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Dose-response relationships of the cholinergic antagonist, atropine methonitrate, and the beta-adrenergic agonist, salbutamol, were examined by cumulative dose techniques. A wet aerosol, 1.5 mg atropine methonitrate produced a maximum response. The response to 200 microgram of salbutamol from a pressurised aerosol was close to maximum. Secondly, the bronchodilator response of salbutamol microgram was compared with atropine methonitrate 2 mg and placebo in 18 asthmatic patients in a randomised crossover study. In 11 of them the bronchodilator response of the combination of salbutamol and atropine methonitrate was evaluated. Atropine methonitrate produced a similar peak bronchodilator effect to salbutamol, but its effect was more prolonged, the response being significantly greater at four and six hours than with salbutamol. The combination of drugs produced a significantly greater and more lasting bronchodilatation than either of the drugs alone. Despite mild side effects, atropine methonitrate, either alone or in combination with an adrenergic drug, appears to have a place in the treatment of sever reversible airway obstruction not adequately controlled by conventional treatment. [ABSTRACT FROM PUBLISHER]

The poem "A Small, Unremarkable Oil-Painting of Doubtful Provenance, Labelled "Allegory of the Artist Trapped in an Idiot's Career"," by C. J. Allen. First Line: The career is a castle by Escher, an impossible knot; Last Line: an owl, badly painted, symbolic, about to take flight.

Introduction: This study examines how frequently family physicians display printed educational materials about mental health problems in their practices and where these materials should be located for optimal effect., Methods: A cross-sectional observational study of pamphlet display practices in 13 family physicians' offices in Hamilton, Ontario, Canada was followed by an intervention which placed selected mental health educational materials in waiting rooms and examining rooms, and monitored the pick up rate from each location by patients., Main Results: The study found that few mental health pamphlets were displayed by the participating physicians, that when a range of these pamphlets was made available, pamphlets on mood disorders were the most popular, and that significantly more pamphlets were picked up from examining rooms than from waiting rooms., Conclusions: We conclude that patients are interested in having access to printed materials about mental health problems, and that the optimal location is in display racks in examining rooms.

Background: Most patients with cough and gastroesophageal reflux disease (GERD) improve on medical treatment with proton pump inhibitors (PPI). Nonresponders may be considered for antireflux surgery, but the selection of patients is difficult., Methods: We have performed laparoscopic Nissen fundoplications (LNF) in 677 patients. Of these patients, 81% have undergone 6-month follow-up assessment with 24-h pH testing, esophageal manometry, symptom scores, and quality-of-life scores., Results: LNF controlled heartburn in 93% and improved cough in 81%. Stepwise multiple regression showed that the preoperative cough score (r = 0.620, p <0.0001) and change in cough on and off PPI (r = 0.296, p = 0.0002) predicted improvement after surgery. A positive result on a randomized acid infusion test was associated with a greater improvement in cough after surgery (p = 0.0243)., Conclusion: An acid infusion test and assessment of cough on and off PPI may be useful preoperative tools for the selection of patients with cough for LNF.

Background: Gastroesophageal reflux (GER) is commonly associated with chronic cough and asthma, but there is little or no information on the nature of any associated airway inflammation., Objective: To observe whether the association with GER worsens airway inflammation in patients with chronic cough or asthma., Patients and Methods: The airway inflammatory indexes in induced sputum and exhaled air were examined in a cross-sectional study of 11 patients with cough and GER, nine patients with mildly symptomatic asthma and GER, nine patients with mildly symptomatic asthma without GER and nine normal, healthy control subjects. GER was shown objectively by 24 h ambulatory pH recording., Results: The sputum total cell count, the proportion of neutrophils and macrophages, and the fibrinogen level were normal in all four groups, with no significant differences among the groups. The sputum eosinophil and metachromatic cell percentages, and eosinophil cationic protein levels were normal in patients with cough and GER. They were significantly increased in patients with asthma compared with healthy subjects (P<0.01) and patients with cough (P<0.01), but were not different between groups with and without GER. Exhaled nitric oxide levels showed similar results (P<0.01). The correlations between the number of episodes of reflux and the proportion of sputum eosinophils, neutrophils or exhaled nitric oxide were modest but not significant., Conclusions: GER, when associated with cough or mildly symptomatic asthma, does not cause or aggravate existing airway inflammation as measured by induced sputum cell counts and fibrinogen level, or by exhaled nitric oxide.

