Cytotoxic activity of rheumatoid and normal lymphocytes against allogeneic and autologous synovial cells in vitro.

The possibility that lymphocytes from patients with rheumatoid arthritis (RA) might be sensitized to RA synovial cell antigens was investigated with a 51Cr release cytotoxicity assay. Peripheral blood lymphocytes from rheumatoid and normal donors were tested for cytotoxic activity against their own synovial cells and against allogeneic rheumatoid and nonrhemuatoid synovial cells. In the allogeneic studies, the degree of cytotoxicity was significantly influenced by the age in culture (passage number) of the synovial target cells (P less than 0.001). When the passage number of the target cells was considered in the analysis, rheumatoid lymphocytes were found to have greater cytotoxic activity than normal lymphocytes against young cultures (low passage number) of both RA and non-RA synovial cells (P = 0.0042). Differences in susceptibility to lysis between RA and non-RA synovial cells were more susceptible to both RA and normal lymphocyte-induced lysis than were non-RA synovial cells (P = 0.0048). No evidence of cytotoxicity was detected when lymphocytes from nine RA patients and two osteoarthritis patients were reacted against their own synovial cells. Although the data demonstrated an increased cytotoxic activity of peripheral blood lymphocytes from some RA patients against allogeneic synovial cells, the fact that this reactivity was seen against both non-RA and RA synovial cells and was not demonstrated against autologous synovial cells argues against the presence of an immunospecific response of RA lymphocytes to RA synovial cell antigens.

Altered waveform of plasma nocturnal melatonin secretion in premenstrual depression.

The nocturnal secretion of plasma melatonin was determined under dim to dark conditions in eight patients with prospectively confirmed premenstrual syndrome and in eight age- and menstrual cycle phase-matched normal control subjects. Plasma samples for melatonin were collected every 30 minutes from 6 PM to 9 AM during the early follicular, late follicular, midluteal and late luteal phases of the menstrual cycle. Compared with normal controls, patients with premenstrual syndrome had an earlier (phase-advanced) offset of melatonin secretion, which contributed to a shorter secretion duration and a decreased area under the curve. No statistically significant differences were found between women with premenstrual syndrome and normal controls for melatonin onset or peak concentration, or for estradiol or progesterone levels. The data demonstrate that women with premenstrual syndrome have chronobiological abnormalities of melatonin secretion. The fact that these patients respond to treatments that affect circadian physiology, such as sleep deprivation and phototherapy, suggests that circadian abnormalities may contribute to the pathogenesis of premenstrual syndrome.

Lack of efficacy of polysorbate 60 in the treatment of male pattern baldness.

Anecdotal reports have indicated that the nonionic detergent polysorbate 60 may be of some value in male pattern baldness. In this double-blind placebo-controlled trial, a photographic and objective scalp measurement system was developed to assess new hair growth. No significant difference was detected between subjects treated for 16 weeks with polysorbate 60 and control subjects treated with glycerin, indicating that polysorbate 60 is ineffective. Of the 141 subjects who completed the trial, 25% perceived that they grew new hair, 67% said they did not, and 8% were uncertain. Subject-reported new hair growth did not correlate with measurements, indicating that the placebo effect may be a major factor in reports of baldness "cures".

Plasma melatonin circadian rhythms during the menstrual cycle and after light therapy in premenstrual dysphoric disorder and normal control subjects.

