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Content 7


The Doctor and the Pharmacist

Radio Show Articles:
March 19, 2011

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Pattern Recognition in Red Faces
Diabetes Adversely Affects Breast Cancer Outcomes
Mammograms: Not Just for Breast Cancer Screening?
Does Waist Circumference Measure Up?
At-Home Use of Bulb Syringes May Reduce Clinic Visits for Earwax
FDA: Another Tainted Drug Crisis Seems Inevitable
$4 Lipitor "Coupons" Could Increase Health Costs for All!
Zinc Inhibits Gastric Acid Secretion
Assessing Cancer Risk in Patients with Barrett Esophagus
Automated vs. Manual BP Monitoring for Systolic Hypertension
A Snapshot of Children with ADHD
Active or Passive Smoking and Breast Cancer Risk
Ramifications of Over-the-Counter Availability on Oral Contraceptive Use
Illness Course in Women with Bipolar Disorder
Intravitreal Bevacizumab Shows Promise for Treatment of Retinopathy of Prematurity
Rising Rates of Adult Hospitalizations for Diarrhea
More Follow-Up from the ACCORD Trial
CRP Itself Is Unlikely to cause Heart Disease
Cocoa’s Gene Effects Reinforce its Heart-Health Rep

J Invest Dermatol 2011 Mar; 131:688
Pattern Recognition in Red Faces
In rosacea, overexpression of a toll-like receptor may reflect disorder in the body's innate defenses against bacteria.
     Innate immune effector molecules are consistently upregulated in patients with erythematotelangiectatic rosacea, leading to low-grade inflammation, redder faces, and sensitive skin. The epidermis in these patients contains high levels of the antimicrobial peptide cathelicidin and its processing enzyme kallikrein 5, as though the skin were attempting to fend off a microbial threat.
     To see if the innate immune systems of rosacea patients are reacting to external danger signals associated with bacteria, investigators measured the constitutive expression of the toll-like receptors (TLRs) 1–9 in biopsied rosaceous skin. TLRs are proteins whose role in the innate immune system involves pattern recognition of bacteria. Rosaceous skin had higher TLR2 mRNA expression than normal skin. Other TLRs were not increased, and increased TLR2 was not detected in normal skin or in inflamed skin of patients with atopic dermatitis or psoriasis. TLR2 activation usually induces expression of tumor necrosis factor-α, which was also elevated in the rosaceous skin. TLR2's capacity to increase kallikrein 5 release from keratinocyte cytoplasmic granules was strongly dependent on calcium flux.
     Comment: Here we have more evidence of the role skin surface bacteria may play in rosacea. TLR2 binds to repeat recognition pattern molecules in bacteria, particularly those associated with lipoteichoic acids and peptidoglycans. Normally the skin balances its innate defense, paying less attention to commensal bacteria and more attention to pathogens probably reflecting virulence factor variances. In rosacea, this balance is disrupted, perhaps because TLRs in rosacea are abnormally activated by normal bacteria or because normal bacteria behave abnormally in rosaceous skin. Propionibacterium acnes do not appear to be the culprit, because these bacteria only slightly increased mRNA for kallikrein 5. I suspect Staphylococcus epidermidis.
Mark V. Dahl, MD Published in Journal Watch Dermatology March 18, 2011
Citation(s): Yamasaki K et al. TLR2 expression is increased in rosacea and stimulates enhanced serine protease production by keratinocytes. J Invest Dermatol 2011 Mar; 131:688. http://www.ncbi.nlm.nih.gov/pubmed/21107351?dopt=Abstract
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J Clin Oncol 2011 Jan 1; 29:54
Diabetes Adversely Affects Breast Cancer Outcomes
All-cause mortality was higher among women with diabetes and breast cancer than among their nondiabetic counterparts; breast cancer diagnosis and treatment differed for women with versus without diabetes.
     Women with diabetes have higher breast-cancer–related mortality than do women without diabetes, possibly because of delays in diagnosis, less-common use of adjuvant therapy, and diabetes-related comorbidities. Now, researchers have conducted a prospective cohort study and a meta-analysis to distinguish among these and other factors that influence breast cancer outcomes in women with diabetes.
     In the first report, investigators assessed baseline blood samples from the Women's Healthy Eating and Living Study, in which breast cancer survivors were followed. Among 3003 women whose glycosylated hemoglobin (HbA1c) levels were measured, 6% had levels 6.5% (diagnostic for chronic hyperglycemia). At a median follow-up of 7.3 years, 503 women experienced distant or locoregional recurrences or new breast primary tumors. Of 414 deaths at a median follow-up of 10.3 years, 372 were caused by breast or other cancers, 22 were from other causes, and 11 were caused by heart disease. In adjusted analysis, HbA1c levels 7.0% compared with levels <6.5% were associated with more than twofold higher risk for all-cause mortality, although not with higher risk for breast cancer recurrence
     The meta-analysis included eight breast cancer outcome studies in women with preexisting diabetes. Pooled results during 1- to 12-year follow-up showed that women with breast cancer and diabetes had higher all-cause mortality risk than did women with breast cancer but no diabetes (hazard ratio, 1.5). In two studies, researchers addressed breast-cancer–specific mortality; in one, among women who received chemotherapy, those with diabetes had slightly higher mortality than did those without diabetes (odds ratio, 1.2; 95% confidence interval, 1.07–1.35). Of four studies in which breast cancer stage at diagnosis was reported, three showed positive associations between preexisting diabetes and excess risk for late-stage breast cancer diagnoses. Three studies identified treatment differences for women with diabetes versus those without diabetes. One study showed that diabetes adversely affected disease-free survival.
