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The Faculty of Medicine of Dalhousie University (the Faculty) has applied a mission-based approach to the allocation of the academic budget since 1993. Over the ensuing decade, large shifts in budgets to academic departments have been effected, and two goals that required special emphasis-the successful implementation of a tutorial-based undergraduate medical curriculum and an increase in research activity-have been achieved. This has occurred despite significant reductions in the overall academic budget over the ten-year period. The budgeting process provided the Faculty with a tangible means of supporting its mission and also gave each department a transparent report of its relative contribution to the overall mission of the Faculty, which helped instill pride. In some years, misunderstandings of the budget process arose because of confusion over the impact of the overall total academic budget reductions experienced by the Faculty in that year. This meant that recognition of a department's contribution resulted, in most instances, in a relatively smaller reduction in budget rather than a budget increase. Further misunderstandings have arisen because of confusion between mission-based and activity-based budgeting. This confusion was reinforced because the assessments of education outcomes were measurements of activity rather than of outcomes. However, these measures were chosen to be the best-available indirect measures of the desired educational outcome. After ten years, the fundamentals of the mission-based process introduced in 1993 remain unchanged as the basis for allocation of the academic budget for the Faculty.

Background Professionalism is increasingly emphasised in medical education. Non-cognitive goals, including values, attitudes and skills, remain challenging to define and measure. The purpose of this study was to better understand these goals and their achievement in the MD programme. Methods Graduating medical students, faculty preceptors, residents and other health professionals (OHPs) completed a systematically developed mailed survey, rating achievement of 25 attribute statements. Following analyses of means and standard deviations, factor analysis of responses was conducted. Responses were compared across respondent groups. Results The overall response rate was 50.1% (191/396), comprising 57.5% of the students, 54.1% of the faculty members, 30.9% of the residents and 50% of the OHPs. Five items received mean ratings over 4/5; none were below 3/5. Five factors explained 65% of variance. They were: ‘Teamwork and interprofessional skills’; ‘Duty and responsibility’; ‘Communication and interpersonal skills’; ‘Professionalism and values’, and ‘Trustworthiness and ethical behaviour’. The groups differed significantly on 2 factors: Teamwork and interprofessional skills (P ≤ 0.0001) and Communication and interpersonal skills (P ≤ 0.001). Conclusions Important curriculum goals received high mean ratings. Ratings differed significantly across groups, suggesting differing perceptions of the extent to which goals were met. More study is needed to understand the basis of these perceptions.

In 1987, workers in the kitchen of one of the teaching hospitals in Halifax, Nova Scotia began to experience symptoms of pruritus, folliculitis, wheezing, conjunctival irritation, sore throat and headache, all suggestive of an indoor air quality (IAQ) problem. Approximately 127 of 160 kitchen workers were affected over a 2-year period and the complaints included cognitive difficulties and reactivity to environmental irritants. Workers in other parts of the hospital developed increasingly serious problems, including bronchial hyperreactivity, nausea, diarrhoea, weight loss, hair loss, recurrent infections, myalgia and arthralgia as well as more sinister neurotoxic effects of memory loss, poor concentration, visual perceptual losses, peripheral paraesthesia, Raynaud's phenomenon, severe fatigue, dizziness and neuromuscular incoordination. Between 1991 and 1993, more than 700 workers, out of a total workforce of 1250, reported symptoms. Over 300 workers were off work for periods of from 3 months to 3 years a...

In a phase I/II trial assessing the toxicity, pharmacokinetics, and activity of the (-)enantiomer of 2'-deoxy-3'-thiacytidine (3TC, lamivudine), 97 patients with AIDS or advanced human immunodeficiency virus (HIV) disease were administered 3TC at 0.5-20.0 mg/kg/day. The cohort's median entry CD4 cell count was 128/mm3 (range, 7-357). A toxic dose was not reached, although some patients reported mild headache, insomnia, and abdominal symptoms, and there was a general downward trend in neutrophil counts at the highest doses. Although subjective and difficult to interpret, increases in energy and appetite were noted, particularly in patients receiving > or = 8.0 mg/kg/day. Immunologic and virologic parameters showed evidence of at least transient anti-HIV activity at those higher doses. Although further studies of 3TC as monotherapy are needed, its favorable toxicity profile, evidence of at least transient clinical activity, and results of in vitro resistance experiments support further clinical testing in combination therapy.