The aim of this study was to replicate and extend previous work in which the authors observed lower, shorter, and advanced nocturnal melatonin secretion patterns in premenstrually depressed patients compared to those in healthy control women. The authors also sought to test the hypothesis that the therapeutic effect of bright light in patients was associated with corrective effects on the phase, duration, and amplitude of melatonin rhythms. In 21 subjects with premenstrual dysphoric disorder (PMDD) and 11 normal control (NC) subjects, the authors measured the circadian profile of melatonin during follicular and luteal menstrual cycle phases and after 1 week of light therapy administered daily, in a randomized crossover design. During three separate luteal phases, the treatments were either (1) bright (> 2,500 lux) white morning (AM; 06:30 to 08:30 h), (2) bright white evening (PM; 19:00 to 21:00 h), or (3) dim (< 10 lux) red evening light (RED). In PMDD subjects, during the luteal phase compared to the follicular menstrual cycle phase, melatonin onset time was delayed, duration was compressed, and area under the curve, amplitude, and mean levels were decreased. In NC subjects, melatonin rhythms did not change significantly during the menstrual cycle. After AM light in PMDD subjects, onset and offset times were advanced and both duration and midpoint concentration were decreased as compared to RED light. After PM light in PMDD subjects, onset and offset times were delayed, midpoint concentration was increased, and duration was decreased as compared to RED light. By contrast, after light therapy in NC subjects, duration did not change; onset, offset, and midpoint concentration changed as they did in PMDD subjects. When the magnitude of advance and delay phase shifts in onset versus offset time with AM, PM, or RED light were compared, the authors found that in PMDD subjects light shifted offset time more than onset time and that AM light had a greater effect on shifting melatonin offset time (measured the following night in RED light), whereas PM light had a greater effect in shifting melatonin onset time. These findings replicate the authors' previous observation that nocturnal melatonin concentrations are decreased in women with PMDD and suggest specific effects of light therapy on melatonin circadian rhythms that are associated with mood changes in patient versus control groups. The differential changes in onset and offset times during the menstrual cycle, and in response to AM and PM bright light compared with RED light, support a two-oscillator (complex) model of melatonin regulation in humans.

Blunted phase-shift responses to morning bright light in premenstrual dysphoric disorder.

Patients with premenstrual dysphoric disorder (PMDD) respond therapeutically to sleep deprivation and light therapy. They have blunted circadian rhythms of melatonin. The authors sought to test the hypothesis that these disturbances are a reflection of a disturbance in the underlying circadian pacemaker or, alternatively, that they reflect a disturbance in the input pathways to the clock. To test these hypotheses, after a 2-month diagnostic evaluation, 8 patients who met DSM-IV criteria for PMDD and 5 normal control (NC) subjects underwent two studies to determine whether PMDD subjects showed (1) altered melatonin sensitivity to light suppression (Study 1) and (2) altered phase-shift responses to morning light as a measure of the functional capacity of the underlying pacemaker (Study 2). In both studies, measurements were made during asymptomatic follicular and symptomatic luteal menstrual cycle phases in PMDD patients. The results of Study 1 showed no significant effect of group or menstrual cycle phase on the amount or percentage of suppression of melatonin by light. The results of Study 2 showed that with respect to the variable of offset time, PMDD subjects, when symptomatic, showed a reduced and directionally altered melatonin phase-shift response to a morning bright light stimulus; in 4 of 5 NC subjects, melatonin offset was advanced by bright morning light, whereas in PMDD subjects, it was delayed (3 subjects) or not shifted (5 subjects) (group effect, p = .045). Study 2 also revealed that area under the curve also changed differentially in PMDD versus NC subjects. In summary, the primary findings from this pilot study suggest that in PMDD there is a maladaptive (directionally altered and blunted) response to light in the symptomatic luteal phase. Because the suppressive effects of light were similar in PMDD and NC subjects, the previously observed low melatonin levels in this disorder do not likely represent a disturbance in pineal reactivity to suprachiasmatic nucleus efferents. Instead, the findings support a possible disturbance in PMDD in the clock itself or its coupling mechanisms.

Sex differences in bone mineral density in 1653 men and women in the sixth through tenth decades of life: the Rancho Bernardo Study.

This cross-sectional population-based study examined the effect of age and sex on bone mineral density (BMD) in the elderly. BMD was measured at the spine and hip using dual-energy x-ray absorptiometry and at midshaft and ultradistal radius using single-photon absorptiometry in 672 men and 981 women aged 50-98 years. In both sexes, mean BMD levels decreased significantly with age at all sites except the male spine. In linear regression models, the slope of loss was significantly greater in women than in men at all sites except the ultradistal radius. The slope was steeper at most sites in women aged 50-59 years than in older women, 60-98 years. In both age groups, mean age-adjusted BMD levels were lower at all sites in women who were past or never users of replacement estrogen than in women who were current estrogen users. Current estrogen users generally had lower slopes of loss with age than never or past estrogen users; however, few of these differences were statistically significant. We conclude that BMD levels decrease in old age in both sexes. Continued bone loss in old age raises the possibility that intervention to retard further loss may still be warranted in the elderly.

