Clifford Qualls

Weight Loss, Exercise, or Both and Physical Function in Obese Older Adults

BACKGROUND Obesity exacerbates the age-related decline in physical function and causes frailty in older adults; however, the appropriate treatment for obese older adults is controversial. METHODS In this 1-year, randomized, controlled trial, we evaluated the independent and combined effects of weight loss and exercise in 107 adults who were 65 years of age or older and obese. Participants were randomly assigned to a control group, a weight-management (diet) group, an exercise group, or a weight-management-plus-exercise (diet-exercise) group. The primary outcome was the change in score on the modified Physical Performance Test. Secondary outcomes included other measures of frailty, body composition, bone mineral density, specific physical functions, and quality of life. RESULTS A total of 93 participants (87%) completed the study. In the intention-to-treat analysis, the score on the Physical Performance Test, in which higher scores indicate better physical status, increased more in the diet-exercise group than in the diet group or the exercise group (increases from baseline of 21% vs. 12% and 15%, respectively); the scores in all three of those groups increased more than the scores in the control group (in which the score increased by 1%) (P<0.001 for the between-group differences). Moreover, the peak oxygen consumption improved more in the diet-exercise group than in the diet group or the exercise group (increases of 17% vs. 10% and 8%, respectively; P<0.001); the score on the Functional Status Questionnaire, in which higher scores indicate better physical function, increased more in the diet-exercise group than in the diet group (increase of 10% vs. 4%, P<0.001). Body weight decreased by 10% in the diet group and by 9% in the diet-exercise group, but did not decrease in the exercise group or the control group (P<0.001). Lean body mass and bone mineral density at the hip decreased less in the diet-exercise group than in the diet group (reductions of 3% and 1%, respectively, in the diet-exercise group vs. reductions of 5% and 3%, respectively, in the diet group; P<0.05 for both comparisons). Strength, balance, and gait improved consistently in the diet-exercise group (P<0.05 for all comparisons). Adverse events included a small number of exercise-associated musculoskeletal injuries. CONCLUSIONS These findings suggest that a combination of weight loss and exercise provides greater improvement in physical function than either intervention alone. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00146107.).

A short form of the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12)

The aim of this study was to develop the short form of a condition-specific, reliable, validated and self-administered instrument to evaluate sexual function in women with pelvic organ prolapse and/or urinary incontinence. The Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire –12 (PISQ-12) was developed from the data of 99 of 182 women surveyed to create the long form (PISQ-31). An additional 46 patients were recruited for further validation. All subsets regression analysis identified 12 items likely to predict PISQ-31 scores. Short form scores underwent correlation analysis with long form, Incontinence Impact Questionnaire – 7 (IIQ-7), Sexual History Form –12 (SHF-12) and Symptom Questionnaire (SQ) scores. Test–retest reliability was checked with a subset of 20 patients. All subsets regression analysis with R>0.92 identified 12 items that predicted PISQ-31 scores. Short form scores were highly correlated with long form scores (R=0.75–0.95). Correlations of the PISQ-12 with SHF-12 (R=–0.66 and –0.68) and IIQ-7 (R=–0.38 and –0.54) scores were similar to correlation of the PISQ-31 with these other measures. Reliability was moderate to high, with weighted κ values from 0.56 to 0.93. PISQ-12 scores were lower in patients with low sexual function as measured on the SHF-12 (P <0.001), and lower in women with depression as measured on the SQ (P <0.001). The PISQ-12 is a validated and reliable short form that evaluates sexual function in women with urinary incontinence and/or pelvic organ prolapse and predicts PISQ-31 scores. It is able to distinguish women with poor sexual function as measured on the SHF-12.

