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.     

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.     

A Survey of the Practice of Lead Extraction in the United States

Background: Endovascular lead extraction is an important component of the management of patients with chronically implanted arrhythmia control devices. Although it is associated with the potential for significant morbidity and mortality, there is little information about its scope and practice. Methods: We surveyed 1,000 physician members of the Heart Rhythm Society via e‐mail solicitation. Results: Of the 252 respondents (25%), 221 (88%) reported either performing extractions themselves (63%), or having privileges at a hospital where extractions are performed (25%). Electrophysiologists perform extractions at most sites (83%) but cardiac surgeons perform endovascular lead extraction at a significant minority of sites (20%). Most respondents report low annual volumes of extractions at their site: 15% reported <10 procedures/year, 42% 10–25 procedures/year, 23% 26–50 procedure/year, and only 19% reported >50 procedures/year. Thirty‐six percent of respondents reported that extractions were done in the operating room (OR) with surgeon present or immediately available, 39% in the electrophysiology (EP) lab with surgeon and OR identified and available, and 25% in EP lab without a surgeon or OR identified. The overall risks of lead extraction were felt to be 1–5% of major complication and 0.5–1% of mortality, roughly in line with published data. Conclusions: While there is agreement as to the risk of major complication and death from lead extraction, the degree of surgical availability varies considerably. The new guidelines document recommends the ability to promptly initiate an emergent surgical procedure, and this should be an important goal for all extractionists. (PACE 2010; 33:721–726)     

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     

Inbred mice infected with Plasmodium yoelii differ in their antimalarial immunoglobulin isotype response

Antibodies are known to be important in mediating malarial immunity, but the influence of the various immunoglobulin isotypes on parasite elimination is unclear. The purpose of this study was to provide basic information on the induction of isotype expression in genetically different mice during primary malaria. Parasitaemias and the serum antimalarial IgM, IgG1, IgG2, IgG3 and IgA antibody titres measured in a radioimmunoassay were followed in outbred and 11 inbred strains of mice infected with 17XNL Plasmodium yoelii. Severity of infection, as judged by length of infection, peak parasitaemias and death, was found to differ between the strains. All strains developed rapid IgM responses, but only 3/11 inbred strains produced significant antimalarial IgG1 levels during primary infection. All strains produced an IgG2 response, which developed slightly more quickly in strains with the least severe courses of malaria. A large variation in the IgG3 response was noted between strains. In general, IgG3 antibodies were the first IgG-isotype to appear in serum. They were detected as early as day 8 in strains that developed mild infections but were not present until around day 20 in strains with the most severe cases of malaria. Only one strain produced detectable antimalarial IgA antibodies. These results show that different patterns of isotype expression are induced in inbred strains of mice during primary P. yoelii infection.     

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.