Because optimal management of iron chelation therapy in patients with sickle cell disease and transfusional iron overload requires accurate determination of the magnitude of iron excess, a variety of techniques for evaluating iron overload are under development, including measurement of serum ferritin iron levels, x-ray fluorescence of iron, magnetic resonance imaging, computed tomography, and measurement of magnetic susceptibility. The most promising methods for noninvasive assessment of body iron stores in patients with sickle cell anemia and transfusional iron overload are based on measurement of hepatic magnetic susceptibility, either using superconducting quantum interference device (SQUID) susceptometry or, potentially, magnetic resonance susceptometry.

The diagnostic properties of a "lipid index" of macrophages in induced sputum as a noninvasive marker of aspiration of acidic gastric contents were evaluated. In a cross-sectional study, 33 subjects (17 with symptoms suggestive of gastrooesophageal reflux) with normal chest radiographs and no symptoms of aspiration or sinus disease, underwent dual-channel 24-h ambulatory oesophageal pH recording and sputum induction. Oropharyngeal reflux, defined as at least one episode of a fall in pH to <4 at the upper oesophageal electrode, was considered indicative of aspiration of acidic gastric contents ("gold standard"). An index for the presence of intracellular lipid in sputum macrophages, detected by oil red O stain, was obtained. The sensitivity, specificity and predictive values of this "lipid index" were calculated. The "lipid index" could be calculated in 29 of 33 samples with high interobserver repeatability (intraclass correlation coefficient 0.96). Twenty subjects showed oropharyngeal reflux and nine did not. The median "lipid index" in subjects with oropharyngeal reflux (24.5) was significantly greater than that in those without reflux (1.0) (p<0.001). A "lipid index" of 7.0 had a sensitivity of 90%, a specificity of 89%, a positive predictive value of 95% and a negative predictive value of 80%. A "lipid index" of 7.0 in the macrophages of induced sputum is a good marker of oropharyngeal reflux.

Objective: To examine general practitioners' knowledge and practices concerning reporting of notifiable conditions, and to examine barriers to notification of infectious diseases by general practitioners and identify strategies for improving the notification process., Design and Setting: Audit of the 100 most recent notifications received by the South Eastern Sydney Public Health Unit of cases of each of hepatitis A, pertussis and measles; and focus groups with GPs practising in Sydney's eastern and southern suburbs, some of whom were selected on the basis of their notification practices., Results: Although these diseases are notifiable on clinical suspicion, only about 40% of the hepatitis A and pertussis cases and 80% of measles cases (54% overall) had been notified by GPs. Delays between doctor and laboratory notifications were an average of seven days for hepatitis A, 19 days for pertussis and seven days for measles. Focus groups showed that at least some GPs have poor understanding of the process of notification, most felt uncomfortable notifying an unconfirmed case, many preferred to leave notification to the laboratory because of concerns about damaging the doctor-patient relationship, and that there is need for financial or other incentives., Conclusions: There are deficiencies in the completeness and timeliness of notification by GPs which may adversely affect the timing of prophylaxis and outbreak control. Notification by GPs may be improved by such strategies as better notification forms and better feedback to doctors on the outcomes.

The incidence and severity of dysphagia before and 6 months after laparoscopic Nissen fundoplication without routine division of short gastric vessels are presented. Laparoscopic Nissen fundoplication was undertaken in 195 patients over 32 months with 116 patients who had prospective follow-up longer than 6 months. Patients underwent a 24-h pH recording, esophageal manometry, and symptom score assessment before and 6 months after surgery. There was a significant (p < 0.0001) improvement in the percent of reflux in 24-h (8.61 +/- 0.74 to 0.68 +/- 0.12), lower esophageal pressure (8.53 +/- 0.51 to 23.11 +/- 1.1 mm Hg), and reflux symptom scores (40.97 +/- 1.13 to 12.11 +/- 1.1) at 6 months. A similar improvement (p < 0.0001) was also observed in the dysphagia symptom score (4.58 +/- 0.38 to 1.96 +/- 0.32), with more than half the patients reporting improvement after surgery. No correlation was observed between the change in dysphagia score and the postoperative lower esophageal pressure or esophageal motor function. These data suggest that the incidence of clinically significant dysphagia after laparoscopic Nissen fundoplication, even without division of short gastric vessels, is low. Improvement in the dysphagia score after surgery is interesting and warrants further investigation.