Outcomes of Treatment for Hepatitis C Virus Infection by Primary Care Providers

BACKGROUND The Extension for Community Healthcare Outcomes (ECHO) model was developed to improve access to care for underserved populations with complex health problems such as hepatitis C virus (HCV) infection. With the use of video-conferencing technology, the ECHO program trains primary care providers to treat complex diseases. METHODS We conducted a prospective cohort study comparing treatment for HCV infection at the University of New Mexico (UNM) HCV clinic with treatment by primary care clinicians at 21 ECHO sites in rural areas and prisons in New Mexico. A total of 407 patients with chronic HCV infection who had received no previous treatment for the infection were enrolled. The primary end point was a sustained virologic response. RESULTS A total of 57.5% of the patients treated at the UNM HCV clinic (84 of 146 patients) and 58.2% of those treated at ECHO sites (152 of 261 patients) had a sustained viral response (difference in rates between sites, 0.7 percentage points; 95% confidence interval, -9.2 to 10.7; P=0.89). Among patients with HCV genotype 1 infection, the rate of sustained viral response was 45.8% (38 of 83 patients) at the UNM HCV clinic and 49.7% (73 of 147 patients) at ECHO sites (P=0.57). Serious adverse events occurred in 13.7% of the patients at the UNM HCV clinic and in 6.9% of the patients at ECHO sites. CONCLUSIONS The results of this study show that the ECHO model is an effective way to treat HCV infection in underserved communities. Implementation of this model would allow other states and nations to treat a greater number of patients infected with HCV than they are currently able to treat. (Funded by the Agency for Healthcare Research and Quality and others.).