Objective: To assess the effect of oral corticosteroids in patients with mild Pneumocystis carinii pneumonia and the acquired immune deficiency syndrome (AIDS). Design: Prospective, double blind, placebo controlled, randomized trial. Methods: Included were AIDS patients having their first episode of P. carinii pneumonia, who had no other known active pulmonary pathology, who had no contraindications for corticosteroids and who had received no other anti- P. carinii medications for more than 48 h. Subjects received either prednisone, 60 mg/day for 7 days, followed by a progressive tapering over 14 days, or identical placebo. The present analysis pertains to patients with mild P. carinii pneumonia as defined by a baseline resting oxygen saturation greater than 90% and a decrease in oxygen saturation during exercise while breathing room air of not less that 5 percentage points. Early deterioration, the end-point of the trial, was defined as a 10% decrease from baseline oxygen saturation on day 3 or thereafter. Results: At study termination, there were 12 subjects in the placebo group and 11 in the corticosteroid group. Baseline characteristics were not statistically different between the treatment groups. Early deterioration developed in 7 and 1 patients in the placebo and corticosteroid groups respectively ( P = 0.027). In addition, by day 3, a number of parameters were less favorable in the placebo group relative to the corticosteroid group including median oxygen saturation (85% vs 97%; P = 0.003), lactic dehydrogenase (1514 vs 763; P = 0.013), median respiratory rate (30 vs 22; P = 0.003), median heart rate (100 vs 81; P = 0.002), and median temperature (39 vs 37; P = 0.024). Even though patients suffering early deterioration in the placebo group were switched to corticosteroids, significant differences between the groups remained at day 30 with regard to exercise tolerance. More than half of patients assigned to the corticosteroid group exercised for a median of 6.5 min on day 30 ( P = 0.017). Conclusion: Oral corticosteroids prevent early deterioration and increase exercise tolerance in patients with mild AIDS-related P. carinii pneumonia as defined on the basis of pulse oximetry.

Objective To describe the frequency of aerosol pentamidine-induced bronchoconstriction, its relationship to nonspecific airway responsiveness, and its response to preventive therapy using salbutamol, ipratropium bromide, or sodium cromoglycate. Methods Consecutive HIV-infected individuals starting prophylactic AP were eligible if they had not been previously treated with this agent. Simple spirometry was performed before and 10 min after a single 60-mg dose given through an ultrasonic nebulizer. Methacholine challenge was performed in all subjects 24 h to four days after the initial AP dose. Subjects with a change in FEV 1 (ΔFEV 1 )≥10 percent decrease after the initial AP dose were restudied on three separate occasions (=24 hours apart) after premedication with two puffs of salbutamol (200 μg), ipratropium bromide (40 μg), or sodium cromoglycate (2 mg), in random order. Results Fifty-three subjects were studied. The median ΔFEV 1 after a single dose of AP was — 7.0 percent (range: -47 percent, 1.8 percent). The ΔFEV 1 following AP was only partially predicted by the degree of nonspecific bronchial responsiveness as measured by a standard methacholine challenge. Age, current smoking, history of asthma, baseline FEV 1 , or a prior episode of PCP failed to predict the ΔFEV 1 following AP. Eighteen subjects (34 percent) had a ΔFEV 1 ≥10 percent decrease (median: —17.0 percent). In these subjects, after premedication with salbutamol, ipratropium bromide, and sodium cromoglycate, the median ΔFEV 1 was 1.0, 0.8, and —9.6 percent, respectively. Conclusion: Aerosol pentamidine produced a decrease in FEV 1 ≥10 percent in 34 percent of subjects. This was not accurately predicted by the methacholine response. The bronchoconstriction induced by AP was effectively prevented by either salbutamol or ipratropium, whereas cromoglycate was only partially effective. (Chest 1991; 100:624-27)