     Comment: Although all-cause mortality was consistently higher among women with diabetes and breast cancer than among their nondiabetic counterparts, whether and how this relation is causal remain unknown. The authors of the cohort study suggest that altered levels of insulin, insulin-like growth factors, sex hormones, and inflammatory markers might directly affect breast cancer progression in women with diabetes. We need more studies designed to determine whether both expedited diagnosis and better control of diabetes will improve breast cancer outcomes.
Diane E. Judge, APN/CNP Published in Journal Watch Women's Health February 3, 2011
Citation(s): Erickson K et al. Clinically defined type 2 diabetes mellitus and prognosis in early-stage breast cancer. J Clin Oncol 2011 Jan 1; 29:54.
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Obstet Gynecol 2011 Feb; 117:233
Mammograms: Not Just for Breast Cancer Screening?     
Women with mammographically identified breast arterial calcifications were at excess risk for developing coronary heart disease or stroke within 5 years.
     Breast arterial calcification (BAC), considered a benign finding, is inconsistently reported in mammographic records. Mammographically detected BAC is associated with presence of coronary heart disease (CHD), but whether BAC can predict future CHD risk is unknown. To address this question, investigators conducted a 5-year prospective study that involved 1500 women who underwent screening mammography in 2004 in Hartford, Connecticut. At baseline and at 2, 4, and 5 years, participants completed demographic questionnaires about CHD risk factors (smoking, exercise habits, menopausal status, hypertension, diabetes, elevated cholesterol, and family histories of CHD) as well as self-reported CHD, angina, or stroke.
     Compared with women without BAC, those with BAC were older (mean age, 69 vs. 54 at baseline) and were more likely to report developing CHD during the study period (20.8% vs. 5.4%; P<0.001). In analysis controlled for age, women with BAC had 3.5-fold higher relative risk for developing CHD within 5 years (P<0.001). This risk for new-onset CHD was greater than that associated with hypertension (adjusted OR, 2.8), hypercholesterolemia (AOR, 2.4), or family history of CHD (AOR, 1.7). Women with BAC also were significantly more likely to experience strokes (58.3% vs. 13.3%; P<0.001).
     Comment: Mammographically detected breast arterial calcification identifies women at excess risk for CHD, even when age and other coronary artery risk factors are taken into account. The questionnaires used in this study only identified women who had symptomatic or diagnosed CHD; the true prevalence of CHD could be higher. Radiologists should develop a standardized approach for reporting BAC on mammograms to alert clinicians about their patients' risk for CHD and stroke. Clinicians then can help patients modify other CHD risk factors such as smoking, inactivity, diabetes, elevated cholesterol, and hypertension.
Wendy S. Biggs, MD Published in Journal Watch Women's Health March 3, 2011
Citation(s): Schnatz PF et al. The association of breast arterial calcification and coronary heart disease. Obstet Gynecol 2011 Feb; 117:233.
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Am J Clin Nutr 2011 Feb; 93:392
Does Waist Circumference Measure Up?
Independent of body-mass index, increases in waist circumference predicted changes in cardiovascular disease risk factors in postmenarcheal white adolescents.
     Cross-sectional studies suggest that visceral fat, measured by magnetic resonance imaging, is positively related to cardiovascular risk factors in children and adolescents. To determine whether changes in waist circumference — an indirect measure of central adiposity — predicts longitudinal change in cardiovascular risk factors, investigators analyzed data from 2379 black and white girls (age range, 9–10 years) enrolled in the National Heart, Lung, and Blood Institute Growth and Health Study in 1987–1988. Girls who had at least two postmenarcheal study visits during the 10 years of follow-up were included in the analysis.
     After adjustment for body-mass index (BMI) z score, steeper age-related increases in waist circumference were significantly associated with greater increases in LDL cholesterol, systolic and diastolic blood pressure, and insulin resistance (homeostasis model assessment) in white but not black girls. Changes in waist circumference were not related to changes in HDL cholesterol, triglycerides, insulin, or glucose concentrations in either white or black girls.
     Comment: This is one of many studies to suggest that monitoring waist circumference might identify adolescents at risk for emergence of certain cardiovascular disease risk factors. Although this might be true, I remain skeptical about its clinical usefulness. The authors don't tell us whether measuring waist circumference identifies girls who by BMI criteria would not be targeted for intervention or whether it simply identifies a subset of overweight/obese girls at particular risk. To the extent that girls in the highest percentiles of waist circumference are already identified as being overweight/obese, ongoing monitoring of blood pressure and LDL levels would already be indicated and such patients would also receive the same counseling: Exercise more and control weight, both of which would improve cardiovascular disease risk factors. Finally, until studies demonstrate that measuring waist circumference will not trigger or exacerbate disordered eating in teenage girls, we need more-compelling evidence before it is incorporated into routine care.