Blood pressure change and survival after age 75.

Higher diastolic pressure predicted better survival in men 75 years or older in two prior analyses in the Rancho Bernardo population. Diastolic change was implicated as a possible explanation. We studied this by assessing survival according to blood pressure change in 795 men and women aged 75 years and older at the time of a second measurement taken an average of 11 years after the first, who were then followed for 5 years. Sex-specific analyses compared participants with a diastolic decrease of 5 mm Hg or greater and participants with a systolic decrease of 10 mm Hg or greater with those whose blood pressure levels did not change or increased. In men, after adjustment for baseline pressure, a decrease in diastolic pressure of 5 mm Hg or greater was associated with higher all-cause mortality (relative risk, 2.33; 95% confidence interval, 1.39 to 3.91) and cardiovascular mortality (3.13, 1.47 to 6.66). The mortality risk was strongest in men who took antihypertensive medication and had a fall in diastolic pressure (12.33, 2.73 to 55.72) compared with treated men whose pressures did not decrease. Among men with isolated systolic hypertension, those treated whose diastolic pressure remained stable had the best survival. A systolic fall in men and a decrease in either diastolic or systolic in women was not associated with poorer survival after adjustment for baseline pressure. We conclude that a fall in diastolic pressure of 5 mm Hg was associated with poor survival in men after age 75. This risk was strongest in men who took antihypertensive medication.

Controlled trial of bright light for nonseasonal major depressive disorders.

Psychotropic drug-free hospitalized veterans with nonseasonal major depressive disorders or depressed forms of bipolar disorder were treated with light for 1 week. Twenty-five patients were randomly assigned to bright white light treatment (2000-3000 lux), and 26 patients were randomized to dim red light placebo control treatment. Unlike those treated with dim red light, those treated with bright white light showed declines in three measures of depression during treatment. Partial relapse appeared within 2 days. A global depression score showed a statistically significant (p = 0.02) difference favoring bright white light treatment. Two bright-light-treated patients became mildly hypomanic, but side effects were mild. Improvement was not correlated with patient expectations; indeed, patients expected somewhat greater benefit from the placebo. Patients treated in summer responded as well as those treated in winter. Baseline electroencephalogram (EEG) sleep stage data (e.g., rapid eye movement; REM latency) did not predict treatment responses. These 1-week treatment results suggest that bright light might produce benefits for patients with nonseasonal depression. Bright light should not be recommended for routine clinical application before additional assessments with longer treatment durations are done.

Sleep duration, illumination, and activity patterns in a population sample: effects of gender and ethnicity.

BACKGROUND: Current knowledge of the population's sleep durations emanates primarily from questionnaires and laboratory studies. Using Actillumes, we investigated whether self-reported sleep durations were indicative of a population decline in sleep duration. We also explored illumination and activity patterns. METHODS: San Diego adults (n = 273, age range: 40-64) were recruited through random telephone calls and were monitored at home while engaging in usual daily routines. RESULTS: Volunteers slept an average of 6.22 hours and received an average of 554 lux (environmental illumination). The timing of sleep, illumination, and activity occurred at 2:44, 12:57, and 13:43, respectively. Irrespective of ethnicity, age, and time reference, men received greater illumination than did women, but this gender effect was not independent of work status. Women and men exhibited a similar circadian activity profile; however, women exhibited better sleep-wake patterns. Interactions between gender and ethnicity suggested worse sleep-wake patterns among minority men. An age-related decline in activity was found, but no age trend in sleep duration or illumination patterns was observed. CONCLUSIONS: This study showed an objective population decline in sleep duration. Sociodemographic effects should be considered in analyses of sleep-wake patterns and illumination exposures.