Oxygen consumption is pathologically dependent on oxygen delivery in ARDS and sepsis. We asked whether oxygen consumption is dependent on oxygen delivery in severe acute respiratory failure secondary to AIDS-related PCP. In five patients who had AIDS-related PCP, diffuse bilateral pulmonary infiltrates, no evidence of bacterial infection, and acute respiratory failure requiring mechanical ventilation with arterial oxygen tensions less than 75 mm Hg while breathing at least 50 percent oxygen, and PEEP greater than 10 cm H2O, we determined oxygen delivery and consumption by calculation from thermodilution cardiac output and arterial and mixed venous oxygen contents. Oxygen delivery was increased using transfusion of two units of packed red blood cells over one hour. Oxygen delivery increased 22 percent (638 +/- 204 to 778 +/- 201 ml/min.m2, p less than or equal to 0.006). Oxygen consumption increased 11 percent (134 +/- 34 to 149 +/- 29 ml/min.m2, p less than or equal to 0.02). The oxygen extraction ratio did not change. We conclude that similar to ARDS and sepsis, oxygen consumption may be pathologically dependent on oxygen delivery in patients who have severe acute respiratory failure secondary to AIDS-related PCP.

The validity and reliability of methods of screening for neurologic abnormality were assessed as part of an investigation of an outbreak of methylmercury exposure in two northern Canadian communities. Four hundred and forty-five Cree Indians were examined by one of five neurologists in a complete neurologic examination and by a trained paramedical observer in a short screening examination which included a selection of tests from the complete examination. The screening examinations were recorded on videotape and those for 176 men were reviewed by the five neurologists and the paramedical observer 1 year after the field studies. The prevalence of abnormality assessed in the field screening examination was greater than that assessed during the complete neurologic examination, for neurologic features included in both examinations. However, agreement between examinations in identifying individuals with abnormality was poor with the sensitivity of the screening examination falling under 50% for half of the neurologic features examined. In contrast, specificity was over 80% for 14 of 18 features. Review of the videotapes revealed marked interobserver variation in the assessment of the prevalence of neurologic abnormality and poor agreement with the neurologic examinations in the identification of abnormality in individuals, with kappa less than 0.2 for most neurologic features. The levels of agreement between the neurologic examinations and the screening examinations conducted in the field and by videotape review suggest that neither screening examination provides equivalent information in the identification of the presence of abnormality to that obtained in the neurologic examination.

Methods of verification of the efficacy and safety of health interventions must be congruent with the underlying health beliefs. It is therefore inappropriate to require scientific validation of health interventions that are not based on science. On the other hand, there is no justification for different standards of validation of health products from alternative sources that are used by the public in a manner similar to prescription and over-the-counter drugs. Public monies for health research should be focused on establishing the criteria for safety and efficacy of interventions based on alternative health belief systems, on understanding the "meaning" response and on clinical/epidemiologic research on a carefully selected small number of alternative interventions based on their "plausibility." Novel ways of surveillance of the safety of alternative therapies should be supported in place of the planned system modelled on the program for drugs.

For the first twenty-five years of Algerian independence most specialists viewed Algeria largely through the prism of its political order, which, being explicitly secular, was easily approachable in political and sociological vocabularies generated in the Western academies. Even scholars specifically focusing on Islam in the Maghrib tended, during most of the 1980s, to see Islamism in Algeria as the least developed and the least coherent of the region’s Islamic movements.1 The striking successes of the Islamists after the explosion of October 1988, however, and particularly their sweeping victories in the elections of June 1990 and December 1991, caught most analysts off-guard.