Alain Joffe, MD, MPH, FAAP Published in Journal Watch Pediatrics and Adolescent Medicine March 16, 2011
     Citation(s): Tybor DJ et al. Independent effects of age-related changes in waist circumference and BMI z scores in predicting cardiovascular disease risk factors in a prospective cohort of adolescent females. Am J Clin Nutr 2011 Feb; 93:392.
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At-Home Use of Bulb Syringes May Reduce Clinic Visits for Earwax
     Home use of a bulb syringe may help relieve earwax occlusion more effectively than a clinical procedure, according to an Annals of Family Medicine study.
     Researchers randomized some 240 adults in the U.K. either to ear drops and home use of a bulb syringe or to ear drops and irrigation by a clinic nurse. Patients were reassessed after 2 weeks, and those with persistent occlusions had their ears irrigated at the clinic.
     At 2 years' follow-up, patients initially managed clinically returned to the clinic for earwax concerns more often than the home-treatment group (73% vs. 60%).
     The authors conclude: "Rather than routine attendance with a clinician, self-treatment with drops and then self-irrigation may offer a significantly less costly alternative."
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FDA: Another Tainted Drug Crisis Seems Inevitable
     The FDA states that as more drugs sold in the U.S. are manufactured overseas, it cannot guarantee their safety. 40% of drugs consumed in the U.S. are imported, while 80% of the ingredients used in U.S. drugs come from other countries.
     The Agency says it must reinvent itself to operate more effectively globally, or another public health crisis like Heparin seems inevitable. The difficulty in monitoring imports is also leading to more counterfeit and adulterated products entering the U.S.
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$4 Lipitor "Coupons" Could Increase Health Costs for All!
     A war over Lipitor could contribute to higher healthcare premiums--even for those who don't use the drug. Late last year, Pfizer launched a coupon card allowing insured patients to purchase a month's supply of Lipitor for as little as $4. The card paid up to $50 of the co-payment of the price, but the patient's insurance company was left paying the rest, which could be four times the total cost of a generic alternative. The insurance plans may have to pay more money because of the program and potentially higher premiums could result. These coupons and co-pay cards promoted by manufactures are an attempt to get consumers to use expensive brands while sticking payers with the extra cost.
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Am J Gastroenterol 2011 Jan; 106:62.
Zinc Inhibits Gastric Acid Secretion
Short-term outcomes of increased pH and decreased acid secretion support zinc's potential use in treatment regimens for gastroesophageal reflux disease.
     For decades, zinc deficiency has been known to increase gastric mucosal cell apoptosis. Studies in the 1980s investigated zinc's potential to heal and regenerate the protective mucosal gel layer of the stomach. These studies also reported an antisecretory effect of zinc on gastric acid but could not establish a biological mechanism.
     To evaluate the potential for zinc to act as a clinical antisecretory agent, investigators conducted a series of in vitro and in vivo studies in rats and humans. Gastric glands from humans (obtained from obese patients who underwent gastric reduction surgery), gastric glands from rats, and rat stomachs were isolated and then stimulated by histamine (100 µM) and monitored for pH levels in both the presence and absence of zinc chloride (300 µM). Apart from these studies, a randomized, crossover study involving 12 healthy human volunteers was conducted. Each participant received four oral regimens — 200 mL of water, 20 mg of omeprazole, 200 mg of zinc sulfate, and both omeprazole and zinc sulfate — on 4 different days (separated by 3 days). Researchers measured gastric pH for 3 hours after treatment began.
     Zinc immediately inhibited acid secretion in the isolated rat and human gastric glands, decreased histamine-stimulated acid secretion in gastric glands, and increased the pH in histamine-stimulated isolated rat stomachs compared with control glands not exposed to histamine. The human intervention study showed that oral zinc (with or without omeprazole) increased gastric pH compared with water or omeprazole alone for a period of 3 hours. The authors concluded that zinc produced a rapid and prolonged inhibition of gastric acid secretion and offers a potential therapeutic alternative to proton-pump inhibitors (PPIs).
     Comment: This study resurrects the concept of zinc as a gastroprotective agent based on its antisecretory properties. The suggestion of widespread use of zinc as an alternative or adjunct to PPIs requires further large-scale trials. Duration of acid inhibition in this study was 3 hours — hardly an alternative to the longer effect of PPIs. The absence of immediate acid inhibition by omeprazole in humans is predictable and should not imply clinical superiority of zinc for long-term therapy. Instead, zinc might provide another option for short-term treatment in combination with long-term acid suppression by PPIs, similar to several other over-the-counter preparations.
David J. Bjorkman, MD, MSPH (HSA), SM (Epid.) Published in Journal Watch Gastroenterology March 18, 2011
     Citation(s): Kirchhoff P et al. Zinc salts provide a novel, prolonged and rapid inhibition of gastric acid secretion. Am J Gastroenterol 2011 Jan; 106:62.
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Am J Gastroenterol 2011 Jan; 106:46
Assessing Cancer Risk in Patients with Barrett Esophagus
Overexpression of epidermal growth factor receptor was an effective marker for progression of BE to esophageal cancer.