Low illumination experienced by San Diego adults: association with atypical depressive symptoms.

We explored the illumination exposure of middle-aged adults to determine normal values and to explore several correlates of daily light exposures. Subjects aged 40-64 years in San Diego, CA were recruited by random telephone dialing. Subjects completed a demographic interview and the Center for Epidemiologic Studies Depression self-rating scale (the CES-D) supplemented with eight questions related to seasonal affective disorders (SAD). Data were analyzed for 106 volunteers who wore a device that monitors illumination exposures and activity. The median subject was exposed to illumination > or = 1000 lux for only 4% of the time observed, that is, only about 58 min per day were spent in daylight. Subjects scoring higher on the atypical SAD mood symptoms spent less time in bright illumination rs = -0.266, p = 0.003. The CES-D depression score was similarly correlated with illumination but of borderline significance (rs = -0.150, p = 0.063). These results suggest the hypothesis that many Americans may be receiving insufficient light exposure to maintain optimal mood.

Mortality hazard associated with prescription hypnotics.

BACKGROUND: The American Cancer Society's Cancer Prevention Study II was a large survey designed primarily to examine cancer risks such as cigarette smoking. From the same survey and methods, data on usage of "prescription sleeping pills" in 1982 were examined. METHODS: Standardized mortality ratios were computed. Because sleeping pill use could be a proxy for other risk factors, cox proportional hazards models were computed to control for possible confounding factors as extensively as the data permitted. RESULTS: Men and women who reported taking prescription sleeping pills 30+ times in the past month had standardized mortality ratios of 3.18 and 2.82, respectively; controlling for 10-year age groups (p < 0.001). The standardized mortality ratios for usage 1-29 times/month were 1.8 and 1.48, respectively (p < 0.001). In proportional hazards models that controlled for 30 other risk factors and comorbidities simultaneously, the excess mortality risk associated with usage 30+ times per month remained significant, but hazard ratios were reduced to 1.35 for men and 1.22 for women. CONCLUSIONS: Use of hypnotics was associated with excess mortality. This methodology could not determine if hypnotic compounds caused the risks associated with their use, nor could the risks of individual compounds be determined. Since millions of Americans are currently taking hypnotics, long-term controlled trials are urgently needed to further guide both patients and physicians.

Light therapy of late luteal phase dysphoric disorder: an extended study.

Nineteen patients with late luteal phase dysphoric disorder (LLPDD) and 11 healthy comparison subjects underwent a 3-month crossover trial of bright (more than 2500 lux) white morning, bright white evening, and placebo dim (less than 10 lux) red evening light, administered daily for 1 week during the premenstrual phase of the menstrual cycle. All light treatments significantly reduced depressive ratings from baseline levels.

Neurological findings in Alzheimer's disease and normal aging.

To determine the potential value of abnormal neurological findings as markers of Alzheimer's disease (AD) and their relationship to the stage of AD, we compared standardized neurological examinations in 135 community-dwelling patients with AD and 91 nondemented elderly individuals. After correcting for differences in age and education between the two groups, we found that rigidity, stooped posture, graphesthesia, neglect of simultaneous tactile stimuli (face-hand test), and snout, grasp, and glabella reflexes were present significantly more often in patients with AD than in control subjects. These findings increased in prevalence in patients with AD according to the severity of dementia. However, in a multivariate logistic regression model only the grasp reflex, graphesthesia, and the face-hand test were statistically significantly associated with the degree of cognitive impairment. Although abnormal neurological findings occur regularly in AD, they are too infrequent early in the course of AD to serve as diagnostic markers. Prospective studies are needed to determine whether patients with the early onset of extrapyramidal or other findings form a distinct subgroup of AD.

The Mini-Mental State Examination in the early diagnosis of Alzheimer's disease.