Objective To describe the rate of development of in vitro HIV resistance to zidovudine (ZDV) and its prognostic implications within the Multicentre Canadian AZT Trial (MCAT). Methods HIV-infected subjects in Centers for Disease Control (CDC) stages IIB, III and IVC-2 with CD4 cell counts > 270 x 10(6)/l were treated with ZDV as part of a dose-range study. Participating volunteers underwent prospective clinical and laboratory evaluations at regular intervals. Viral cultures and sensitivity testing were performed every 12 weeks in a predefined subset of 50 volunteers. An isolate was designated ZDV-resistant if it had a median inhibitory concentration (IC50) for ZDV at least 50-fold higher than that of virus isolated from the same subject before initiation of antiviral chemotherapy. The relationship between resistance and subsequent disease progression was studied using the Mantel and Byar method, for which, at each instance of disease progression, 2 x 2 tables classifying progression versus resistance status were constructed. The observed number of progressions was compared with that expected under the null hypothesis using Mantel-Haenszel methods adjusted for baseline CD4:CD8 ratio. Results The Kaplan-Meier estimate for the cumulative development of in vitro resistance was 64% [95% confidence interval (CI), 41-78] at 180 weeks. Baseline CD4:CD8 ratio was negatively associated (P = 0.10) with the subsequent development of resistance (proportional hazard, 0.44; 95% CI, 0.17-1.10). After adjusting for baseline CD4:CD8 ratio, the numbers of observed and expected progressions following the development of resistance were 15 and 7.6, respectively (P = 0.008). A similar relative risk of progression between resistant and non-resistant states was found in the two CD4:CD8 strata; observed and expected progressions were 4 and 2.3 and 11 and 5.2 in the high and low CD4:CD8 strata, respectively. Conclusions In vitro resistance to ZDV developed in 64% of subjects after 180 weeks of ZDV therapy. Lower CD4:CD8 ratio at baseline was associated with faster development of resistance. In addition, the development of resistance was found to be a marker of subsequent disease progression. This association persisted after adjustment for baseline CD4:CD8 ratio. Whether in vitro resistance to ZDV is merely a surrogate marker or a determinant of disease progression remains to be established.

Excerpt Since it was originally described in 1981, the acquired immunodeficiency syndrome (AIDS) has been a complex therapeutic challenge. In 1983, the discovery of human immunodeficiency virus typ...

The article by Alan Forster and associates[1][1] on adverse events among patients admitted to a Canadian teaching hospital might suggest that this aspect of patient safety is of only recent interest and concern. However, CMAJ readers may be interested to learn of a study with similar findings that

The study objective was to describe the pharmacokinetics of azidothymidine (AZT) in a large population of early, asymptomatic human immunodeficiency virus (HIV)-infected individuals. The study design was a multicenter, prospective, descriptive single-dose pharmacokinetic study. Each of 66 fasting, male, HIV-infected homosexuals older than 18 years of age and in CDC classifications II, III, and IVC2 received a single 400-mg oral dose of AZT with subsequent pharmacokinetic measurements performed during an 8-h period for AZT and its major metabolite, glucuronylazidothymidine (GAZT). Results were obtained in 65 patients (36 smokers, 29 nonsmokers), of whom 3 were noted to have hepatic dysfunction. In those with normal hepatic function, the following parameters were described: AZT, area under the curve (AUC) +/- SD, 9.9 +/- 5.7 microM.h, maximum concentration (Cmax) +/- SD, 7.3 +/- 4.7 microM; time to maximum concentration (Tmax) +/- SD, 0.93 +/- 0.42 h, and half-life (t1/2) +/- SD, 1.0 +/- 0.8 h. Corresponding values for GAZT were: AUC +/- SD 35.7 +/- 10.3 microM.h, Cmax +/- SD 21.3 +/- 7.3 microM, Tmax +/- SD 1.2 +/- 0.50 h, t1/2 +/- SD 0.98 +/- 0.62 h, No significant differences were found in comparisons of study site, CDC classification of disease, smokers versus nonsmokers, and in patients with hepatic dysfunction, although a higher AUC and earlier Cmax for AZT was noted in the latter group. It is concluded that AZT pharmacokinetics are similar in patients with early asymptomatic HIV disease when compared with previous reports in patients with later disease.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine whether oral corticosteroids can prevent early deterioration in patients with acquired immunodeficiency syndrome (AIDS)-related Pneumocystis carinii pneumonia.Prospective, double-blind, placebo-controlled, randomized trial.Included patients were having their first P. carinii pneumonia episode, had no other known active pulmonary pathology, had no contraindications for corticosteroids, received no anti-P. carinii pneumonia medications for more than 48 hours, and had oxygen saturation by pulse oximetry of 85% or more and less than 90% at rest or a 5-percentage-point decrease in oxygen saturation with exercise while breathing room air. Consenting subjects were randomly assigned to prednisone, 60 mg/d for 7 days, followed by a progressive tapering over 14 days or to an identical placebo. Early deterioration, the endpoint of the trial, was defined as a 10% decrease in baseline oxygen saturation on day 3 or thereafter. The cases of patients developing early deterioration were considered to be failures of treatment; the code was then broken, and the patient's treatment was left to the judgment of the treating physician. Sequential analysis was done with the primary variable being development of early deterioration.The trial was terminated 5 April 1989 on the basis of the sequential analysis when a total of nine episodes of early deterioration had occurred in the first 37 patients at an overall significance level of P = 0.0136. A total of 8 of 19 placebo-treated patients (42.1%) developed early deterioration compared with only 1 of 18 patients (5.6%) treated with corticosteroids. Baseline characteristics were not statistically different between the two treatment groups. The adjusted odds ratio for the treatment effect was 5.87 (95% CI, 1.27 to 27.4). The adjusted point estimates for the probability of early deterioration in the placebo and corticosteroid groups were 43% and 12%, respectively. All 8 patients in the placebo group developing early deterioration recovered rapidly with addition of corticosteroid treatment. The single patient with early deterioration in the corticosteroid group died on day 6 from overwhelming P. carinii pneumonia, as documented at autopsy. The corticosteroid group had an increased exercise tolerance on day 7 that persisted at day 30.Oral corticosteroids prevent early deterioration and increase exercise tolerance in patients with moderately severe AIDS-related P. carinii pneumonia.