Diagnosis of adrenal insufficiency

Adrenal insufficiency is an uncommon clinical disorder that results from an inadequate basal or stress level of plasma cortisol. It is important to diagnose adrenal insufficiency because the disorder may be fatal if left unrecognized or untreated. With diagnosis and appropriate adrenocortical hormone replacement, normal quality of life and longevity can be achieved. The presentation of adrenal insufficiency may be insidious and thus difficult to recognize. Once suspected, however, the definitive diagnosis can be confirmed by laboratory evaluation of adrenocortical function. Although many different tests for adrenal insufficiency have been developed, few have been adequately studied and many are inconvenient for testing in the outpatient clinical setting. By contrast, the cosyntropin stimulation test is widely used in many different clinical settings and is easy to perform. In addition, data on test performance in various clinical settings are plentiful. The cosyntropin stimulation test has therefore emerged as the initial test used to evaluate patients for both primary and secondary adrenal insufficiency. Methods We reviewed all English-language studies in humans identified in the MEDLINE database (1966 to 2002) through the Ovid search service. Search terms were adrenal gland hypofunction restricted to diagnosis. For the normal response to high-dose cosyntropin, we selected studies with 10 or more participants. For the diagnosis of primary adrenal insufficiency, we selected studies with 5 or more participants. For evaluation of the sensitivity and specificity of cosyntropin tests in secondary adrenal insufficiency, we selected only studies that stratified all participants with suspected adrenal insufficiency by integrated tests of adrenal function (insulin tolerance or metyrapone tests). Summary receiver-operating characteristic (ROC) curves were developed from sensitivity and specificity values derived from individual studies, as described by Littenberg, Moses, and colleagues (1, 2) (see the Appendix for detailed formulas). Summary ROC curves were compared by using area under the curves (AUCs), as described by Walter (3). For our data sets, we verify the condition (B 0; see the Appendix) that yields explicit formulas for AUC and its CI for the summary ROC curves. The slope parameter (B) did not differ significantly from 0 for all data sets used to generate summary ROC curves. We compared ROC curves for data paired by individual participants using likelihood methods with a program (ROCKIT 0.9B) developed by Metz and colleagues (4) (available at www-radiology.uchicago.edu/cgi-bin/software.cgi). The funding source had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication. Data Synthesis High-Dose Cosyntropin Stimulation Test The standard cosyntropin test is performed by administering one ampule (250 g) of cosyntropin intramuscularly or intravenously and measuring serum or plasma cortisol levels 30 to 60 minutes later. With a normal (negative) test result, the serum cortisol level after cosyntropin stimulation is generally greater than 500 nmol/L. A subnormal cortisol response (<500 nmol/L) is defined as a positive test result and indicates an increased probability of either primary or secondary adrenal insufficiency. The cosyntropin test may be performed at any time of the day. In patients with suspected adrenal insufficiency, a basal plasma cortisol level is not usually necessary because neither the absolute nor the percentage change from the basal level is useful as a diagnostic criterion for the cosyntropin test (5). However, in the absence of corticosteroid-binding globulin deficiency, an unstimulated serum cortisol level, determined between 6:00 and 8:00 a.m., may be helpful because a level less than 80 nmol/L strongly suggests adrenal insufficiency (5). Normal Response to the High-Dose Cosyntropin Test In healthy persons without evidence of adrenal insufficiency, serum cortisol response 30 or 60 minutes after 250 g of cosyntropin is administered intramuscularly or intravenously has been studied extensively (6-22). The responses to intramuscular and intravenous injections are similar, and the responses among normal persons vary. In 10 studies that included a total of 288 participants and that reported the entire range of postcosyntropin serum cortisol levels, the levels ranged from 415 to 2200 nmol/L (9, 10, 12-15, 17, 19-21). The broad range of normal responses to cosyntropin stimulation reflects various factors, including differences in hypothalamicpituitaryadrenal axis set point, serum corticosteroid-binding globulin level, stress level, body composition, time of testing, and performance characteristics of the cortisol assay used. In one detailed study of 100 healthy persons, the distribution curves of serum cortisol levels obtained 30 and 60 minutes after a 250-g intramuscular injection of cosyntropin displayed a non-Gaussian configuration for each of four separate cortisol assays, with the distribution skewed to the right toward higher cortisol levels (22). The 5th percentile lower cortisol cutoff limit for these four assays ranged from 510 to 615 nmol/L at 30 minutes and from 620 to 675 nmol/L at 60 minutes. Other studies also show increases in the cortisol response at 60 minutes compared with 30 minutes (16, 18, 20). In 11 studies involving 340 healthy participants, the data presented as the mean 2 SDs show lower limits ranging from 390 to 620 nmol/L at 30 minutes (6-10, 16-20) and from 500 to 725 nmol/L at 60 minutes (11, 16, 18, 20). Because the distribution curve is non-Gaussian, no conclusion can be drawn from these studies about the percentage of healthy persons with serum cortisol levels less than the lower cutoff limit. The studies described show that an appreciable number of normal persons will have a postcosyntropin cortisol level less than a cutoff limit of 500 nmol/L. However, none of the 288 participants in the 10 studies described earlier (in which the entire range of cortisol responses was reported) had a cortisol level less than 415 nmol/L. Diagnosis of Primary Adrenal Insufficiency Primary adrenal insufficiency (often called Addison disease) is an uncommon disorder that often presents with a slowly progressive increase in nonspecific symptoms. The prevalence of this disorder in the community is approximately 100 cases per 1 million people (23-26); the incidence is 5 cases per year per 1 million people (26). The prevalence of primary adrenal insufficiency is higher (although not precisely known) in persons with HIV disease, family histories of adrenoleukodystrophy, autoimmune endocrine disorders, metastatic cancer, and granulomatous disease. The prevalence among persons with nonspecific symptoms, such as tiredness, fatigue, weakness, listlessness, weight loss, nausea, and anorexia, is not known. More specific symptoms, such as unexplained darkening of the skin, orthostatic dizziness, and salt-craving, may not be among presenting symptoms. Cosyntropin Stimulation Tests in Primary Adrenal Insufficiency Table 1 summarizes the results of 8 studies in which 122 patients with primary adrenal insufficiency and controls were given 250 g of cosyntropin intravenously or intramuscularly and the serum cortisol levels were measured 30 or 60 minutes later. None of the patients in these studies underwent consecutive prospective evaluation for adrenal insufficiency; rather, they were selected for study either because previous evaluation showed that they had typical Addison disease (13, 14, 20, 27-29) or because their cosyntropin tests were compared with historical controls in retrospective surveys (23, 30). Controls in these studies varied from healthy volunteers (13, 14, 23) to participants with nonendocrine illness (14, 27) or suspected adrenal insufficiency (29). Thus, case-patients and controls were not recruited from the same setting. In general, the case-patients with Addison disease in these studies were selected on the basis of typical clinical and nonendocrine laboratory criteria, such as hyperkalemia, supplemented in many cases with elevated plasma adrenocorticotropic hormone (ACTH) levels and low urine steroid responses to intravenous ACTH infusions. In several retrospective analyses using historical controls, cosyntropin tests may have contributed to the diagnosis of Addison disease, but several patients with Addison disease in each of these surveys had normal cosyntropin test results. None of the studies indicated that patients with borderline cosyntropin test results were selectively excluded. However, it is clear that the cases of Addison disease selected in these studies were more advanced and easily recognized by well-established clinical and laboratory criteria. Thus, in most cases in these studies, the diagnosis of Addison disease was based on clinical evidence supported by serum electrolyte, plasma ACTH, and urine steroid levels. Cosyntropin tests were then performed in these patients, and the results were interpreted independently of the original diagnostic criteria. Table 1. The 250-g Cosyntropin Stimulation Test in Patients with Primary Adrenal Insufficiency For the summary ROC curve, which is based on four of the studies in Table 1 (14, 20, 27, 29), the point on the summary ROC where sensitivity and specificity are equal was 96.5% (95% CI, 94.5% to 98.5%) for the diagnosis of primary adrenal insufficiency. When specificity is set at 95%, this summary ROC curve yields a sensitivity of 97.5% (CI, 95% to 100%), with a corresponding positive likelihood ratio of 19.5 (CI, 19.0 to 20.0) and a negative likelihood ratio of 0.026 (CI, 0 to 0.6). The AUC for this summary ROC curve was 0.99 (CI, 0.985 to 1.000), indicating excellent test discrimination. As a result of the selection bias in these studies toward patients with severe Addison disease, the cosyntropin test performance characteristics derived from Table 1 are most

