption by a moderate amount during follow-up had a decreased risk of myocardial infarction.

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Roles of Drinking Pattern and Type of Alcohol Consumed in Coronary Heart Disease in Men

The Alcohol Use Disorders Identification Test (AUDIT) is a 10-item questionnaire designed by the World Health Organization to screen for hazardous alcohol intake in primary health care settings. In this longitudinal study we examine its performance in predicting alcohol-related harm over the full range of its scores using receiver operating characteristic analyses. Three hundred and thirty ambulatory care patients were interviewed using a detailed assessment schedule which included the AUDIT questions. After 2-3 years, subjects were reviewed and their experience of alcohol-related medical and social harm assessed by interview and perusal of medical records. AUDIT was a good predictor of both alcohol-related social and medical problems. Cut-off points of 7-8 maximized discrimination in the prediction a trauma and hypertension. Higher cut-offs (12 and 22) provided better discrimination in the prediction of alcohol-related social problems and of liver disease or gastrointestinal bleeding, but high specificity was offset by reduced sensitivity. We conclude that the recommended cut-off score of eight is a reasonable approximation to the optimal for a variety of endpoints.

The AUDIT questionnaire: choosing a cut-off score

Aims: Over recent decades there has been a striking increase in alcohol consumption and related problems in China. As China holds over 22% of the world's population this has a significant potential impact on world health. Here we review English- and Chinese-language publications on the prevalence of alcohol consumption and related problems in China, and treatment and control measures to reduce these. Methods: Medline search 1976–2002 and search of the China National Knowledge Infrastructure database 1996–2002. Results: While alcohol is a traditional part of Chinese life, commercial alcohol production in China has increased more than 50-fold per capita since 1952. In parallel there is evidence of a marked increase in prevalence of alcohol dependence, which has moved from the ninth to the third most prevalent mental illness. The public health response to increase in alcohol-related disorders has commenced but is in need of further development. Conclusions: There is a need for increased policies and public health programmes to reduce alcohol related harm, and evaluation of outpatient treatment potential.

( Received 13 January 2003; in revised form 30 May 2003 )

Alcohol use in China.

Aims The blood tests used traditionally as markers of excessive drinking are the liver enzymes, gamma glutamyltransferase (GGT), aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and the red blood cell volume (mean corpuscular volume; MCV). Here we review the nature of these markers’ association with alcohol use, their practical application in detecting, assessing or monitoring drinking and increases in understanding of these markers in the past 10 years. Design Articles were identified via Medline search and perusal of bibliographies. Findings The conventional markers have imperfect sensitivity and specificity, but have an added clinical role in the detection of complications of drinking, and of comorbid conditions that may increase risk of drinking. GGT may in part be a marker of the oxidative stress associated with ethanol metabolism. Markers are more likely to be elevated in those aged more than 30 years and in regular drinkers with a longer drinking history. The markers may be useful in opportunistic case finding, in motivating patients to change drinking and in monitoring treatment response. Increased prevalence of obesity and hepatitis C must be considered in interpretation of liver enzyme results. The liver enzymes are prognostic indicators for several medical conditions and for mortality. Conclusions These conventional tests are widely available and relatively inexpensive. While having limited sensitivity and specificity in detection of excessive drinking, they also provide valuable data on complications of drinking, comorbid conditions that may be affected by drinking and, in some cases, prognosis.

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Traditional markers of excessive alcohol use.

Background: Estimates of the performance of carbohydrate deficient transferrin (CDT) and gamma glutamyltransferase (GGT) as markers of alcohol consumption have varied widely. Studies have differed in design and subject characteristics. The WHO/ISBRA Collaborative Study allows assessment and comparison of CDT, GGT, and aspartate aminotransferase (AST) as markers of drinking in a large, well-characterized, multicenter sample. Methods: A total of 1863 subjects were recruited from five countries (Australia, Brazil, Canada, Finland, and Japan). Recruitment was stratified by alcohol use, age, and sex. Demographic characteristics, alcohol consumption, and presence of ICD-10 dependence were recorded using an interview schedule based on the AUDADIS, CDT was assayed using CDTect(TM) and GGT and AST by standard methods. Statistical techniques included receiver operating characteristic (ROC) analysis. Multiple regression was used to measure the impact of factors other than alcohol on test performance. Results: CDT and GGT had comparable performance on ROC analysis, with AST performing slightly less well. CDT was a slightly but significantly better marker of high-risk consumption in men. All were more effective for detection of high-risk rather than intermediate-risk drinking. CDT and GGT levels were influenced by body mass index, sex, age, and smoking status. Conclusions: CDT was little better than GGT in detecting high- or intermediate-risk alcohol consumption in this large, multicenter, predominantly community-based sample. As the two tests are relatively independent of each other, their combination is likely to provide better performance than either test alone, Test interpretation should take account sex, age. and body mass index.

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Katherine M. Conigrave

Papers

Roles of Drinking Pattern and Type of Alcohol Consumed in Coronary Heart Disease in Men

The AUDIT questionnaire: choosing a cut-off score

Alcohol use in China.

Traditional markers of excessive alcohol use.

CDT, GGT, and AST as markers of alcohol use: the WHO/ISBRA collaborative project.