The nutritional status of more than 80% of adult Indians in three bands in a remote area of Quebec was studied during the summer of 1978 and the findings were compared with the results of the 1970 to 1972 Nutrition Canada national and Indian surveys in which the Indian participation rate was 30%. In the present study, hematocrit, serum iron, transferrmn saturation, serum vitamin E, serum folic acid, and urine thiamin excretion patterns showed only minor differences from Nutrition Canada's national and Indian survey. Serum total protein values were slightly higher in Indians than in the national sample, consistent with previous findings. A higher percentage of subjects had low serum concentrations of vitamin A and ascorbic acid than in the previous Indian survey, but not to such a marked degree. Am. J. C/in. Nuir. 34: 2784-2789, 1981.

To characterize the nature, time course and dose dependency of zidovudine-related side effects, we undertook a multicenter, prospective, dose-range finding study. Our study group consisted of 74 HIV-positive homosexual men belonging to groups II B, III and IV C2 from the Centers for Disease Control (CDC) classification of HIV disease. Following a 3-week observation period, volunteers were treated with zidovudine 600 mg/day for 18 weeks, 900 mg/day for 9 weeks and 1200 mg/day for 9 weeks, followed by a washout period of 6 weeks after which they were re-started on 1200 mg/day or the highest tolerated dose at 8-hourly intervals. Subjects were randomly assigned to 4-hourly or 8-hourly regimens within CDC groups while taking 600 and 1200 mg/day. Clinical and laboratory evaluations were performed at 3-week intervals. Symptomatic adverse effects were present in 96% of subjects, most commonly nausea (64%), fatigue (55%) and headache (49%). These were generally self-limited, reappearing briefly at each dose increment. A decrease in hemoglobin occurred shortly after initiation of therapy. This was not dose dependent and reversed rapidly upon discontinuation of treatment. A red blood cell count decrease, a mean cell volume increase and a granulocyte count decrease developed early in a dose-independent fashion, reverting at least partially during the washout phase. The decrease in reticulocyte count was dose related between 600 and 900 mg/day with no further change when the dose was escalated to 1200 mg/day. Bone marrow changes occurred rapidly as demonstrated by megaloblastosis in 95% of 65 specimens at week 18. We conclude that zidovudine-related hematological effects include a mild macrocytic megaloblastic anemia with a decrease in reticulocyte count and granulocytopenia. These effects are dose independent in the range 600–1200 mg/day and rapidly reversible upon discontinuation of the drug.

Calcium salts have been recommended for and used in the treatment of various forms of cardiac arrest for many years. Although calcium plays a major role in excitation-contraction coupling, it can have a deleterious effect in some processes of cellular injury. Clinical trials suggest that calcium salts are not effective in ventricular fibrillation and asystole, but that some patients with electromechanical dissociation may have a favorable hemodynamic response. Because of the potential risks of calcium salts, their use should be limited to specific subsets of patients with cardiac arrest.