Objective: To document the number and pattern of psychiatric and psychosocial referrals to community resources by family physicians (FPs) and to determine whether referral practices correlate with physician variables., Design: Cross-sectional survey of referrals by FPs to 34 key psychiatric and psychosocial community resources identified by a panel of FPs, psychiatric social workers, psychiatric nurses, public health nurses, and the local community information service., Setting: Regional municipality of 434,000 persons in Ontario., Participants: Twenty-seven of 34 (79%) community agencies identified 261 FPs who made 4487 referrals to participating agencies (range 0 to 65, median 15, mean 17.19 +/- 13.42)., Main Outcome Measures: Number of referrals to all agencies; variables, such as physician sex, school of graduation, year of graduation, and certificate status in the College of Family Physicians of Canada, related to referral patterns., Results: Referrals to outpatient psychiatric clinics, support services, and general counseling services accounted for 96% of all referrals. Physicians' average annual referral profile was as follows: 8.6 patients to a support service, 6.3 to an outpatient psychiatric service, 1.6 to a counseling service, and 0.46 to a substance abuse service. Referral profiles of individual physicians varied greatly. Female FPs made fewer referrals than male FPs to support services, but both made similar numbers of referrals to psychiatric, counseling, and substance abuse services. The more recent the year of graduation, the greater the number of referrals to psychiatric (r = 0.158, P = 0.0107) and counseling services (r = 0.137, P = 0.0272) and the higher the fraction of referrals to psychiatric services (r = 0.286, P = 0.0001)., Conclusions: Family physicians in Hamilton-Wentworth made few referrals to psychiatric and psychosocial services. Only physician sex and year of graduation correlated significantly with numbers of referrals made. Recent graduates of both sexes made significantly more referrals to psychiatric clinics and counseling services than their older colleagues.

Previous studies have demonstrated that glial cells in culture express several subtypes of functional adrenergic receptors. To determine if similar receptors are expressed by glia in vivo, we examined the expression of adrenergic receptors in the normal, crushed, and transected optic nerves of the rabbit and rat using quantitative receptor autoradiography. Additionally, we examined the expression of adrenergic receptors in the normal and damaged human optic nerve. High levels of alpha 1-, alpha 2-, beta 1-, and beta 2-adrenergic receptors were identified in the rabbit and rat forebrain. In the normal rabbit, rat, and human optic nerves, only alpha 1 and beta 2 receptors were observed, and these were present in low to moderate densities. Combined immunohistochemistry and autoradiography suggests that the majority of beta 2-adrenergic receptors in the rabbit, rat, and human optic nerve are expressed by astrocytes. After unilateral optic nerve crush or transection, only beta 2- adrenergic receptors were significantly increased. This increase in beta 2 receptors was first detectable at days 7 and 28 post-transection in the rabbit and rat, respectively. The expression of beta 2 receptors in the transected optic nerve continued to increase with time, so that by 90 d post-transection the density of beta 2 receptors in both the rabbit and rat optic nerve was among the highest of any area in the forebrain. Taken together with previous studies, these results suggest that in vivo, beta 2-adrenergic receptors may provide a therapeutic target for regulation of astrocyte functions including glycogen metabolism, cytokine release, and the hypertrophy and proliferation that occurs in response to neuronal injury.

Background: To determine whether deferoxamine prevents the complications of transfusional iron overload in thalassemia major, we evaluated 59 patients (30 were female and 29 male; age range, 7 to 31 years) periodically for 4 to 10 years or until death., Methods: At each follow-up visit, we performed a detailed clinical and laboratory evaluation and measured hepatic iron stores with a noninvasive magnetic device., Results: The body iron burden as assessed by magnetic measurement of hepatic iron stores was closely correlated (R = 0.89, P < 0.001) with the ratio of cumulative transfusional iron load to cumulative deferoxamine use (expressed in millimoles of iron per kilogram of body weight, in relation to grams of deferoxamine per kilogram, transformed into the natural logarithm). Each increase of one unit in the natural logarithm of the ratio (transfusional iron load to deferoxamine use) was associated with an increased risk of impaired glucose tolerance (relative risk, 19.3; 95 percent confidence interval, 4.8 to 77.4), diabetes mellitus (relative risk, 9.2; 95 percent confidence interval, 1.8 to 47.7), cardiac disease (relative risk, 9.9; 95 percent confidence interval, 1.9 to 51.2), and death (relative risk, 12.6; 95 percent confidence interval, 2.4 to 65.4). All nine deaths during the study occurred among the 23 patients who had begun chelation therapy later and used less deferoxamine in relation to their transfusional iron load (P < 0.001)., Conclusions: The early use of deferoxamine in an amount proportional to the transfusional iron load reduces the body iron burden and helps protect against diabetes mellitus, cardiac disease, and early death in patients with thalassemia major.