Sexual Function in Women with and without Urinary Incontinence and/or Pelvic Organ Prolapse

The sexual function of women with and without urinary incontinence and/or pelvic organ prolapse (UI/POP) was compared using a condition-specific validated questionnaire, the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ). Eighty-three women with UI/POP and 56 without agreed to participate. PISQ scores were significantly lower among women with UI/POP than in those without (P = 0.003). No differences in the stages of sexual excitement were noted between groups. The frequency of intercourse was less with UI/POP than without (P = 0.04). Women with UI/POP restricted sexual activity for fear of losing urine more frequently than did those without (P= 0.005). No differences were reported in patients’ or partners’ sexual satisfaction. This study found that women with UI/POP have poorer sexual functioning than those without, as measured by the PISQ, and report less frequent sexual activity. In addition, women with UI/POP are more likely to restrict sexual activity for fear of incontinence, although they report similar levels of satisfaction with their sexual relationships as do women without UI/POP.

Incidence and survival rates for female malignant germ cell tumors.

OBJECTIVE: To evaluate 30-year, population-based trends in incidence and survival rates for malignant germ cell tumors originating within the female genital tract. METHODS: Surveillance, Epidemiology, and End Results data were used to identify malignant germ cell tumors (1973–2002). Overall and 5-year incidence rates, estimated annual percentage change, and survival rates were calculated and compared by age at diagnosis, race, stage, and histology. RESULTS: Of 1,262 cases, there were 414 (32.8%) dysgerminomas, 449 (35.6%) immature teratomas, 37 (2.9%) mature teratomas with malignant degeneration, and 362 (28.7%) mixed germ cell tumors. The 30-year, age-adjusted incidence rate per 100,000 women-years was 0.338, decreasing by 29.4% for dysgerminomas (P = .18) and by 31.5% for mixed germ cell tumors (P = .22). Other nonwhites had higher rates than whites and blacks, but dysgerminoma rates were higher in whites and other nonwhites than in blacks. Using the registries for expanded races, rates were higher for Asian/Pacific Islanders (P = .059) and Hispanics (P = .07). By age at diagnosis, 15–19 year olds had the highest rates and the only significant change in rates (37.5% increase, P = .008). The 5-year relative survival was 83.9%. Survival rates improved significantly over calendar time and varied by histologic subtype, race, stage of disease, and age at diagnosis. CONCLUSION: Over the past 30 years, germ cell tumor incidence rates have declined in women and differ from rising trends reported for testicular tumors. Survival rates have improved but were lower for older women and for nondysgerminoma subtypes. LEVEL OF EVIDENCE: II-3

Recombinant Human Growth Hormone, Insulin-like Growth Factor 1, and Combination Therapy in AIDS-Associated Wasting: A Randomized, Double-Blind, Placebo-Controlled Trial