While the attempt to predict actual political behaviour is generally as risky as it is unrewarding, there appears to be value in identifying and evaluating the variables which may bear upon Israeli intentions and capabilities with regard to the Palestine question in the decade of the 1980's. This article grew out of a paper read in Amman early in 1981 in which the author attempted to assess such behaviour, paying especial attention not only to historically reinforced patterns of initiative and response but also to momentum or drift in determining factors where such motion can be discerned. The thrust of this discussion is not to attempt predictions concerning the evolution in the 1980's of Israeli policy towards Palestine or the Arab states, but rather to propose for consideration a set of variables which can be organized according to three categories. These categories include 1) the evolution of the domestic political process in Israel; 2) the pattern of social and economic development within the country; and 3) the external factors impinging upon Israeli policy-makers as they weigh their options and formulate their programmes.

Pneumocystis carinii pneumonia (PCP) remains the most frequent life-threatening complication of HIV infection. A retrospective study was undertaken in an attempt to establish the incidence of acute respiratory failure (ARF) in AIDS-related PCP, its mortality, and the impact of adjuvant systemic corticosteroids on its outcome. Of 127 AIDS-related PCP episodes diagnosed at St. Paul's Hospital between Jan 1, 1981, and March 31, 1987, 27 developed ARF (21 percent), and the 24 who consented to ICU admission for ventilatory support were reviewed. All were given IV pentamidine or trimethoprim-sulfamethoxazole or both sequentially. Overall mortality of ARF secondary to AIDS-related PCP was 50 percent. The use of adjuvant systemic corticosteroids was associated with a decreased mortality. Of the 18 patients treated with IV hydrocortisone (400 to 1,000 mg/day in divided doses for the duration of ARF followed by a tapering regimen over 10 to 15 days), seven (39 percent) died, while five of six (84 percent) treated without corticosteroids died (p = 0.05). Survivors received ventilation for 5±2 (mean±SD) days and all were discharged from hospital after 20 ± 4 days. Survivors were also younger (34 ±8 vs 43 ±10 years, p=0.034) and presented earlier (14 ±3 vs 34 ±7 days after onset of symptoms p=0.017). Known AIDS, previous PCP episodes, and arterial blood gas values at the onset of ARF did not correlate with outcome. We conclude that ARF secondary to AIDS-related PCP merits aggressive management. In particular, younger patients presenting early after the onset of respiratory symptoms appear to have a better prognosis. The decreased mortality associated with the use of adjunctive corticosteroids supports the need for prospective controlled evaluation of this therapeutic modality.

Acebutolol (ABL) and hydrochlorothiazide (HCT) were compared in patients with mild to moderate essential hypertension and low or normal peripheral renin activity. ABL reduced mean supine blood pressure from 151/97 to 140/87 mm Hg and HCT reduced the mean supine blood pressure from 153/98 to 143/92 mm Hg. ABL reduced heart rate from 73 to 67 beats/min; during HCT therapy it rose from 74 to 77 beats/min. Although the same proportion of patients achieved normal diastolic pressures with ABL (11/19) and with HCT (10/19), tension-time indices were lower during ABL than during HCT therapy. The average daily dose was 621 mg of ABL and 168 mg of HCT. Stimulated peripheral renin activity increased with HCT and was the same or lower with ABL. ABL did not induce adverse effects on serum potassium or uric acid. ABL was as effective in lowering blood pressure HCT but induced larger reductions in tension-time index as a result of the lowered heart rate. Clinical Pharmacology and Therapeutics (1980) 28, 296–301; doi:10.1038/clpt.1980.165

We determined whether drug-resistant variants of HIV-1 could be isolated from the peripheral blood mononuclear cells of 20 individuals with HIV infection (Centers for Disease Control groups II and III) on long-term zidovudine (AZT) therapy. Toward this end, zidovudine (10 microM) has been included in the tissue culture medium used to isolate HIV-1. Under these circumstances, virus with a zidovudine-resistant phenotype was successfully obtained in five out of 20 cases. This property of drug resistance appeared to be stable, and did not disappear upon extended replication of such virus in the absence of drug pressure. Drug-resistant virus could also be isolated from these subjects on subsequent occasions, but was not present in samples obtained prior to therapy. Replication of these zidovudine-resistant isolates in tissue culture was inhibited by each of four other nucleoside analogues. Thus, other drugs may be useful in controlling selective zidovudine-resistant variants of HIV-1.