     Current assessment of cancer risk in patients with Barrett esophagus (BE) involves histological analysis of samples taken during endoscopy, focusing on the presence of high-grade dysplasia (HGD) as a key marker of precancerous tissue. However, endoscopic sampling is prone to error, and experts are keen to supplement such testing with measurement of appropriate molecular markers. One such biomarker might be epidermal growth factor receptor (EGFR), which has been found to be commonly overexpressed in esophageal cancers and has correlated with tumor grade and lymph node metastases (Cancer 2007; 109:658).
     To evaluate EGFR as a biomarker for neoplastic development in patients with BE, investigators in the U.K. assessed 107 previously banked tissue samples from 100 patients. The samples represented the stages of progression from BE to esophageal cancer — from metaplasia to dysplasia to adenocarcinoma.
     EGFR expression was 13 times higher in adenocarcinoma than BE tissue samples. Calculation of a robust H-score (a combination of EGFR staining intensity and the number of positive EGFR cells present) yielded mean scores for EGFR expression for BE, HGD, and adenocarcinoma of 0.7, 3.9, and 9.4, respectively. Overexpression of EGFR, defined as the mean H-score of BE patients plus three standard deviations, was present in 35% of HGD and 80% of adenocarcinoma specimens. Of note, tissue samples with an overexpression of EGFR were more likely to show aneuploidy of chromosome 7 and display amplification of the EGFR locus.
     Comment: This study shows that EGFR is a marker of histological progression from BE to HGD and esophageal adenocarcinoma. With targeted anti-EGFR therapy now available (e.g., cetuximab) and showing some initial promise in treating esophageal adenocarcinoma, coupling EGFR diagnostics to this novel treatment modality might conceivably slow neoplastic progression in some patients. In addition, the membranous nature of EGFR and its location on the luminal surface of the esophagus might be a useful target to guide future endoscopic biopsies.
David A. Johnson, MD Published in Journal Watch Gastroenterology March 18, 2011
Citation(s): Cronin J et al. Epidermal growth factor receptor (EGFR) is overexpressed in high-grade dysplasia and adenocarcinoma of the esophagus and may represent a biomarker of histological progression in Barrett's esophagus (BE). Am J Gastroenterol 2011 Jan; 106:46.
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BMJ 2011 Feb 7; 342:d286
Automated vs. Manual BP Monitoring for Systolic Hypertension
Automated blood pressure monitoring was more accurate.
     Office manual blood pressure (BP) monitoring is fraught with problems, including variable BP measuring skills among healthcare workers, "white-coat hypertension," and digit preference (readings ending in "0"). In this trial, Canadian investigators randomized 67 primary care practices to use either ongoing manual office BP monitoring (control) or automated office BP monitoring using the BpTRU device (intervention; after the BpTRU cuff is positioned properly, the patient is left alone, and the device automatically takes five BP readings and displays an average). Awake ambulatory BP monitoring was the gold standard.
     Overall, 555 patients with systolic hypertension participated in the study. Compared with manual office BP readings, automated office BP readings correlated more strongly with ambulatory BP monitoring. For example, the mean manual office systolic BP after enrollment was 6.5 mm Hg higher than ambulatory BP, whereas mean automated office systolic BP was only 2.3 mm Hg higher than ambulatory BP; this difference was significant. For diastolic BP, mean automated and manual office measurements were both about 4 mm Hg higher than ambulatory measurements. Another striking finding was a fall in automated systolic BP while the patient rested in the exam room: Mean systolic BP fell from 147 to 133 mm Hg during a 10-minute period.
     Comment: Automated BP monitoring (with multiple readings taken while the patient is resting) is more accurate than manual BP monitoring in primary care patients with systolic hypertension. The results have obvious clinical implications, such as limiting unnecessary treatment. Indeed, several years ago, my institution systematically eliminated manual BP monitoring in favor of automated BP monitoring.
Paul S. Mueller, MD, MPH, FACP Published in Journal Watch General Medicine February 17, 2011
     Citation(s): Myers MG et al. Conventional versus automated measurement of blood pressure in primary care patients with systolic hypertension: Randomised parallel design controlled trial. BMJ 2011 Feb 7; 342:d286. (http://dx.doi.org/10.1136/bmj.d286) http://www.ncbi.nlm.nih.gov/pubmed/21300709?dopt=Abstract
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Pediatrics 2011 Mar; 127:462
A Snapshot of Children with ADHD
More than 4 million children in the U.S. have attention deficit/hyperactivity disorder, and most have comorbid conditions.
     To examine comorbidity in children with attention deficit/hyperactivity disorder (ADHD), researchers used data from the 2007 National Survey of Children's Health to conduct a cross-sectional analysis of 61,779 children (age range, 6–17 years), including 5028 children (8%) with parent-reported diagnoses of ADHD.
     Children with ADHD were significantly more likely than children without ADHD to have other neurodevelopmental conditions: learning disabilities (46% vs. 5%), conduct disorder (27% vs. 2%), anxiety (18% vs. 2%), and depression (14% vs. 1%). Only 33% of children with ADHD had no other comorbid conditions, 33% had one comorbidity, and 34% had two or more. Children in low-income families were significantly more likely than children in affluent families to have ADHD and to have three or more comorbid conditions. Children with ADHD were significantly more likely than those without ADHD to repeat a grade at school (29% vs. 9%), to have school-related problems (69% vs. 27%), to use mental health services (48% vs. 6%), and to use special educational services (49% vs. 7%).
