Mechanism of bronchodilator effect in chronic airflow limitation.

OBJECTIVE: To examine the mechanisms through which two bronchodilators (theophylline and salbutamol) influence dyspnea during daily activities. METHODS: Twenty-four patients with chronic airflow limitation participated in a multiple crossover, randomized, placebo-controlled trial. The effect of theophylline and salbutamol, alone or combined, on pulmonary function and dyspnea during daily activities was examined. Correlations of changes in forced expiratory volume in 1 second (FEV1) and maximum expiratory pressures (MIPs) (independent variables) and changes in dyspnea score during daily activities (dependent variable) were also examined. RESULTS: The two drugs proved to be beneficial the effects in general were additive rather than synergistic. The drugs improved the FEV1; theophylline significantly improved the MIPs. The correlation between the changes in FEV1 and those in dyspnea score, after adjustment for the changes in MIPs, was 0.55 (p less than 0.001). The correlation between the changes in MIPs and those in dyspnea score, after adjustment for the changes in FEV1, was 0.39 (p less than 0.001). CONCLUSIONS: Changes in airway calibre and in respiratory muscle strength play an independent and important role in dyspnea during daily activities in patients with chronic airflow limitation. Changes in airway calibre may be of greater importance.     

Acute effects of high-dose thyrotropin releasing hormone infusions in Alzheimer's disease

Thyrotropin releasing hormone (TRH) was administered intravenously to ten patients with Alzheimer's Disease (AD) in a high-dose paradigm, thought to maximize central nervous system effects and potentially produce facilitation of cholinergic function, a known property of the neuropeptide. Acute effects of TRH on behavioral, cognitive and physiologic measures were assessed after patients received 0.1 mg/kg TRH, 0.3 mg/kg TRH and placebo, the higher TRH dose and placebo being given in a randomized, double-blind fashion. Patients showed statistically significant increases in arousal and improvement in affect, as well as a modest improvement in semantic memory, all after receiving the higher TRH dose. Both TRH doses produced transient rises in systolic blood pressure, with no effect on diastolic blood pressure, heart rate or temperature. This study suggests that high-dose TRH can be safely administered to AD patients and is neurobehaviorally active; further studies are needed to determine the extent and mechanism of the cognitive and psychobiological properties of this peptide in AD and other neuropsychiatric disorders.     

Aging-related skin changes: development and clinical meaning

The medical literature is replete with articles that discuss the spectrum of sun-induced changes in human skin. These extrinsic, actinically induced changes, more prevalent in the elderly, include wrinkling and loss of elasticity; dyspigmentation; vascular ectasias and hemorrhage; atrophy; and benign and malignant neoplasms. This article, however, focuses on the intrinsic changes behind geriatric skin problems, providing a non-specialist's illustrated guide to recognizing structural and functional changes due to normal, chronological aging and how they manifest clinically in elderly patients.     

Incidence of adverse events and negligence in hospitalized patients. Results of the Harvard Medical Practice Study I

BACKGROUND. As part of an interdisciplinary study of medical injury and malpractice litigation, we estimated the incidence of adverse events, defined as injuries caused by medical management, and of the subgroup of such injuries that resulted from negligent or substandard care. METHODS. We reviewed 30,121 randomly selected records from 51 randomly selected acute care, nonpsychiatric hospitals in New York State in 1984. We then developed population estimates of injuries and computed rates according to the age and sex of the patients as well as the specialties of the physicians. RESULTS. Adverse events occurred in 3.7 percent of the hospitalizations (95 percent confidence interval, 3.2 to 4.2), and 27.6 percent of the adverse events were due to negligence (95 percent confidence interval, 22.5 to 32.6). Although 70.5 percent of the adverse events gave rise to disability lasting less than six months, 2.6 percent caused permanently disabling injuries and 13.6 percent led to death. The percentage of adverse events attributable to negligence increased in the categories of more severe injuries (Wald test chi 2 = 21.04, P less than 0.0001). Using weighted totals, we estimated that among the 2,671,863 patients discharged from New York hospitals in 1984 there were 98,609 adverse events and 27,179 adverse events involving negligence. Rates of adverse events rose with age (P less than 0.0001). The percentage of adverse events due to negligence was markedly higher among the elderly (P less than 0.01). There were significant differences in rates of adverse events among categories of clinical specialties (P less than 0.0001), but no differences in the percentage due to negligence. CONCLUSIONS. There is a substantial amount of injury to patients from medical management, and many injuries are the result of substandard care.     

Are active and passive smoking harmful? Determining causation

Assessing the evidence regarding any causal question involves examining the strength of the studies conducted and applying a series of "diagnostic tests" for causation. We have reviewed the strength of the evidence incriminating smoking as a cause of lung cancer, and passive smoking as a cause of respiratory illness and decreased pulmonary function in children. There are eight prospective studies of smoking and lung cancer which have consistently shown a strong relationship. These studies have confirmed the temporality of the association and demonstrated a dose-response gradient. The studies addressing the effects of passive smoking in children are considerably weaker. Although they are consistent in suggesting increased infections for children less than one year of age, neither increased risk nor a dose-response gradient is consistently found in older children and the effect size, when present, is small. The rules for assessing causation applied here can be used to integrate new information concerning the health hazards of smoking.     

Acute effects of the selective cholinergic channel activator (nicotinic agonist) ABT-418 in Alzheimer’s disease

To explore further the potential for cognitive enhancement utilizing nicotinic stimulation in Alzheimer’s disease (AD), six otherwise healthy subjects with moderate AD received placebo and three doses (6, 12, and 23 mg) of the novel selective cholinergic channel activator (ChCA) (nicotinic agonist) ABT-418 over 6 h in a double-blind, within-subjects, repeated-measures design. Subjects showed significant improvements in total recall and a decline in recall failure on a verbal learning task. Qualitatively similar improvements were seen in non-verbal learning tasks such as spatial learning and memory, and repeated acquisition. No significant behavioral, vital sign, or physical side effects were seen. These results confirm that stimulating central nicotinic receptors has acute cognitive benefit in AD patients. These findings suggest that selective ChCAs have a potential therapeutic role in dementing disorders, and that further studies with this or similar agents in AD and/or Parkinson’s disease are warranted. Received: 27 February 1998/Final version: 9 September 1998     

Elastase is associated with the neurofibrillary pathology of Alzheimer disease: a putative link between proteolytic imbalance and oxidative stress

This study demonstrates elastase immunoreactivity in the neurofibrillary pathology of Alzheimer disease. Using an antiserum against elastase, we show that elastase immunoreactivity is restricted to neurons and is markedly elevated in a proportion of neurofibrillary tangle-bearing neurons. Elastase is a proteolytic enzyme that might be a candidate protease for the generation of amyloid-β from β-protein precursor. These findings support the hypothesis that proteases play an important role in Alzheimer disease and furthers the notion that an imbalance in proteolytic regulation contributes towards the pathogenic presentation of the disease. Moreover, since α1-antitrypsin, the principal inhibitor of elastase, is highly susceptible to oxidative stress, our findings suggest a link between proteolytic imbalance and oxidative stress in the pathogenesis of Alzheimer disease.     

Effects of cost sharing in health insurance on disability days

We assess how cost sharing for medical services affects restricted activity days (RADs) and work loss disability days (WLDs), using data from a controlled experiment. We grouped the experimental insurance plans into four categories, one providing free care and the other three requiring varying amounts of cost sharing. RADs per person per year decreased by one to two days with greater cost sharing, with the strongest effects among those of average or poor health status, especially the non-poor. Unlike RADs, WLDs showed no systematic differences by plan.