All cases of bacterial endocarditis confirmed or diagnosed at autopsy in the Philadelphia General Hospital during two periods were studied. Each period included approximately 10,000 consecutive autopsies. They were designated period I, the pre-antibiotic era, and period II, the antibiotic era. In period I there has been a significant decrease (p Infection in period II has been replaced by congestive heart failure in period II as the most common cause of death. Perforations of heart valves have increased from 15.6 per cent in period I to 44.5 per cent in period II, and are associated with most cases (64.5 per cent) of congestive heart failure in period II. The relationship of perforations of the valves to duration of illness, age of patient, valve involved, pre-existing valvular disease, adequacy of treatment and causative organism was studied. It is concluded that changes in the group of organisms associated with fatal cases account for the increase in perforations observed in period II, and that perforations of the valves secondary to the bacterial infection are responsible for the increased incidence of congestive heart failure.

A comparison was made in normal volunteers of measurements of glomerular filtration rate (G.F.R.) with 57Co-B12 and inulin. With the method of Cutler and Glatte (J. Lab. Clin. Med. 65,1041 (1965)), the mean ratio of 99 simultaneous renal clearances of 57Co-B12 and inulin was 0.43 in comparison with that of 0.88 averaged from six published reports. During clearances, the fraction of vitamin bound to plasma protein averaged 57% in our studies with a dextran–charcoal method to measure binding, compared with a 16% average in reports where exhaustive dialysis was used. Correction of clearances for unbound 57Co-B12 estimated by coated-charcoal adsorption resulted in a mean ratio of free B12 to inulin clearances of 1.0 in two patients. Because of the difference in 57Co-B12 binding in our patients compared with others, we studied three methods of determining the binding of vitamin B12 added to plasma in vitro in concentrations of 0.2 to 2000.0 ng/ml. With all three techniques, ultrafiltration, dextran-coated charcoal adsorption, and exhaustive dialysis, the percent of added 57Co-B12 bound to plasma decreased with increasing concentrations of vitamin. At concentrations above 20.0 ng/ml, binding differed with each technique. The highest binding was observed with ultrafiltration, the lowest with exhaustive dialysis. Dilution of the plasma or reduction of incubation temperatures from 37 °C to 20 °C reduced the amount bound. Studies of binding of 57Co-B12 in our patients showed a variation with time. Unless binding is measured for each clearance period by a standardized technique, 57Co-B12 should not be used as a replacement for inulin in the measurement of G.F.R.

The selection of an antibiotic to treat purulent meningitis is based upon the minimal inhibitory concentration of the drug for the infecting organism and the concentration of the antibiotic in the blood and cerebrospinal fluid following systemic administration. Few antibiotics reach the cerebrospinal fluid of normal animals in appreciable concentrations. All reach higher levels in the presence of meningitis. Several semisynthetic penicillins possess novel properties suggesting that the drugs should be useful in the treatment of meningitis. The distribution of these drugs in the cerebrospinal fluid in meningitis is not known. Experiments were carried out in which the concentrations of nine semisynthetic penicillins were assayed in the blood, cerebrospinal fluid, and brain of rabbits with purulent meningitis. Appreciable concentrations of all penicillins were found in the cerebrospinal fluid. A correlation was shown between the levels reached in the cerebrospinal fluid and the amount of penicillin bound by plasma protein. Cerebrospinal fluid levels did not accurately reflect brain tissue concentrations.

A double-blind parallel randomized study comparing naproxen 600 mg, naproxen 400 mg, and propoxyphene 65 mg was performed in 105 patients suffering from pain after orthopedic surgery. A significant difference in analgesic effectiveness was shown between the three drugs with successful analgesia recorded in 66 % of patients who received naproxen 600 mg, 37 % of those who received naproxen 400 mg, and 20% of those who received propoxyphene 65 mg (X2 2dt= 15.34, p