     Comment: The obvious limitation of this study is that it is based on parental report. However, the prevalence figures are similar to those in other studies. The results suggest that more than 4 million children in the U.S have ADHD, most have comorbid conditions, and about half use special education and mental health services.
Howard Bauchner, MD Published in Journal Watch General Medicine March 17, 2011
     Citation(s): Larson K et al. Patterns of comorbidity, functioning, and service use for US children with ADHD, 2007. Pediatrics 2011 Mar; 127:462. (http://dx.doi.org/10.1542/peds.2010-0165)
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BMJ 2011 Mar 1; 342:d1016
Active or Passive Smoking and Breast Cancer Risk
Risk was elevated for smokers and women with intense exposure to passive smoking.
     Emerging evidence suggests that active and passive smoking are associated with breast cancer risk. In this report from the prospective cohort component of the Women's Health Initiative, investigators assessed the association between active and passive smoking and risk for invasive breast cancer among 80,000 postmenopausal women (age range, 50–79).
     During mean follow-up of 10.3 years, 3520 women developed invasive breast cancer. Compared with never-smokers, former smokers had 9% higher risk and current smokers had 16% higher risk for breast cancer. Breast cancer risk rose with intensity and duration of smoking. Among former smokers, elevated breast cancer risk persisted for up to 20 years after quitting. Compared with women who reported no exposure to passive smoking, women who reported passive smoking exposure of greater than or equal to 10 years as children, greater than or equal to 20 years at home as adults, and greater than or equal to 10 years in the workplace had 32% higher risk for breast cancer. Women who reported less-intense exposures to passive smoking did not have elevated risk. All analyses were adjusted for potential confounders, including alcohol intake.
     Comment: These results, which strongly suggest that active smoking and intense exposure to passive smoking raise risk for invasive breast cancer among postmenopausal women, lend support to efforts to prevent smoking, encourage quitting, and restrict exposure to secondhand smoke.
Paul S. Mueller, MD, MPH, FACP Published in Journal Watch General Medicine March 10, 2011
Citation(s):Luo J et al. Association of active and passive smoking with risk of breast cancer among postmenopausal women: A prospective cohort study. BMJ 2011 Mar 1; 342:d1016. (http://dx.doi.org/10.1136/bmj.d1016) http://www.ncbi.nlm.nih.gov/pubmed/21363864?dopt=Abstract
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Obstet Gynecol 2011 Mar; 117:551.
Ramifications of Over-the-Counter Availability on Oral Contraceptive Use
Users of over-the-counter oral contraceptive pills were more likely to continue their contraceptive method but were more likely to have contraindications.
     About half of women who initiate oral contraceptive pills (OCPs) discontinue use during the first year. Over-the-counter availability could promote continuation by lowering barriers to access; however, such access might allow women with contraindications to obtain OCPs. In two 9-month studies in El Paso, Texas, researchers used baseline and periodic surveys to assess rates of continuation and contraindications in women (age range, 18–44; primarily Mexican-born) who obtained OCPs by prescription from a city clinic versus over the counter in neighboring Mexico.
     At baseline in the continuation study, most women reported that they intended to use OCPs for longer than 1 year. At 9 months, 119 of 474 prescription users (25%) and 97 of 466 over-the-counter users (21%) had discontinued OCPs, mostly because of side effects or other OCP-associated problems. In adjusted analysis, risk for discontinuation was similar in over-the-counter users and in women who were prescribed greater than or equal to 6 packs at a time (hazard ratio for discontinuation, 1.1) but was higher in women who received 1 to 5 packs at a time (HR, 1.8).
     In the contraindication study, investigators used data from 514 prescription and 501 over-the-counter OCP users who self-reported conditions consistent with relative (category 3) or absolute (category 4) OCP contraindications according to WHO Medical Eligibility Criteria. Over-the-counter OCP users were substantially more likely to have relative contraindications than were prescription users (13% vs. 9%; P=0.006). Prevalence of absolute contraindications was similar between groups at about 6%. Hypertension was the most commonly reported contraindication.
     Comment: The design of this study is intriguing, and, although the results do not make a convincing argument for over-the-counter OCP dispensing, they offer some insights. Over-the-counter pill users were more likely to continue the method, whether because of cost, convenience, or other factors that were not examined. Women who were prescribed ≥6 packs were also more likely to continue, suggesting that we should prescribe multiple OCP packs at a time. However, the authors comment that clinicians might have judged who would continue OCPs and prescribed accordingly; furthermore, some insurance plans limit the number of OCP packs dispensed at one time. Women who chose OCPs without medical guidance were more likely to have contraindications; nonetheless, for some of these women, OCPs still might have been appropriate, given the risks associated with pregnancy.
Diane E. Judge, APN/CNP Published in Journal Watch Women's Health March 17, 2011
     Citation(s): Potter JE et al. Continuation of prescribed compared with over-the-counter oral contraceptives. Obstet Gynecol 2011 Mar; 117:551.
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Am J Psychiatry 2011 Feb 15
Illness Course in Women with Bipolar Disorder
Premenstrual exacerbations are associated with a more difficult course of bipolar illness.
