Rhett Butler and the superior physician

We describe post-splenectomy lymphocytosis (PSL) in 23 patients, a majority (20/23) of whom have undergone splenectomy as a staging procedure for Hodgkin's disease. The absolute lymphocyte count ranged from 4.0 to 8.7 x 10(9)/l. The lymphocytosis was noted 4-242 (median 70) months after splenectomy and persisted almost unchanged in most patients on prolonged follow up (median 50 months). Immunophenotyping of the lymphocytes revealed no monoclonal B cell population.     

Low particulate type IV phosphodiesterase activity in hypothyroid rat atria

Rats were made hypothyroid by adding propylthiouracil (PTU) to their drinking water. Some of the PTU-treated rats were given thyroid hormone injections for 5 days. Both soluble and particulate cAMP-phosphodiesterase activities of adipose and ventricular tissues were increased by 25-60% in hypothyroidism. In left atria, soluble cAMP-phosphodiesterase activity was not significantly altered in hypothyroidism, while total particulate cAMP-phosphodiesterase activity was lowered by 30%. This lowering was due to diminished isoenzyme IV activity, as studied with the isoenzyme-specific inhibitors rolipram and SK&F 94836. In conclusion, the present results show decreased particulate type IV cAMP-phosphodiesterase activity in hypothyroid rat atria. This may explain the increased responsiveness to isoproterenol in hypothyroid atria.     

Responses of dogs with food allergies to single-ingredient dietary provocation

OBJECTIVE: To characterize specific food ingredients causing allergic reactions in dogs and to assess cross-reactivity between proteins derived from a single animal source or from different plant products. DESIGN: Prospective study. ANIMALS: 25 dogs with histories and cutaneous signs consistent with food-allergic dermatitis. PROCEDURE: Dogs were fed a food-elimination diet until resolution of clinical signs and then challenged with their original diet. A diagnosis of food allergy was made if there was complete return of pruritus within 14 days of challenge exposure. After diagnosis, dogs were fed the food-elimination diet until signs related to dietary challenge abated. The dogs then were fed beef, chicken, chicken eggs, cows' milk, wheat, soy, and corn in single-ingredient provocation trials for 1 week. Any cutaneous reactions to these food ingredients were recorded by their owners. RESULTS: Beef and soy most often caused adverse cutaneous reactions, although all ingredients induced clinical signs in at least 1 dog. Mean number of allergens per dog was 2.4, with 80% reacting to 1 or 2 proteins and 64% reacting to 2 or more of the proteins tested. A significant difference was found between dogs reacting to beef versus cows' milk and between dogs reacting to soy versus wheat; thus, the hypothesis of cross-reactivity to ingredients derived from a single animal source or to different plant products was not supported. Similar differences between chicken meat and eggs were not identified. CLINICAL IMPLICATIONS: Long-term management of dogs with food allergies is facilitated by identification of the most commonly encountered food allergens. Because cross-reactivity cannot be verified, each protein source should be included separately in food-provocation trials.     

Phase I study of a five-day dose schedule of 4-Ipomeanol in patients with non-small cell lung cancer

The mammalian pulmonary toxin 4-ipomeanol (IPO) is activated by the cytochrome P450 system in bronchial Clara cells in animals. The resulting metabolites bind rapidly to macromolecules, producing localized cytotoxicity. IPO has in vitro and in vivo antitumor activity in non-small cell lung cancer (NSCLC) and thus was proposed as a lung cancer-specific antitumor agent. We have completed a directed Phase I trial in patients with NSCLC. Forty-four patients (34 men and 10 women) with NSCLC were treated with IPO. All but two patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. They received 91 courses of therapy with i.v. IPO; 82 courses were administered daily for five days, and 9 were single bolus doses. The dose-limiting toxicity of elevated serum transaminases was observed in three of seven patients at 922 mg/m2/day. The maximum tolerated dose was 693 mg/m2/day on 5 consecutive days every 3 weeks. One patient developed grade 4 pulmonary toxicity at 167 mg/m2/day. There was no significant hematological or renal toxicity. No objective antitumor responses were observed. Pharmacokinetic analysis of 39 patients from day 1 of IPO administration showed biexponential elimination with mean half-lives of 8.6 (alpha half-life) and 76 min (beta half-life). There was a linear relationship between the area under the plasma drug concentration-time curve and the dose of IPO. There was no significant difference between the pharmacokinetic parameters measured on day 1 and day 5. Using a 4-day in vitro cytotoxicity assay, two tumor cell lines established from patients treated at 693 mg/m2/day had IC50s of approximately 6 mM, a concentration more than 75-fold higher than the plasma levels measured in these patients. Thus, although the total amount of drug administered per cycle on a daily times five dose schedule is more than 2.5-fold higher than the recommended single daily dose, IPO is unlikely to be a useful drug for patients with lung cancer.     

A parametric confidence interval for a moment-based scaled criterion for individual bioequivalence

Confidence intervals of proposed individual bioequivalence metrics are difficult to determine in closed form because their stochastic distributions are unknown. In this article, it is shown that, with slightly modified weights, the Relative Individual Risks (RIR) moment-based scaled statistic for individual bioequivalence that was presented by Schall and Williams has an exact noncentral Fisher's F distribution with noncentrality parameter give by a scaled squared difference in formulations means. This can be approximated by a central F with adjusted degrees of freedom from which it follows that an upper (1-alpha) confidence bound for RIR is given by [formula: see text] where [formula: see text] is the least square estimate of RIR; dfER is the degrees of freedom associated with the reference intrasubject variance estimate, v is the subject-by-formulation degrees of freedom adjusted for noncentrality and alpha is the significance level. Individual bioequivalence is concluded if UL does not exceed the regulatory limit. The performance of this confidence interval was investigated by comparing its experimental bioequivalence rate to that of the unweighted metric under known parameter situations through simulations of two formulations in a fully replicated study design. Results showed that the proposed metric is slightly less biased and more precise than the unweighted metric.     

Clinical experience in temporomandibular joint arthroscopy

Clinical experience of arthroscopy in 12 temporomandibular joints with a clinical diagnosis of closed lock was described. There were 10 patients and all were females with a mean age of 31.2 years (range 20 to 59 years). The antero-lateral approach was used for entry into 11 joints. The clinical findings were adhesions (64%), fibrillation (64%), anterior displacement of disc (36%) and scuffing of the articular surface of the glenoid fossa (9%). Two of the joints that had arthrocentesis prior to arthroscopy did not show any different findings from the rest. Of the 8 patients who had pre-arthroscopy pain, 7 patients (88%) had reduction of the symptom. Three patients (38%) had complete resolution of pain. The range of mouth opening (measured as maximal incisor opening) increased in all patients two weeks following arthroscopy. The average change in maximal incisor opening was 40.3% with a range of 22% to 85%. The mean follow-up was 34 months (range 4 to 68 months).