Neuropeptide Y (NPY) has been suggested to exert antinociceptive actions by inhibiting the release of neurotransmitters from trigeminal and dorsal root ganglia (DRG) neurons, but the site of direct NPY action in vivo and the NPY receptor subtype mediating these effects are unknown. 125I-peptide YY (PYY) was used to localize and characterize NPY receptor binding sites in trigeminal ganglia, DRG, and spinal cord of the rat, rabbit, and monkey. In the rat, rabbit, and monkey, 5-20% of trigeminal ganglia and DRG neurons express NPY binding sites. Unilateral cuff-induced neuropathy or transection of the rat sciatic nerve did not significantly alter the density or number of DRG neurons expressing NPY receptors. A unimodal size distribution for L4 and L5 DRG neurons expressing NPY binding sites in the rat was determined, with a mean cross-sectional area of 947 microns 2. In the spinal cord the highest concentration of NPY receptors is found in laminae I, II, V, X, and Onuf's nucleus. Pharmacological experiments using selective Y1 and Y2 receptor antagonists suggest that Y2 is the prominent NPY receptor subtype expressed in trigeminal ganglia neurons, DRG neurons, and spinal cord. Previous studies have demonstrated that a population of large-diameter, presumably myelinated primary afferents express NPY after peripheral nerve injury. NPY released from these injured large-diameter DRG neurons may act in a paracrine fashion to block the transmission of nociceptive information from the small- and medium-diameter DRG neurons that constitutively express NPY receptors. NPY receptors are therefore uniquely positioned to inhibit primary afferent nociceptors directly, especially after peripheral nerve injury.

A major pathological feature of Alzheimer's disease (AD) is the presence of a high density of amyloid plaques in the brain tissue of patients. The plaques are predominantly composed of human beta-amyloid peptide beta A4, a 40-mer whose neurotoxicity is related to its aggregation. Certain metals have been proposed as risk factors for AD, but the mechanism by which the metals may exert their effects is unclear. Radioiodinated human beta A4 has been used to assess the effects of various metals on the aggregation of the peptide in dilute solution (10(-10) M). In physiological buffers, 10(-3) M calcium, cobalt, copper, manganese, magnesium, sodium, or potassium had no effect on the rate of beta A4 aggregation. In sharp contrast, aluminum, iron, and zinc under the same conditions strongly promoted aggregation (rate enhancement of 100-1,000-fold). The aggregation of beta A4 induced by aluminum and iron is distinguishable from that induced by zinc in terms of rate, extent, pH and temperature dependence. These results suggest that high concentrations of certain metals may play a role in the pathogenesis of AD by promoting aggregation of beta A4.

[125I]Peptide YY was used to localize and characterize peptide YY and neuropeptide Y receptor binding sites in the heart. In the rat and rabbit heart, nearly every artery and arteriole that could be histologically identified also expressed saturable binding sites for [125I]peptide YY. In the arteries, these [125I]peptide YY binding sites were primarily associated with the smooth muscle layer. Pharmacological experiments demonstrated that peptide YY and neuropeptide Y were equipotent in competing for [125I]peptide YY binding in the heart. In another competition series, [Leu31,Pro34]-neuropeptide Y (a Y1 receptor-specific agonist when used with [125I]peptide YY) was significantly more potent than neuropeptide Y (a Y2 receptor-specific agonist when used with [125I]peptide YY) in competing for [125I]peptide YY binding from coronary arteries, suggesting that the receptor binding sites on cardiac arteries and arterioles are of the Y1 subtype. These results demonstrate that smooth muscle cells of the atrial and ventricular arteries and arterioles in rat and rabbit heart express Y1 receptors and suggest a possible direct effect of neuropeptide Y on coronary blood vessels to induce vasoconstriction.

To examine the relationship between hepatic iron stores and plasma ferritin concentration in individuals treated with red cell transfusion and iron chelation therapy, 37 patients with sickle cell anemia and 74 patients with thalassemia major were studied. In each patient, hepatic iron stores were measured by an independently validated noninvasive magnetic method, and plasma ferritin was determined by immunoassay. The correlation between hepatic iron and plasma ferritin was significant both in patients with sickle cell anemia (R = 0.75, P < 0.0001) and in those with thalassemia major (R = 0.76, P < 0.0001). Regression analysis showed no significant difference between the two groups in the linear relationships between hepatic iron stores and plasma ferritin. Considering all 111 transfused patients as a group, the coefficient of correlation between hepatic iron stores and plasma ferritin was highly significant (R = 0.76, P < 0.0001). Regression analysis found that variation in body iron stores, as assessed by magnetic determinations of hepatic iron, accounted for only approximately 57% of the variation in plasma ferritin, suggesting that the remainder was the result of other factors, such as hemolysis, ineffective erythropoiesis, ascorbate deficiency, inflammation, and liver disease. The 95% prediction intervals for hepatic iron concentration, given the plasma ferritin, were so broad as to make a single determination of plasma ferritin an unreliable predictor of body iron stores. Variability resulting from factors other than iron status limits the clinical usefulness of the plasma ferritin concentration as a predictor of body iron stores.