     Up to two thirds of women with affective disorders have reported premenstrual exacerbation of mood, but premenstrual mood worsening has not been detected in small studies of bipolar disorder. Using data on menstruating women with bipolar disorder (age range, 18–40) from the STEP-BD study, investigators examined the potential impact of premenstrual mood exacerbation on illness course. Analyses adjusted for psychotropic medications, hormonal contraceptives, comorbidities, number of mood episodes in the previous year, and irregular menstrual cycles.
     Of 293 women, 65% reported premenstrual exacerbation of mood symptoms. At 1-year follow-up, those with self-reported premenstrual exacerbation had more mood episodes (primarily depression) than those without — but not more rapid cycling. The researchers examined time to relapse in a partially overlapping cohort of 129 women who had recovered by study entry; 51% had reported premenstrual exacerbation. When relapse was defined to include subsyndromal episodes, women reporting premenstrual exacerbation had greater risk for relapse and shorter time to relapse (4.5 months vs. 8.5 months) than those without, but this difference became nonsignificant after adjustment for the greater number of mood episodes reported by those with premenstrual exacerbation.
     Comment: Taken together, the findings suggest that women with premenstrual cycling are likely to experience more-severe and more-frequent episodes of bipolar disorder, but not more rapid cycling per se. Sensitivity and susceptibility of mood to fluctuating levels of ovarian steroids may be contributory. That less premenstrual exacerbation of mood is seen prospectively than reported retrospectively suggests that some women may incorrectly attribute some perimenstrual mood fluctuations to their bipolar disorder. Clinicians can help patients better distinguish one from the other and can expect a more difficult course for many women with premenstrual exacerbation.
Joel Yager, MD Published in Journal Watch Psychiatry March 14, 2011
Citation(s): Dias RS et al. Longitudinal follow-up of bipolar disorder in women with premenstrual exacerbation: Findings from STEP-BD. Am J Psychiatry 2011 Feb 15; [e-pub ahead of print]. (http://dx.doi.org/10.1176/appi.ajp.2010.09121816)
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N Engl J Med 2011 Feb 17; 364:603
Intravitreal Bevacizumab Shows Promise for Treatment of Retinopathy
of Prematurity
Intravitreal bevacizumab was significantly better than laser therapy for zone I disease.
     Retinopathy of prematurity (ROP) is a devastating consequence of prematurity and a leading cause of childhood blindness and vision loss. In the immature retina, in which vascularization is not complete, the pathogenesis of ROP involves increased oxygen exposure and decreased vascular endothelial growth factor (VEGF) followed by decreased oxygen and increased VEGF. During the past 2 decades, treatment has evolved from cryotherapy to laser therapy to halt the aberrant growth, but this treatment destroys cells that produce VEGF and compromises future development of the vasculature of the retina.
     In a randomized multicenter trial, investigators compared intravitreal bevacizumab (IB) with conventional laser therapy in 143 preterm infants (birth weight, less than or equal to 1500 g and gestational age, less than or equal to 30 weeks) with stage 3+ ROP (neovascularization extending into the vitreous) in zone I (circle around the optic disc whose radius is twice the distance from disc to macula) or zone II posterior (surrounding zone I with a radius 3 times the distance from disc to macula) who survived to 54 weeks postmenstrual age. ROP reoccurred in 4 infants (6 of 140 eyes, 4%) in the IB group and 19 infants (32 of 146 eyes, 22%) in the laser group (a significant difference). The treatment effect was significant for zone I disease but not zone II disease. The authors conclude that IB showed a significant treatment benefit over laser therapy but caution that the trial was too small to assess safety.
     Comment: Although the improved survival of very preterm infants has been truly remarkable, a reduction in morbidity has lagged. Studies such as this give hope that we can overcome some complications associated with prematurity and offer improved quality of life for surviving infants. Although the authors were careful to note that safety was not adequately assessed, the only reported complications were in laser-treated patients.
William P. Kanto, Jr., MD Published in Journal Watch Pediatrics and Adolescent Medicine March 16, 2011
     Citation(s): Mintz-Hittner HA et al. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med 2011 Feb 17; 364:603. http://www.ncbi.nlm.nih.gov/pubmed/21323540?dopt=Abstract
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Clin Infect Dis 2011 Feb 15; 52:466
Rising Rates of Adult Hospitalizations for Diarrhea
Norovirus is thought to account for a substantial fraction of these hospitalizations.
     In developing countries, diarrhea is a well-known scourge of childhood. In the U.S., by contrast, most diarrhea-related deaths occur among the elderly. To examine the epidemiology of severe diarrhea among U.S. adults and, in particular, the role of norovirus as a causative agent, CDC researchers probed a representative national database of hospital discharge codes with a nomogram designed to identify the presence of infectious gastroenteritis. The numbers of norovirus cases, which are seldom specifically identified in clinical practice, were estimated with a statistical tool based on the infection's marked seasonality.
     Overall, between 1996 and 2007, rates of gastroenteritis decreased in infants and children (age, <18), but increased in all adult age groups, especially among those aged 65 or older. Cases of diarrhea caused by Clostridium difficile increased markedly during that period, as did cases with no identified microbiological cause. Norovirus was implicated in an estimated 20% of these no-known-cause discharges in children and 13% of those in adults — with considerably higher rates during years of known norovirus epidemics.