The Mini-Mental State Examination (MMSE), a brief test of cognitive function, has been widely used to screen for dementia. We administered the MMSE to 74 community-dwelling patients meeting criteria for probable Alzheimer's disease (AD) and 74 age- and education-matched controls. Twenty-four patients with AD performed in the nondemented range by scoring above the recommended cutoff point of 23 of a possible 30 on the MMSE. We compared the scores for items of the MMSE in controls and subjects with AD and used logistic regression to model a shorter MMSE that retained the accuracy of the complete test. A score summing tests of recall and orientation for place had similar sensitivity to the full MMSE. Adding a verbal fluency test to the MMSE reduced the error rate by improving the accuracy of diagnosis of patients with AD scoring in the nondemented range.

Clinical validity of the Mattis Dementia Rating Scale in detecting Dementia of the Alzheimer type. A double cross-validation and application to a community-dwelling sample.

OBJECTIVE: To assess the clinical validity of the Dementia Rating Scale (DRS) in detecting patients with dementia of the Alzheimer type (DAT). BACKGROUND: The DRS is widely used to evaluate cognitive functioning in older adults. Adequate normative data are unavailable; studies addressing the clinical validity of the DRS are limited by small sample sizes. DESIGN AND METHODS: Administered the DRS to 254 outpatients with DAT and 105 healthy elderly subjects. Performed (1) multiple regressions of demographic factors on the DRS and its subscales; (2) derivation of optimal DRS cutoff scores using receiver operating characteristic curves; (3) double cross-validation with stepwise logistic regressions; and (4) application of results to a community-dwelling sample. RESULTS: Age- and education-adjusted DRS scores were computed. The optimal DRS cutoff score for DAT of 129 or less revealed a sensitivity of 98% and a specificity of 97%. The logistic regressions resulted in a combination of the Memory and Initiation/Perseveration subscales that correctly classified 98% of all subjects, 92% of a subsample of 76 patients with mild DAT, and 100% of the 51 patients with autopsy-confirmed DAT. The resultant equation was then applied to a community-dwelling sample (238 healthy elderly subjects and 44 patients with DAT): 91% of patients and 93% of normal subjects were correctly classified. Of an additional 77 individuals with questionable DAT, 43 were classified as demented and 34 were classified as nondemented. CONCLUSIONS: The DRS is a clinically valid psychometric test for the detection of DAT. The Memory and Initiation/Perseveration subscales are its best discriminative indexes for an abbreviated version.

Dementia: characteristics of a referral population and factors associated with progression.

We evaluated in a standard fashion 375 patients presenting with complaints of memory loss. Etiology of memory loss included senile dementia of the Alzheimer type (SDAT)-70%, vascular dementia-5%, mixed dementia (SDAT + vascular)-9%, and other etiologies-16%. Incontinence, transient symptoms, and gait disturbances occurred more frequently in vascular dementia than in SDAT. A history of cardiovascular disease and stroke was more common in vascular dementia than SDAT. Disturbances of gait, bradykinesia, and pyramidal tract findings were commonly seen in vascular dementia. Advanced technology aided diagnosis in only 6% of patients and CT was the most useful of such tests. An earlier age of onset was noted in those with a positive family history of SDAT. Duration of symptoms at presentation for SDAT patients varied inversely with the rate of progression of dementia 15 to 55 months later, suggesting that individuals who progress more slowly require more time to elapse before the family or patient realizes the need for medical attention.

Localizing and prognostic value of auditory evoked responses in coma after closed head injury.

We studied brainstem auditory evoked responses (BAERs) in 26 comatose patients after head injury, and long-latency auditory evoked responses (AERs) in 24 patients. BAERs-AERs were graded for abnormality to evaluate graded outcome. Only six patients had central BAER abnormalities. AERs were abnormal in 21, and all patients with abnormal BAER had abnormal AER, implying that the major site of injury affected the cerebral hemispheres. BAER was abnormal in only 5 of 12 with decerebration, suggesting that decerebration may occur with diffuse hemispheric injury. BAER (p less than 0.01) and AER (p less than 0.01) strongly correlated with outcome. Preservation of AER and normal BAER indicated good quality of survival; absent AER and normal BAER, survival; and absent AER and abnormal BAER, severe disability or death. BAER-AER predicted outcome as accurately as the detailed neurologic examination and occasionally added predictive power.