Wasting associated with the acquired immunodeficiency syndrome (AIDS) is a serious complication of human immunodeficiency virus (HIV) infection that causes progressive loss of both lean body mass and, more variably, fat mass [1-4]. The pathogenesis is probably multifactorial and includes the underlying viral infection, tissue cytokines, intercurrent infections, and poor intake of calories [1, 2]. Recombinant human insulin-like growth factor 1 (rhIGF-1) alone and recombinant human growth hormone (rhGH) alone have been administered to humans during various catabolic states, including fasting, the period immediately after surgery, and trauma, and have had positive effects on lean body mass [5-7]. The beneficial effects of rhGH on body composition and metabolism are reportedly mediated by increased levels of IGF-1 [4, 5]. Furthermore, animal studies have shown that rhIGF-1 has beneficial effects on lymphopoieses [8]. Limited studies of rhGH or rhIGF-1 treatment alone in patients with AIDS have also been promising, resulting in an increase in circulating IGF-1 levels, lean body mass, and muscle function [9-11]. We hypothesized that treating AIDS-associated wasting with rhIGF-1, alone or in combination with rhGH, would reverse the catabolic effects characteristic of this wasting. We further hypothesized that if rhGH therapy increased lean body mass, then physical strength, immune function, and quality of life would improve. We therefore did a randomized, double-blind, placebo-controlled trial to assess the effects of rhGH and rhIGF-1 therapy in patients with AIDS-associated wasting. The primary end points were changes in weight and lean body mass. The secondary end points were changes in muscle function, immune status, quality of life, and protein catabolism. The Institutional Review Boards of the University of New Mexico and the University of Texas Southwestern Medical Center approved the study, and all patients gave written informed consent before entering the study. Methods Patients We recruited 60 patients (58 men and 2 women) with AIDS (as defined by the Centers for Discase Control and Prevention [12]), unexplained wasting (defined as weight loss 10% of the weight before diagnosis or body mass index 19.8 kg/m2), and a CD4 count less than 200 cells/mm3. Weight before diagnosis was defined as the weight that an adult patient maintained for at least 2 years during the time the patient believed that he or she was healthy. In New Mexico, patients were recruited by postings at the University of New Mexico Hospital Infectious Disease Clinic and Veterans Administration Hospital and by physician referral from private practices in Albuquerque and Santa Fe. In Texas, patients were recruited from the University of Texas Southwestern Medical Center at Dallas, a collaborating institution, and private practices throughout the Southwest. In addition, an advertisement was placed in the directory of the American Federation for AIDS Research. The patients were admitted to the University of New Mexico Clinical Research Center for a 2-day inpatient screening assessment. This assessment included physical examination, neurologic examination, electrocardiography, and chest radiography. Additional inclusion criteria were a hematocrit of 0.28 or greater, negative result of a pregnancy test (in women), negative 7-day blood culture for Mycobacterium avium intracellulare within 4 weeks before study entry, negativity for cryptococcal antigen in serum within 4 weeks before study entry, and a chest radiograph showing no evidence of acute cardiopulmonary disease within 28 days before study entry. Exclusion criteria were body mass index of 26.0 kg/m2 or greater, opportunistic infection that resolved less than 4 weeks before study entry, diarrhea (defined as five or more bowel movements per day or identification of an enteric pathogen), history of endocrine disease associated with hypoglycemia or hyperglycemia, any disorder associated with moderate or severe edema, history of cancer within 3 years of study entry, active Kaposi sarcoma, diagnosed cardiovascular disease (including congestive heart failure and cardiomyopathy), medically significant liver dysfunction (serum alanine aminotransferase level > 200 IU, total bilirubin level > 51.3 mmol/L) and renal dysfunction (creatinine level > 176.8 mmol/L). Baseline dietary histories were analyzed; at study entry, all patients were consuming at least 25 kcal/kg of body weight and none was receiving intravenous or tube feeding. None had received therapy with anabolic or catabolic agents, including interferon, megestrol, dronabinol, oxandrolone, and corticosteroids, within 30 days of study entry. No patient had received any experimental agent or procedure within 30 days of enrollment other than prophylactic antimicrobial therapy directed at fungal, bacterial, viral, mycobacterial, or parasitic infections. All patients had been receiving antiretroviral therapy for at least 3 months before study entry