     Comment: This report highlights the morbidity and expense associated with norovirus infections in U.S. adults — hospitalizations cost an estimated $500 million annually. The authors note that growing segment of the population now lives in long-term care institutions, which can be vulnerable to norovirus outbreaks, and call for more specific diagnostics to be devised and made available for this often-overlooked infection.
Abigail Zuger, MD Published in Journal Watch General Medicine March 8, 2011
Citation(s): Lopman BA et al. Increasing rates of gastroenteritis hospital discharges in US adults and the contribution of norovirus, 1996–2007. Clin Infect Dis 2011 Feb 15; 52:466. (http://dx.doi.org/10.1093/cid/ciq163) http://www.ncbi.nlm.nih.gov/pubmed/21258098?dopt=Abstract
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N Engl J Med 2011 Mar 3; 364:818.
More Follow-Up from the ACCORD Trial
Once again, intensive glycemic treatment cannot be recommended for older patients with long-standing type 2 diabetes.
     In the landmark ACCORD trial, 10,000 older patients with long-standing type 2 diabetes were randomized to achieve a target glycosylated hemoglobin (HbA1c) level of <6% or a target of 7% to 7.9%. The study was stopped after average follow-up of 3.5 years, when mortality was significantly higher in the intensive-treatment group than in the standard-treatment group (5% vs. 4%). During further follow-up of 1.5 years, the intensity of glucose-lowering in the intensive-treatment group was relaxed. Now, researchers report outcomes at 5 years (the originally planned study duration).
     Overall mortality remained significantly higher in the intensive-treatment group than in the standard group (7.6% vs. 6.4%). Compared with the standard group, the intensive-treatment group had fewer nonfatal myocardial infarctions, a similar number of nonfatal strokes, and a higher incidence of cardiovascular death. For a primary composite endpoint that combined these three individual outcomes, no significant difference was noted between the intensive-treatment and standard-treatment groups. Within the intensive glucose-lowering group, patients who were also assigned to intensive blood pressure (BP)-lowering (systolic target <120 mm Hg) in a BP substudy experienced higher all-cause mortality than those assigned to a target BP of <140 mm Hg.
     Comment: This extended follow-up from ACCORD doesn't change the original message: HbA1c should not be driven lower than 7% in older patients with long-standing type 2 diabetes. The reason for the excess mortality with intensive glycemic treatment remains unknown. The observed detrimental interaction between intensive glucose-lowering and intensive BP-lowering is an interesting hypothesis-generating finding that deserves additional study.
Allan S. Brett, MD Published in Journal Watch General Medicine March 2, 2011 >
     Citation(s): The ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 2011 Mar 3; 364:818. (http://www.nejm.org/doi/full/10.1056/NEJMoa1006524)
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BMJ 2011 Feb 15; 342:d548
CRP Itself Is Unlikely to Cause Coronary Heart Disease
Genetically elevated C-reactive protein was not associated with CHD.
     Inflammation plays a role in the pathogenesis of coronary heart disease (CHD). Elevated levels of plasma C-reactive protein (CRP), a biomarker of inflammation, are associated with excess risk for CHD. However, whether elevated plasma CRP levels cause CHD or whether CHD causes elevated plasma CRP is unknown. In this meta-analysis of 47 studies, investigators used genetic and epidemiological data to determine whether elevated plasma CRP causes CHD.
     Of 194,000 participants (mean age, 59; 89% of European descent), 24% had CHD. Data were available on CRP levels, other CHD risk factors, and a panel of four single nucleotide polymorphisms in the CRP gene that account for as much as a 30% difference in baseline CRP levels among European populations. Although CRP levels overall, as expected, were associated significantly with CHD risk, a complex analysis of the data showed that the genetic contribution to elevated CRP was not associated with CHD risk or with conventional CHD risk factors.
     Comment: These results suggest that elevated CRP does not cause CHD. As noted by an editorialist, the previously observed associations between CRP and CHD likely were due to reverse causality (i.e., CHD causes elevated CRP levels) or residual confounding by other factors.
Paul S. Mueller, MD, MPH, FACP Published in Journal Watch General Medicine March 15, 2011      Citation(s):C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC). Association between C reactive protein and coronary heart disease: Mendelian randomisation analysis based on individual participant data. BMJ 2011 Feb 15; 342:d548. (http://dx.doi.org/10.1136/bmj.d548)
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Cocoa’s Gene Effects Reinforce its Heart-Health Rep
Clinical study pinpoints a “nutrigenomic” effect of cocoa on a gene targeted by blood pressure medications by Craig Weatherby
     At this point, the clinical and lab evidence that cocoa and dark chocolate benefit cardiovascular health seems pretty persuasive.
     (For example, consider the 2009 study we reviewed in “Chocolate Linked to Heart Health, Again” ... and peruse our Cocoa, Tea & Coffee news archive to learn about its brain and skin benefits.)
     And it’s very clear that these heart benefits flow from cocoa’s rare blend of polyphenols, including flavanols, procyanidins, and catechins.
      In fact, no cardiovascular benefits appear when people eat cocoa treated with alkali (“Dutched”) … a nearly universal cocoa-making practice that destroys most of its polyphenols.
