Chronic Dietary Toxicity/Oncogenicity Studies on 2,4-Dichlorophenoxyacetic Acid in Rodents

Forms of 2,4-dichlorophenoxyacetic acid (collectively knownas 2,4-D) are herbicides used to control a wide variety of broadleafand woody plants. Doses in the 2-year chronic/oncogenicity ratstudy were 0, 5, 75, and 150 mg/kg/day. The chronic toxicityparalleled subchronic findings, and a NOEL of 5 mg/kg/day wasestablished. A slight increase in astrocytomas observed (inmales only) at 45 mg/kg/day in a previously conducted chronicrat study was not confirmed in the present study at the highdose of 150 mg/kg/day. Doses in the 2-year mouse oncogenicitystudies were 0, 5, 150, and 300 mg/kg/day for females and 0,5, 62.5, and 125 mg/kg/day for males. No oncogenic effect wasnoted in the study. In summary, the findings of these studiesindicate low chronic toxicity of 2,4-D and the lack of oncogenicresponse to 2,4-D following chronic dietary exposure of 2,4-Din the rat and mouse.     

MONOCYTIC LEUKEMIA AND TUBERCULOSIS

A case of monocytic leukemia associated with active tuberculosis of pleura,pericardium, and lymph nodes is reported.

The criteria for the diagnosis of monocytic leukemia and the factors excludinga leukemoid reaction are presented.

The rarity of monocytic leukemia in contrast with the frequency of tuberculousinfections and the rarity of active tuberculosis in the reported cases of monocyticleukemia indicate that the association of the two diseases is probably coincidental.

Note: Grateful acknowledgment is due to Miss Anne Shiras and Mortimer Cohen, M.D., for the photo-micrographs.

     

Acute tubulointerstitial nephritis,treatment with steroid and impact on renal outcomes

Background: The use and timing of steroids in the management of acute tubulointerstitial nephritis (ATIN) remains debatable. Aims: To determine the incidence and aetiology of ATIN in our unit, and to examine trends in the use of steroids and their impact on renal outcomes. Methods: Patients with a histological diagnosis of ATIN over a 9‐year period were identified and divided into steroid‐treated (StG) and steroid‐naïve groups (SnG). Mean change in estimated glomerular filtration rate (eGFR) was determined. Results: Forty‐nine patients had ATIN as their main diagnosis, 67% of cases were drug‐induced, and proton pump inhibitors (PPI) were the second commonest implicated drug category. Majority (75%) of patients received steroids, and eGFR improved to a significantly greater degree in these steroid‐treated patients (3.4‐fold improvement vs 2.0‐fold in SnG; P < 0.05, unpaired t‐test). Despite comparable eGFR at presentation (StG: 11.7; SnG: 15.4), steroid‐treated patients were less likely to receive dialysis, although not significantly so (OR 0.27; 95% CI 0.06–1.15, P = 0.066, chi‐squared test). However, there was no significant relation between the degree of eGFR improvement and delay in starting steroids (Pearson r = ?0.25, P > 0.45), and no difference in eGFR at the time of last follow‐up (StG: 33 ± 3; SnG: 32 ± 7; P > 0.9, unpaired t‐test). Conclusion: StG patients had a greater degree of improvement in renal function, but with no correlation between degree of improvement in eGFR and delay in starting steroids, and similar eGFR values at final follow‐up. PPI were the second commonest drug category among drug‐induced cases.     

Hereditary Hemolytic Disease Secondary to Glucose-6-Phosphate Dehydrogenase Deficiency: Report of Three Cases with Special Emphasis on ATP Metabolism

1. Three cases of hereditary hemolytic disease secondary to G-6-PD deficiency are described. Two of the cases were first cousins of Scotch-Irish-English descent and the mode of inheritance was believed to be sex-linked.The third case was of Turkish origin; no family studies were availale.

2. The mothers, who were heterozygous for G-6-PD deficiency, showed onlyminimal expression of the defect, which was manifested by a slightly decreasedred cell survival in both mothers and an abnormal methemoglobin reductiontest in one of them.

3. All three cases showed a more pronounced fall in erythrocyte ATP afterincubation with phenylhydrazine than that observed in primaquine-sensitiveNegroes whose red cells were less deficient in G-6-PD.

4. It is suggested that the inability of the G-6-PD-deficient erythrocyte tomaintain adequate levels of ATP may be an important factor in the pathogenesis of the hemolytic process.

Submitted on August 26, 1963 Accepted on October 24, 1963     

NON-PARAMETRIC METHODS FOR COMPARING MULTIPLE TREATMENT GROUPS TO A CONTROL GROUP,BASED ON INCOMPLETE NON-DECREASING REPEATED MEASUREMENTS

In the comparison of two or more treatment groups to a control group, consider a study with non-decreasing repeated measurements of the same characteristic taken over a common set of time points for each subject. Based on the vector of possibly incomplete responses from each subject, this paper considers asymptotically distribution-free tests of the equality of the groups. I propose consistent point estimators of the overall treatment differences and I derive non-parametric simultaneous confidence regions for the treatment effects. An example using data from a bladder cancer study illustrates the proposed methods.     

SITE VARIABILITY IN A MULTISITE GERIATRIC DEPRESSION TRIAL

We studied differences in outcome and characteristics among 29 clinical sites of a multisite, double-blind antidepressant trial for geriatric depression. Six hundred and seventy-one outpatients aged 60 years or older (mean±SD=67.7±5.7) met DSM-III-R criteria for unipolar major depression, had baseline 17-item Hamilton Depression Rating Scale (HAMD₁₇) scores ≥16 and were randomized to fluoxetine (20 mg daily) or placebo. Effect sizes (ESs, expressed as mean differences between effects divided by the pooled standard deviation of the differences) were calculated for each site using selected outcome measures. ES ranged from 1.84 (favoring fluoxetine) to −0.91 (favoring placebo) for incidence of remitters (endpoint HAMD₁₇ total score of ≤8). A large, positive ES favoring fluoxetine for remission rates (ES≥0.65) was found at only six sites, moderate ES (0.35–0.64) at eight and small ES (0–0.34) at seven; ES favored placebo (<0) at eight of 29 sites. Private clinics showed an overall HAMD₁₇ ES for change scores more than twice that of university sites. These results suggest that individual practitioners may have vastly different clinical experiences in large, multisite trials for geriatric depression. Interrater reliability, subject selection, recruitment, inadequate or fixed dosing, few patients per site, brief study duration, heterogeneity of geriatric depression, financial incentive and characteristics of individual sites may contribute to response variability.