and received prophylaxis for Pneumocystis carinii throughout the treatment period. Genentech, Inc. (South San Francisco, California), randomly assigned the 60 patients into four groups of 15 patients each so that balance was maintained across the groups with respect to body mass index, CD4 count, type of antiretroviral therapy, and age. The type of antiretroviral therapy was divided into five categories: zidovudine alone, didanosine alone, simultaneous administration of zidovudine and didanosine, simultaneous administration of zidovudine and zalcitabine, and other. The schedule for the subcutaneously injected therapy was as follows: Group 1 received 1.4 mg of rhGH once daily and 1 mL of placebo twice daily; group 2 received 5 mg of rhIGF-1 twice daily and 1 mL of placebo once daily; group 3 received 5 mg of rhIGF-1 twice daily and 1.4 mg of rhGH once daily; and group 4 received 1 mL of placebo three times daily. All patients received three subcutaneous injections per day for 12 weeks. Both patients and clinicians were blinded to treatment group assignments. The rhGH dosage used in this study was approximately one half the dosage used in our previous study [9]. The decision to use this dosage was based on the 2 2 analysis of variance (ANOVA) design and concern about the potential for increased incidence and severity of side effects if full doses of rhGH and rhIGF-1 were used in the patients receiving rhGH plus rhIGF-1. Patients were withdrawn from the study if they did not administer all three injections each day for 7 continuous days throughout the treatment period. Injection compliance was assessed by counting vials and interviewing the study clinician during assessment visits. In addition, IGF-1 levels were monitored in all patients and were compared with values at baseline and those in placebo recipients. The intended duration of all treatments was 12 weeks. Body Composition Lean body mass, fat mass, and percentage of body fat were measured by using dual-energy x-ray absorptiometry (Hologic QDR-1000/W, Waltham, Massachusetts), as described elsewhere [13]. Total Body Water We measured total body water using bioelectric impedance analysis (model 106, bioelectrical impedance analysis, RJL Systems, Detroit, Michigan). Testing was done between 1300 and 1500 hours, and all patients were fed and well hydrated before testing. We calculated body water by fitting the impedance measurements of resistance and reactance into previously derived prediction equations [14]. Protein Catabolism Protein catabolism was estimated by turnover of [2H5]phenylalanine (Cambridge Isotope Laboratories, Woburn, Massachusetts), as described elsewhere [15, 16]. The plasma phenylalanine level was measured by using gas chromatography mass spectrometry after being derivatized to its t-butyldimethylsilyl ester [17]. The concentration and level of [2H5]phenylalanine in plasma were analyzed by using multiple ion detection under electron-impact ionization conditions [17]. Muscle Function Computerized isotonic dynamometry (Baltimore Therapeutic Equipment, Baltimore, Maryland) was used to evaluate maximal voluntary contraction and maximum power (20%, 40%, and 60% maximal voluntary contraction) for a knee extension and a compound movement of the upper body. Quality of Life We measured quality of life using a self-administered 36-item Medical Outcomes Study questionnaire, which was previously validated in HIV-positive patients with AIDS-associated complex [18]. We accounted for missing values by averaging scores across completed items in the same scale for a particular patient. Eleven domains and three generalized domains were analyzed: 1) Total score was the average of the scores for all 36 questions; 2) functional status was the average of the scores in the domains for physical functioning, role functioning, social functioning, and cognitive functioning; and 3) well-being was the average of the scores in the domains for pain, mental health, energy and fatigue, health distress, and quality of life. Endocrine Assays Serum insulin levels were measured by using double-antibody radioimmunoassay (Pharmacia Diagnostics AB, Piscataway, New Jersey), and growth hormone levels were measured by using Tandem-R human growth hormone immunoradiometric assay (Hybritech, Inc., San Diego, California). Total IGF-1 levels were measured by double-antibody radioimmunoassay using rabbit antihuman IGF-1 antibody generated by Peter Gluckman (Auckland, New Zealand) at Genentech, Inc. Immunologic Studies Levels of HIV p24 antigen were measured in serum after acid dissociation by solid-phase sand-wich-type immunoassay that used a signal amplification technique (acid dissociated enzyme-linked immunoassay, DuPont Co., Boston, Massachusetts) [19]. CD3, CD4, and CD8 counts and percentage of total lymphocytes were measured in Ficol-separated peripheral blood mononuclear cell by flow cytometry using appropriate monoclonal antibodies and FACscan IV (Becton-Dickinson, Mountain Vi