Functional status, education, and the diagnosis of dementia in the Shanghai survey.

We examined the relationship of culturally adapted Chinese versions of the Mini-Mental State Examination (CMMS) and several functional measures to the effect of education on the clinical diagnosis of dementia in 554 subjects (55 to 95 years; median, 74) who had undergone intensive evaluation during the Shanghai survey of dementia. Low education was associated with increased prevalence of clinically diagnosed dementia. The standardized history and one functional scale (Pfeffer Outpatient Disability Scale [POD]) clustered closely with clinical diagnosis on factor analysis, whereas the CMMS, Instrumental Activities of Daily Living scale (IADL), and Activities of Daily Living scale (ADL) loaded additionally onto an education-weighted component. A logistic equation based on the CMMS, history, POD, and IADL was the best predictor of the clinical diagnosis of dementia, but history, POD, and IADL without a mental status score also predicted the diagnosis with a sensitivity of 88.6%, a specificity of 89.3%, a positive predictive value of 66.0%, and a negative predictive value of 97.1%. When dementia was diagnosed using an algorithm based on the three functional scales alone, low education continued to be associated with increased age-specific risk of dementia.

Episodic memory changes are associated with the APOE-epsilon 4 allele in nondemented older adults.

OBJECTIVE: To compare the memory performances of nondemented older adults with and without the epsilon 4 allele of the apolipoprotein E (APOE-epsilon 4). BACKGROUND: Few studies have examined the cognitive status of subjects at high risk for the development of dementia of the Alzheimer type (DAT). A newly reported risk factor for DAT allows for an examination of the cognitive performances of nondemented subjects who are at risk by virtue of being either heterozygous or homozygous for the APOE-epsilon 4 allele. METHODS: The California Verbal Learning Test (CVLT) was administered to 52 nondemented older adults. Subjects were divided into two groups on the basis of the presence (n = 17) or absence (n = 35) of one or two APOE-epsilon 4 alleles. RESULTS: APOE- epsilon 4 and non-epsilon 4 groups did not significantly differ in demographic, mental status, and functional characteristics. APOE-epsilon 4 subjects demonstrated significantly poorer mean performances than non-epsilon 4 subjects on nine CVLT variables. Seven group differences remained significant, and three approached significance (0.05 < p < 0.10), after the effects of age and gender were taken into account. Six of the 14 APOE-epsilon 4 subjects who completed annual follow-up evaluations developed either DAT or questionable DAT, whereas none of the 26 non-epsilon 4 subjects who received follow-up demonstrated any cognitive decline. CONCLUSIONS: Results suggest that episodic memory changes in older adults are associated with APOE-epsilon 4 allele; sensitive cognitive markers such as those of the CVLT may precede the subsequent development of DAT.

IgE and cardiovascular disease. Results from a population-based study.

Because previous reports have suggested that IgE-mediated events may lead to both platelet activation and arterial spasm, a population-based study of 262 men and 315 women, aged 38 to 82, was conducted to investigate the association of serum IgE levels with myocardial infarction, stroke, and noninvasively diagnosed large-vessel peripheral arterial disease. In men with previous myocardial infarction, previous stroke, or current large-vessel peripheral arterial disease, geometric mean serum IgE levels were increased 119 percent, 164 percent, and 78 percent, respectively. These associations were statistically significant (p less than 0.05). Because IgE was positively or inversely correlated with several traditional cardiovascular disease risk factors, logistic regression was used to evaluate the independent association of IgE with any cardiovascular disease (myocardial infarction, stroke, or large-vessel peripheral arterial disease). In a model including age, cigarette smoking, fasting plasma glucose level, diastolic blood pressure, and low-density lipoprotein cholesterol level as covariates, IgE was positively and independently associated with any cardiovascular disease (p = 0.03). Similar evaluations in women revealed no correlation between IgE and cardiovascular disease by either univariate or multivariable analysis. These data indicate that IgE may be an independent marker for cardiovascular disease in men, and thus suggest IgE-mediated events may play a role in the pathogenesis of cardiovascular disease.