The other top sources of cocoa-type polyphenols include grape skins, red wine, green and white tea, blackberries, boysenberries, wild blueberries, chokeberries, and Brazil’s acai fruit – but cocoa is uniquely rich in all three kinds.
     Better artery “performance” and lower blood pressure rank as cocoa’s most convincingly demonstrated cardiovascular benefits. As the German authors of an evidence review wrote four years ago, “The magnitude of the hypotensive [blood-pressure-lowering] effects of cocoa is … in the range that is usually achieved with … beta-blockers or angiotensin-converting enzyme [ACE] inhibitors.” (Taubert D et al. 2007)
     (Despite its similar polyphenol profile, the authors found no evidence that tea reduces blood pressure.)
     Last year, Australian evidence-reviewers came to a similar conclusion, and detailed the apparent upper boundaries of cocoa’s powers:
“… dark chocolate is superior to placebo in reducing systolic hypertension or diastolic prehypertension. Flavanol-rich chocolate did not significantly reduce mean blood pressure below 140 mmHg systolic or 80 mmHg diastolic.” (Ried K et al. 2010)
     (The U.S. National Heart, Lung, and Blood Institute defines normal blood pressure as less than 120 mmHg systolic and 80 mmHg diastolic. Stage I hypertension is defined as systolic pressure between 140 and 159 mm Hg or diastolic pressure of 90 to 99 mm Hg.)
     So-called “ACE inhibitors” – drugs such as benazepril, fosinopril, and lisinopril – work by inhibiting the conversion of angiotensin I to the potent vasoconstrictor (artery tightener) angiotensin II, thereby lowering blood pressure and easing blood flow.
     Swedish study affirms cocoa’s healthy heart effects
The new study combined tests in human endothelial (artery-lining) cells with measurements in volunteers (Persson IA et al. 2011). The results indicate that – like raw, non-Dutched cocoa – dark chocolate (75 percent cocoa solids) influences the genes that control blood pressure and artery dilation/relaxation. Eating dark chocolate exerted beneficial influences over the enzyme targeted by blood pressure drugs, called angiotensin-converting enzyme or ACE. Confirming that this effect on genes that control ACE had a practical impact, dark chocolate also lowered blood pressure in the people participating in the clinical portion of the study.
     And in the test tube portion of the new study, cocoa polyphenols raised levels of nitric oxide (NO) in human endothelial cellsan effect that usually causes arteries to relax and dilate. However, no rise in volunteers’ NO levels were seen in the clinical part of the study … possibly because that effect takes longer to manifest than the three hours that passed between the time the volunteers ate chocolate and their and NO levels were tested.
     Cocoa’s “nutrigenomic” effects on blood pressure and arteries
Researchers at Sweden’s at Linkoping University recruited 16 volunteers aged between 20 and 45 years (Persson IA et al. 2011). Every day for two weeks, the participants ate 75 grams (2.6 ounces) of dark chocolate containing 72 percent cocoa solids.  Any chocolate containing 60 percent or more cocoa is considered “dark”, with Vital Choice brand being 80 percent cocoa.) The results showed a significant, 18 percent drop in ACE activity after eating the 72 percent dark chocolate … a reduction comparable to the cut produced by the leading ACE inhibitor drugs.
     Interestingly, the degree of inhibition of the AC enzyme depended on the volunteers’ individual “genotype” or genetic profile. People can have one of three genotypes related to angiotensin-converting enzyme ACE, called D/D, I/D, and I/I, distributed about equally across the human population. Three hours after consuming dark chocolate, ACE was inhibited by 21 percent in people with the I/I genotype, and by 28 percent in people with the D/D genotype. (The authors did not report an ACE-inhibition figure for the I/D genotype, perhaps because there were too few volunteers with that type to draw a clear conclusion.) As the Swedish team wrote, “Our results indicate that lifestyle changes, with the help of foods that contain high catechin and procyanidin content, prevent cardiovascular disease.” (Persson IA et al. 2011)
Sources: Engler MB, Engler MM, Chen CY, Malloy MJ, Browne A, Chiu EY, Kwak HK, Milbury P, Paul SM, Blumberg J, Mietus-Snyder ML. Flavonoid-rich dark chocolate improves endothelial function and increases plasma epicatechin concentrations in healthy adults. J Am Coll Nutr. 2004 Jun;23(3):197-204. Faridi Z, Njike VY, Dutta S, Ali A, Katz DL. Acute dark chocolate and cocoa ingestion and endothelial function: a randomized controlled crossover trial. Am J Clin Nutr. 2008 Jul;88(1):58-63. Persson IA, Persson K, Hägg S, Andersson RG. Effects of cocoa extract and dark chocolate on angiotensin-converting enzyme and nitric oxide in human endothelial cells and healthy volunteers--a nutrigenomics perspective. J Cardiovasc Pharmacol. 2011 Jan;57(1):44-50. Ried K, Sullivan T, Fakler P, Frank OR, Stocks NP. Does chocolate reduce blood pressure? A meta-analysis. BMC Med. 2010 Jun 28;8:39. Taubert D, Roesen R, Schömig E. Effect of cocoa and tea intake on blood pressure: a meta-analysis. Arch Intern Med. 2007 Apr 9;167(7):626-34.

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