Aortic root disease and valve disease associated with ankylosing spondylitis

OBJECTIVES This study sought to determine the prevalence, characteristics, relation to clinical features and evolution of aortic root disease and valve disease associated with ankylosing spondylitis (AKS). BACKGROUND Aortic root disease and valve disease are common in patients with AKS, but their clinical and prognostic implications have not been well defined. METHODS Forty-four outpatients with AKS and 30 age- and gender-matched healthy volunteers underwent initial transesophageal echocardiography and rheumatologic evaluations. Twenty-five patients underwent clinical and echocardiographic follow-up 39+/-10 months later. RESULTS Aortic root disease and valve disease were common in patients (82%) as compared with controls (27%; p < 0.001). Aortic root thickening, increased stiffness and dilatation were seen in 61%, 61% and 25% of patients, respectively. Valve thickening (41% for the aortic and 34% for the mitral valve) manifested predominantly (74%) as nodularities of the aortic cusps and basal thickening of the anterior mitral leaflet, forming the characteristic subaortic bump. Valve regurgitation was seen in almost half of patients, and 40% had moderate lesions. Except for the duration of AKS, aortic root disease and valve disease were unrelated to the activity, severity or therapy of AKS. During follow-up of 25 patients, in up to 24% new aortic root or valve abnormalities developed, in 12% existing valve regurgitation worsened significantly and in 20% abnormalities resolved. Twenty percent of patients developed heart failure, underwent valve replacement, had a stroke or died, as compared with 3% of control subjects. CONCLUSIONS Aortic root disease and valve disease are common in patients with AKS, are unrelated to clinical features of AKS, can resolve or progress over time and are associated with clinically important cardiovascular morbidity.

Blood–Brain Barrier Permeability Abnormalities in Vascular Cognitive Impairment

Background and Purpose— Disruption of the blood–brain barrier has been proposed to be important in vascular cognitive impairment. Increased cerebrospinal fluid albumin and contrast-enhanced MRI provide supporting evidence, but quantification of the blood–brain barrier permeability in patients with vascular cognitive impairment is lacking. Therefore, we acquired dynamic contrast-enhanced MRI to quantify blood–brain barrier permeability in vascular cognitive impairment. Method— We studied 60 patients with suspected vascular cognitive impairment. They had neurological and neuropsychological testing, permeability measurements with dynamic contrast-enhanced MRI, and lumbar puncture to measure albumin index. Patients were separated clinically into subcortical ischemic vascular disease (SIVD), multiple and lacunar infarcts, and leukoaraiosis. Twenty volunteers were controls for the dynamic contrast-enhanced MRI studies, and control cerebrospinal fluid was obtained from 20 individuals undergoing spinal anesthesia for nonneurological problems. Results— Thirty-six patients were classified as SIVD, 8 as multiple and lacunar infarcts, and 9 as leukoaraiosis. The albumin index was significantly increased in the SIVD group compared with 20 control subjects. Permeabilities for the patients with vascular cognitive impairment measured by dynamic contrast-enhanced MRI were significantly increased over control subjects (P<0.05). Patient age did not correlate with either the blood–brain barrier permeability or albumin index. Highest albumin index values were seen in the SIVD group (P<0.05) and were significantly increased over multiple and lacunar infarcts. Ki values were elevated over control subjects in SIVD but were similar to multiple and lacunar infarcts. Conclusions— There was abnormal permeability in white matter in patients with SIVD as shown by dynamic contrast-enhanced MRI and albumin index. Future studies will be needed to determine the relationship of blood–brain barrier damage and development of white matter hyperintensities.

Randomized, double-blind, placebo-controlled trial of orlistat for weight loss in adolescents.

OBJECTIVE To evaluate the efficacy of orlistat to enhance weight loss in obese adolescents. METHODS The study was a 6-month randomized, double-blind, placebo-controlled trial to compare the effects of orlistat (120 mg orally 3 times a day) and placebo on reduction of body mass index (BMI). Forty adolescents between 14 and 18 years of age with a mean BMI of 40 kg/m2 entered the protocol between December 2002 and February 2003. Study subjects stayed overnight in the General Clinical Research Center, during which dietary records were reviewed and lifestyle recommendations were given. The study participants received either orlistat (120 mg orally 3 times a day) or placebo and were assessed monthly for 6 months. At 0, 3, and 6 months, fasting laboratory tests were performed. The primary end point was the change in BMI from baseline to 6 months. Secondary outcomes included changes in weight, lean body mass, and results of blood chemistry studies. RESULTS No statistically significant difference was noted between the 2 study groups for decrease in BMI from baseline to 6 months (P = 0.39). The decrease in BMI within the orlistat group (-1.3 +/- 1.6 kg/m2; P = 0.04) and within the placebo group (-0.8 +/- 3.0 kg/m2; P = 0.02), however, was statistically significant. Laboratory measurements did not differ between the 2 groups. In comparison with the placebo group, the orlistat group had increased adverse events, primarily gastrointestinal symptoms and findings. CONCLUSION In this study of obese adolescents, orlistat did not significantly reduce BMI in comparison with placebo at 6 months.