125I-Bolton-Hunter sulfated cholecystokinin-8 was used to localize and characterize cholecystokinin (CCK) receptor binding sites in trigeminal and dorsal root ganglia, and in the spinal cord of the rat, rabbit, and monkey. In the rabbit and monkey, a substantial number, 90 +/- 21% and 24 +/- 8%, respectively, of trigeminal and dorsal root ganglion neurons express CCK binding sites. In the spinal cord, the highest concentration of CCK receptors is found in laminae I and II, which is the major termination site of dorsal root ganglia neurons expressing CCK receptor binding sites. Neonatal capsaicin treatment of the rat results in a 70% decline in CCK receptor binding sites in laminae I and II of the spinal cord, indicating that dorsal root ganglia neurons are a major source of CCK receptors in the spinal cord. Pharmacological experiments using selective CCK-A and CCK-B receptor antagonists demonstrate that CCK-B is the prominent CCK receptor subtype in trigeminal and dorsal root ganglia neurons in the rat, rabbit, and monkey. In the rat and rabbit spinal cord, CCK-B binding sites are the prominent subtype, whereas in the monkey cord, CCK-A is the prominent receptor subtype. These results demonstrate that CCK-B receptors are expressed by a substantial percentage of dorsal root ganglion neurons at all spinal levels, and that CCK may antagonize opiate analgesia at the level of the primary afferent neuron itself.

Sympathetic ganglia are innervated by neuropeptide-containing fibers originating from pre- and postganglionic sympathetic neurons, dorsal root ganglion neurons, and in some cases, myenteric neurons. In the present report receptor autoradiography was used to determine whether sympathetic ganglia express receptor binding sites for several of these neuropeptides including bombesin, calcitonin gene-related peptide-alpha, cholecystokinin, galanin, neurokinin A, somatostatin, substance P, and vasoactive intestinal polypeptide. The sympathetic ganglia examined included the rat and rabbit superior cervical ganglia and the rabbit superior mesenteric ganglion. High levels of receptor binding sites for cholecystokinin, galanin, somatostatin, substance P, and vasoactive intestinal polypeptide were observed in all sympathetic ganglia examined, although only discrete neuronal populations within each ganglion appeared to express receptor binding sites for any particular neuropeptide. These data suggest that discrete populations of postganglionic sympathetic neurons may be regulated by neuropeptides released from pre- and postganglionic sympathetic neurons, dorsal root ganglion neurons, and myenteric neurons.

Symptomatic gastroesophageal reflux occurs daily in an estimated 7% of adults and weekly or monthly in 29%. Untreated it can lead to esophageal erosions, ulceration and stricture formation. The pathogenesis is often multifactorial: defects in the function of the lower esophageal sphincter, esophageal clearance mechanisms and gastric emptying combine to produce frequent lengthy periods during which the lower esophagus is bathed in regurgitated acid. In most patients reflux disease is easily recognized as recurrent heartburn, regurgitation or dysphagia, or a combination. When acute chest pain or respiratory illness is the primary presenting complaint the patient needs particularly careful investigation to determine whether the symptoms are due to a primary cardiac or respiratory condition, are secondary to gastroesophageal reflux alone or represent a combination of disorders. Endoscopy with biopsy and long-term pH monitoring are the most reliable ways of determining whether reflux disease is present. Additional investigations, such as exercise testing, cardiac catheterization or inhalation challenge, may be needed in patients with cardiac or respiratory symptoms. Treatment should follow a stepped-care approach and in most patients should begin with changes in lifestyle, including dietary manipulation, reducing alcohol and cigarette consumption, and raising the head of the bed, together with appropriate use of antacids or alginate-antacid combinations. H2-receptor antagonists and agents to improve both gastric emptying and the tone of the lower esophageal sphincter may be added in sequence. Most patients will respond well to this regimen. Surgery should be considered only for those with intractable symptoms or with complications (e.g., stricture formation, bleeding, development of dysplastic epithelium in those with Barrett's esophagus, or secondary pulmonary disease that does not respond to medical management). It is successful in 85% of well-selected patients and has few complications.